Lipid nanoparticle mRNA vaccines

Abstract

To provide improved cationic lipids and lipid nanoparticles for delivery of oligonucleotides.SOLUTION: The lipid nanoparticle of the present invention comprises a cationic lipid and / or a PEG lipid and an mRNA compound comprising an mRNA sequence encoding an antigenic peptide or protein. The invention further relates to the use of said lipid nanoparticle as a vaccine or a drug, in particular for influenza or rabies vaccination.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] Background of the Invention The present invention relates to mRNA-containing lipid nanoparticles that are useful as mRNA-based vaccines. In addition, the present invention relates to compositions comprising mRNA-containing lipid nanoparticles and the use of mRNA-containing lipid nanoparticles or compositions for the preparation of pharmaceutical compositions, particularly vaccines, for use in the prevention or treatment of, for example, infectious diseases, tumor or cancer diseases, allergies, or autoimmune diseases. The present invention further describes methods for the treatment or prevention of the aforementioned diseases. [Background technology]

[0002] Gene therapy and gene vaccination are among the most promising and rapidly developing approaches in modern medicine, which may offer highly specific and individualized options for the treatment of a wide variety of diseases.

[0003] Genetic vaccination induces a desired immune response against a selected antigen, such as a bacterial surface feature, a viral particle, or a tumor antigen. Overall, vaccination is one of the most important achievements of modern medicine. However, effective vaccines are currently available for only a limited number of diseases. Therefore, millions of people still suffer from infectious diseases each year that cannot be prevented by vaccination.

[0004] Generally, vaccines can be subdivided into "first-generation," "second-generation," and "third-generation" vaccines. "First-generation" vaccines are typically whole-cell vaccines, which are based on either live-attenuated or killed pathogens, e.g., viruses, bacteria, etc. The main drawback of live-attenuated vaccines is the risk of reversion to life-threatening mutations. Thus, although attenuated, such pathogens still pose an inherently unpredictable risk. Killed pathogens may not be as effective as expected in generating a specific immune response. In an attempt to minimize these risks, "second-generation" vaccines have been developed, which are typically subunit vaccines consisting of defined antigens or recombinant protein components derived from the pathogen.

[0005] Genetic vaccines, i.e., vaccines for genetic vaccination, are generally understood to be "third generation" vaccines. They are typically made of genetically engineered nucleic acid molecules that express peptide or protein (antigen) fragments characteristic of pathogens or tumor antigens in vivo. When administered to a patient, genetic vaccines are expressed after uptake by target cells. Expression of the administered nucleic acid results in the production of the encoded protein. If such a protein is recognized as foreign by the patient's immune system, an immune response is elicited.

[0006] In the context of genetic vaccination, both DNA and RNA can be used as the nucleic acid molecule to be administered. DNA is known to be relatively stable and easy to handle. However, the use of DNA carries the risk of unwanted insertion of the administered DNA fragment into the patient's genome, potentially resulting in mutagenic events, such as loss of function of the affected gene. An additional risk is the generation of unwanted anti-DNA antibodies. Another drawback is that DNA must be transcribed before the resulting mRNA can be translated, and because transcription requires entry into the nucleus, the level of expression of the encoded peptide or protein that can be achieved when DNA is administered is limited. Among other reasons, the expression level of the administered DNA depends on the presence of specific transcription factors that regulate DNA transcription. In the absence of such factors, DNA transcription will not produce sufficient amounts of RNA. As a result, the level of peptide or protein translation that can be achieved is limited.

[0007] The use of RNA instead of DNA for genetic vaccination minimizes or avoids the risk of unwanted genomic integration and the generation of anti-DNA antibodies. However, RNA is considered a rather unstable molecular species that can easily be degraded by ubiquitous RNases.

[0008] mRNA vaccines comprising antigen-encoding mRNA complexed with protamine have already been described in the prior art (e.g., Petsch et al., Nat Biotechnol. 2012 Dec;30(12):1210-6; Schnee et al., PLoS Negl Trop Dis. 2016 Jun 23;10(6):e0004746; EP 1083232; WO 2010 / 037539; WO 2012 / 116811; WO 2012 / 116810; and WO 2015 / 024665). WO 2016 / 176330 also describes lipid nanoparticle compositions comprising nucleoside-modified RNA encoding various antigens.

[0009] Despite the great progress made in recent years, there is still a need in the art to provide an efficient mRNA vaccination method that allows the induction of adaptive immune responses without administration being significantly impaired by insufficient translation of mRNA due to premature degradation of antigens or insufficient release of mRNA in cells. Furthermore, there is an urgent need to reduce the dose of mRNA vaccines, thereby reducing potential safety concerns and making vaccines affordable for the third world.

[0010] The challenges associated with delivering nucleic acids to produce desired responses in biological systems are many. Nucleic acid-based therapeutics, such as vaccines, have enormous potential, but realizing this potential remains a need for more effective delivery of nucleic acids to appropriate sites within cells or organisms.

[0011] However, currently, the use of oligonucleotides in therapeutic contexts faces two problems. First, free RNA is susceptible to nuclease digestion in plasma. Second, free RNA has limited ability to reach intracellular compartments where the relevant translation machinery resides. Lipid nanoparticles formed with cationic lipids and other lipid components, such as neutral lipids, cholesterol, PEG, PEGylated lipids, and oligonucleotides, have been used to prevent RNA degradation in plasma and promote cellular uptake of oligonucleotides. Summary of the Invention [Problem to be solved by the invention]

[0012] There remains a need for improved cationic lipids and lipid nanoparticles for delivering oligonucleotides. Preferably, such lipid nanoparticles would provide an optimal drug:lipid ratio, protect the nucleic acid from degradation and clearance in serum, be suitable for systemic or local delivery, and provide intracellular delivery of the nucleic acid. In addition, such lipid-nucleic acid particles would be well tolerated and provide an adequate therapeutic index, such that patient treatment with an effective dose of nucleic acid would not be associated with unacceptable toxicity and / or risk to the patient. The present invention provides these and related advantages. [Means for solving the problem]

[0013] Summary of the Invention The present invention provides mRNA-containing lipid nanoparticles or pharmaceutical compositions containing the nanoparticles, as well as uses thereof. The mRNA-containing lipid nanoparticles of the present invention are (i) a cationic lipid having the formula (I): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof [wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , L 2 , a, b, c, d and e are as defined herein]; and / or Cationic lipids having formula (II): [ka] or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R 1a , R1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , L 2 , G 1 , G 2 , G 3 , a, b, c and d are as defined herein]; and / or preferably Cationic lipids having formula III: [ka] or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R 1 , R 2 , R 3 , L 1 , L 2 , G 1 , G 2 , and G 3 is as defined herein] and / or a PEG lipid having formula (IV) [ka] [In the formula, R 8 and R 9 are each independently a linear or branched, saturated or unsaturated alkyl chain containing 10 to 30 carbon atoms, the alkyl chain optionally being interrupted by one or more ester bonds; and w has a mean value in the range of 30 to 60]; and optionally a neutral lipid and / or a steroid or steroid analogue wherein the mRNA compound is encapsulated in or associated with said lipid nanoparticle.

[0014] The present invention further provides pharmaceutical compositions comprising said lipid nanoparticles, as well as methods for producing said nanoparticles. In a further aspect, the present invention relates to medical uses of lipid nanoparticles or pharmaceutical compositions comprising same.

[0015] In a further aspect, the present invention relates to a method for medical prevention or treatment using said mRNA-containing lipid nanoparticles.

[0016] definition For purposes of clarity and ease of reading, the following scientific background information and definitions are provided. Any technical feature disclosed thereby may be part of any embodiment of the present invention. Further definitions and explanations may be provided in the context of this disclosure.

[0017] Unless otherwise defined, or unless otherwise required by specific context, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the relevant art.

[0018] Unless the context otherwise indicates or requires, the words "comprise," "comprises," "comprising," and similar expressions are to be interpreted in the present description and claims in their open, inclusive sense, "including but not limited to."

[0019] The phrases "one embodiment," "an embodiment," "a specific embodiment," etc. mean that the particular feature, characteristic, or property, or particular group or combination of features, characteristics, or properties, as referred to in connection with the respective phrase, is present in at least one embodiment of the invention. The appearances of these phrases in various places throughout this description do not necessarily refer to the same embodiment. Furthermore, the particular features, characteristics, or properties may be combined in any suitable manner in one or more embodiments.

[0020] The singular forms "a," "an," and "the" should be understood to include plural referents unless the context clearly dictates otherwise.

[0021] In connection with numerical values, percentages should be understood as relative to the total number of the respective item. In other cases, and unless the context indicates otherwise, percentages should be understood as percentages by weight (wt.-%).

[0022] In the context of the present invention, a "composition" refers to any type of composition in which the specified components may be formulated, optionally together with any further components, typically at least one pharmaceutically acceptable carrier or excipient. Thus, the composition may be a dry composition such as a powder or granules, or a solid unit such as a lyophilized form or tablet. Alternatively, the composition may be in liquid form, with each component formulated separately in dissolved or dispersed (e.g., suspended or emulsified) form. In one preferred embodiment, the composition is formulated as a sterile solid composition, such as a powder or lyophilized form for reconstitution with an aqueous liquid carrier. Such formulations are also preferred for compositions of the type comprising nucleic acid cargo, as described in more detail below.

[0023] As used herein, "compound" refers to a chemical substance that is a material made up of molecules with essentially the same chemical structure and properties. For small molecule compounds, the molecules are typically identical in terms of their atomic composition and structural arrangement. For macromolecular or polymeric compounds, the molecules of the compound are highly similar, but not necessarily all identical. For example, a segment of a polymer designated as consisting of 50 monomer units may also contain individual molecules of, for example, 48 or 53 monomer units.

[0024] Lipidoid compounds, also simply called lipidoids, are lipid-like compounds, i.e. amphiphilic compounds with lipid-like physical properties. In the context of the present invention, the term lipid is considered to encompass lipidoids.

[0025] Unless otherwise clear from the specific context, the term "cationic" means that the respective structure carries a positive charge, either permanently or not permanently but in response to certain conditions such as pH. Thus, the term "cationic" encompasses both "permanently cationic" and "cationizable."

[0026] As used herein, "permanently cationic" means that the respective compound, group, or atom is positively charged at any pH value or hydrogen ion activity in its environment. Typically, the positive charge is the result of the presence of a quaternary nitrogen atom. If a compound has multiple such positive charges, it may be referred to as permanently polycationic, a subcategory of permanently cationic.

[0027] Cationic moiety / compound: The term "cationic moiety / compound" typically refers to a charged molecule that is positively charged (cationic) at a pH of about 1 to 9. In some embodiments, the cationic moiety / compound is preferably charged at a pH of 9 or less (e.g., 5 to 9), 8 or less (e.g., 5 to 8), or 7 or less (e.g., 5 to 7), most preferably at a physiological pH, e.g., a pH of about 7.3 to 7.4. Thus, the cationic peptide, protein, polysaccharide, lipid, or polymer according to one embodiment of the present invention is positively charged under physiological conditions, particularly under physiological salt conditions of cells in vivo. In another preferred embodiment, the lipid nanoparticle, cationic peptide, protein, polysaccharide, lipid, or polymer according to the present invention is uncharged, neutrally charged, or electrically neutral, respectively, under physiological conditions, particularly under physiological salt conditions of cells in vivo. Cationic peptides or proteins preferably contain a higher number of cationic amino acids than other amino acid residues, e.g. a higher number of Arg, His, Lys or Orn (particularly more cationic amino acids than anionic amino acid residues such as Asp or Glu), or contain blocks formed mainly by cationic amino acid residues. The expression "cationic" can also refer to "polycationic" moieties / compounds.

[0028] Cationic component / compound can also refer to cationic lipids that have the ability to become positively charged. Exemplary cationic lipids include one or more amine groups that are positively charged. Preferred cationic lipids are ionizable and can exist in a positively charged form or a neutral form depending on the pH. The ionization of cationic lipids affects the surface charge of lipid nanoparticles (LNPs) under different pH conditions. This charge state can affect plasma protein absorption, blood clearance and tissue distribution (Semple, SC, et al., Adv. Drug Deliv Rev 32:3-17 (1998)), as well as the ability to form non-bilayer structures, which are crucial for intracellular delivery of nucleic acids (Hafez, IM, et al., Gene Ther 8:1188-1196 (2001)). As described elsewhere, the pKa of the formulated cationic lipid correlates with the efficacy of the LNP for delivery of nucleic acids (see Jayaraman et al., Angewandte Chemie, International Edition (2012), 51(34), 8529-8533; Semple et al., Nature Biotechnology 28, 172-176 (2010)). In some embodiments of the invention, the preferred pKa range is about 5 to about 7.

[0029] In this context, the prefix "poly" refers to multiple atoms or groups of each property in a compound. In parentheses, the presence of multiple is optional. For example, (poly)cationic means cationic and / or polycationic. However, the absence of a prefix should not be construed as excluding multiple. For example, polycationic compounds are also cationic compounds and can be referred to as such.

[0030] "Cationizable" means that a compound, or group or atom, becomes positively charged when the pH of its environment is low and uncharged when the pH is high. Also, in non-aqueous environments where the pH value may be indeterminable, a cationizable compound, group or atom will be positively charged when the hydrogen ion concentration is high and uncharged when the hydrogen ion concentration or activity is low. The pH or hydrogen ion concentration at which it is charged or uncharged depends on the individual properties of the cationizable or polycationizable compound, specifically the pK of each cationizable group or atom. a In a dilute aqueous environment, the proportion of cationizable compounds, groups or atoms that carry a positive charge can be estimated using the so-called Henderson-Hasselbalch equation, which is well known to those skilled in the art.

[0031] For example, in some embodiments, if the compound or moiety is cationizable, it is preferred that it be positively charged at a pH value of about 1-9, preferably 4-9, 5-8, or even 6-8, more preferably 9 or less, 8 or less, or 7 or less, and most preferably at a physiological pH, e.g., about 7.3-7.4, i.e., under physiological conditions, particularly the physiological salt conditions of cells in vivo. In other embodiments, the cationizable compound or moiety is predominantly neutral at physiological pH values, e.g., about 7.0-7.4, but preferably becomes positively charged at lower pH values. In some embodiments, the preferred pKa range for the cationizable compound or moiety is about 5 to about 7.

[0032] Nucleic acid: The term nucleic acid refers to any DNA or RNA molecule. The term can be used for polynucleotides and / or oligonucleotides. Whenever a nucleic acid or nucleic acid sequence encoding a specific protein and / or peptide is mentioned herein, said nucleic acid or nucleic acid sequence, respectively, preferably also comprises regulatory sequences that allow its expression, i.e., transcription and / or translation of the nucleic acid sequence encoding the specific protein or peptide, in a suitable host, for example a human.

[0033] Nucleoside modification: In the context of the present invention, the term nucleoside modification refers to an mRNA molecule or compound that contains a nucleoside that is not normally part of mRNA, preferably a non-natural nucleoside. In particular, the term preferably refers to mRNA nucleosides other than adenine, guanine, cytosine, uracil, and in some cases thymine.

[0034] Peptide: A peptide is an oligomer or polymer of at least two amino acid monomers. Typically, the monomers are joined by peptide bonds. The term "peptide" does not limit the length of the polymer chain of amino acids. In some embodiments of the invention, a peptide may contain, for example, fewer than 50 monomer units. Longer peptides, also referred to as polypeptides, typically have 50-600 monomer units, more specifically 50-300 monomer units.

[0035] Protein: A protein typically consists of one or more peptides and / or polypeptides that fold into a three-dimensional form to facilitate a biological function.

[0036] Influenza pandemic or pandemic flu: An influenza pandemic can occur when a non-human (novel) influenza virus acquires the ability for efficient and sustained human-to-human transmission and then spreads worldwide. Influenza viruses that have the potential to cause a pandemic are called "influenza viruses with pandemic potential" or "pandemic influenza viruses."

[0037] Examples of influenza viruses with pandemic potential include two different "bird flu" viruses, avian influenza A (H5N1) and avian influenza A (H7N9). These are non-human viruses (i.e., they are novel in humans and circulate in birds worldwide), and therefore humans have little or no immunity to them. Although infection of humans with these viruses has rarely occurred, if either of these viruses were to change in a way that allowed it to readily infect humans and spread easily from person to person, an influenza pandemic could occur.

[0038] Pandemic influenza (flu) vaccine or pandemic influenza (flu) vaccine: A vaccine against a pandemic influenza virus is referred to herein as a pandemic influenza (flu) vaccine or pandemic influenza (flu) vaccine.

[0039] Influenza (flu) season: An influenza season is an annually recurring period characterized by the spread of influenza (flu) outbreaks. Seasons occur during the cooler months of the year in each hemisphere. Influenza activity is sometimes predicted and even tracked geographically. The onset of large-scale influenza activity during each season varies by location, but in any particular location, these smaller epidemics typically peak over approximately three weeks and then decline significantly over another three weeks. Influenza vaccination is used to reduce the effects of influenza seasons; pneumonia vaccination further reduces the effects and complications of influenza seasons. Because the Northern and Southern Hemispheres experience winter at different times of the year, there are actually two influenza seasons each year.

[0040] Vaccines for seasonal influenza (influenza / flu) or seasonal influenza (influenza / flu vaccines): Vaccines against influenza viruses that occur seasonally during influenza epidemics are referred to herein as "vaccines for seasonal influenza (influenza / flu) or seasonal influenza (influenza / flu vaccines."

[0041] Immune System: The immune system can protect an organism from infection. If a pathogen breaks through an organism's physical barriers and invades the organism, the innate immune system provides an immediate, but non-specific, response. If a pathogen evades this innate response, vertebrates are equipped with a second layer of defense, the adaptive immune system. Here, the immune system adapts its response during infection to improve its pathogen recognition. This improved response is then retained in the form of immunological memory after the pathogen is eliminated, allowing the adaptive immune system to launch a faster and more powerful attack each time the pathogen is encountered. Accordingly, the immune system comprises the innate immune system and the adaptive immune system. Each of these two parts comprises what are called humoral and cellular components.

[0042] Immune response: An immune response can typically be either a specific response of the adaptive immune system against a particular antigen (the so-called specific or adaptive immune response), or a non-specific response of the innate immune system (the so-called non-specific or innate immune response). The present invention is at its core related to a specific response of the adaptive immune system (adaptive immune response). In particular, the present invention relates to an adaptive immune response against infection by a virus, such as an influenza virus. However, this specific response can be supplemented by an additional non-specific response (innate immune response). Therefore, the present invention also relates to compounds that induce an efficient adaptive immune response by co-stimulation of the innate and adaptive immune systems.

[0043] Adaptive immune system: The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The adaptive immune response endows the vertebrate immune system with the ability to recognize and remember specific pathogens (to generate immunity) and launch a more powerful attack each time the pathogen is encountered. This system is highly adaptable due to somatic hypermutation (a process in which somatic mutation frequency increases) and V(D)J recombination (irreversible genetic recombination of antigen receptor gene segments). This mechanism allows a small number of genes to give rise to a vast number of different antigen receptors, which are then uniquely expressed in each individual lymphocyte. Gene rearrangement leads to irreversible changes in each cell's DNA, so that all of that cell's progeny (descendants) in turn inherit genes encoding the same receptor specificity, including memory B and T cells, which are key to long-lived specific immunity. The immune network theory is a theory of how the adaptive immune system works that is based on the interactions between the variable regions of T-cell and B-cell receptors and the variable regions of molecules made by T-cells and B-cells that contain variable regions.

[0044] Adaptive immune response: Adaptive immune responses are typically understood to be antigen-specific. Antigen specificity allows for the generation of responses tailored to specific antigens, pathogens, or pathogen-infected cells. The ability to mount such tailored responses is maintained in the body by "memory cells." If a pathogen infects the body more than once, these specific memory cells are used to quickly eliminate it. In this context, the first step in the adaptive immune response is the activation of naive antigen-specific T cells or various immune cells capable of inducing antigen-specific immune responses by antigen-presenting cells. This occurs in lymphoid tissues and organs through which naive T cells constantly pass. Cell types that can act as antigen-presenting cells include dendritic cells, macrophages, and B cells, among others. Each of these cells has a different function in eliciting an immune response. Dendritic cells take up antigens by phagocytosis and macropinocytosis and, upon stimulation, for example, by contact with a foreign antigen, migrate to local lymphoid tissues, where they differentiate into mature dendritic cells. Macrophages ingest particulate antigens such as bacteria and express MHC molecules when induced by infectious agents or other appropriate stimuli. The unique ability of B cells to bind and internalize soluble protein antigens via their receptors may also be important for T cell induction. Presentation of antigens on MHC molecules leads to T cell activation, which triggers their proliferation and differentiation into armed effector T cells. The most important functions of effector T cells are killing infected cells via CD8+ cytotoxic T cells and activating macrophages via Th1 cells (together forming cell-mediated immunity), as well as activating B cells via both Th2 and Th1 cells to produce different classes of antibodies, thereby driving humoral immune responses. T cells recognize antigens via their T cell receptors, which do not directly recognize and bind antigens but rather recognize short peptide fragments of protein antigens, such as those derived from pathogens, bound to MHC molecules on the surface of other cells.

[0045] Cellular Immunity / Cell-Mediated Immune Response: Cellular immunity typically involves the activation of macrophages, natural killer cells (NK), and antigen-specific cytotoxic T lymphocytes, and the release of various cytokines in response to antigens. More generally, cellular immunity does not involve antibodies, but rather the activation of cells of the immune system. Cellular immune responses are characterized by the activation of antigen-specific cytotoxic T lymphocytes, which can induce apoptosis in somatic cells that display antigenic epitopes on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells that display tumor antigens; the activation of macrophages and natural killer cells, which enable them to destroy pathogens; and the stimulation of cells to secrete various cytokines that affect the function of other cells involved in adaptive and innate immune responses.

[0046] Humoral immunity / humoral immune response: Humoral immunity typically refers to antibody production and the ancillary processes that may accompany it. Humoral immune responses can typically be characterized by, for example, Th2 activation and cytokine production, germinal center formation and isotype switching, affinity maturation, and memory cell generation. Humoral immunity can also typically refer to antibody effector functions, including neutralization of pathogens and toxins, classical complement activation, and promotion of opsonized phagocytosis and pathogen clearance.

[0047] Innate immune system: The innate immune system, also known as the nonspecific immune system, comprises the cells and mechanisms that nonspecifically defend the host against infection by other organisms. This means that the cells of this innate system generally recognize and respond to pathogens, but unlike the adaptive immune system, do not confer long-lasting or protective immunity on the host. The innate immune system may, for example, react with pathogen-associated molecular pattern (PAMP) receptors, such as ligands for Toll-like receptors (TLRs), or other accessory substances, such as lipopolysaccharide, TNF-α, CD40 ligand, or cytokines, monokines, lymphokines, interleukins, or chemokines, such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, IL-42, IL-43, IL-44, IL-45, IL-46, IL-47, IL-48, IL-49, IL-50, IL-51, IL-52, IL-53, IL-54, IL-55, IL-56, IL-57, IL-58, IL-59, IL-60, IL-61, IL-62, IL-63, IL-64, IL-65, IL-66, IL-67, IL-68, IL-69, IL-70, IL-71, IL-72, IL-73 The IL-1 receptors can be activated by ligands of human Toll-like receptors TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, ligands of mouse Toll-like receptors TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 or TLR13, ligands of NOD-like receptors, ligands of RIG-I-like receptors, immunostimulatory nucleic acids, immunostimulatory RNA (isRNA), CpG-DNA, antibacterial agents, or antiviral agents, such as IL-33, IFN-α, IFN-β, IFN-γ, GM-CSF, G-CSF, M-CSF, LT-β, ​​TNF-α, growth factors, and hGH. Typically, the response of the innate immune system includes recruitment of immune cells to the site of infection through the production of chemical factors, including specialized chemical mediators called cytokines; activation of the complement cascade; identification and removal of foreign substances present in organs, tissues, blood, and lymph by specialized white blood cells; activation of the adaptive immune system through a process known as antigen presentation; and / or acting as a physical and chemical barrier against infectious agents.

[0048] Adjuvant / Adjuvant Component: In the broadest sense, an adjuvant or adjuvant component is typically an agent or composition (e.g., pharmacological or immunological) that can modify, e.g., enhance, the effectiveness of another agent, such as a drug or vaccine. Traditionally, this term, in the context of the present invention, refers to a compound or composition that serves as a carrier or auxiliary substance for immunogens and / or other pharmaceutically active compounds. This should be interpreted broadly and refers to a wide range of substances that can enhance the immunogenicity of an antigen formulated in or co-administered with the adjuvant. In the context of the present invention, an adjuvant will preferably enhance the specific immunogenic effect of the active agent of the present invention. Typically, "adjuvant" or "adjuvant component" have the same meaning and can be used interchangeably. Adjuvants can be divided, for example, into immunostimulants, antigenic delivery systems, or even combinations thereof.

[0049] The term "adjuvant" is typically understood to exclude agents that confer immunity alone. Adjuvants nonspecifically assist the immune system, e.g., by promoting the presentation of antigens to the immune system or the induction of nonspecific innate immune responses, such that antigen-specific immune responses are enhanced. Furthermore, adjuvants can preferably modulate, e.g., antigen-specific immune responses, e.g., by shifting a predominantly Th2-based antigen-specific response to a more Th1-based antigen-specific response, or vice versa. Thus, adjuvants can advantageously modulate cytokine expression / secretion, antigen presentation, type of immune response, etc.

[0050] Immunostimulatory RNA: In the context of the present invention, immunostimulatory RNA (isRNA) can typically be RNA capable of inducing an innate immune response itself. It usually does not have an open reading frame and therefore does not provide a peptide antigen or immunogen, but instead induces an innate immune response, for example, by binding to a specific type of Toll-like receptor (TLR) or other suitable receptor. However, it is understood that mRNAs that have an open reading frame and encode a peptide / protein (e.g., an antigenic function) can also induce an innate immune response.

[0051] Antigen: In the context of the present invention, "antigen" typically refers to a substance that can be recognized by the immune system, preferably the adaptive immune system, and that has the ability to elicit an antigen-specific immune response, e.g., by the formation of antibodies and / or antigen-specific T cells as part of the adaptive immune response. Typically, an antigen may be or comprise a peptide or protein that can be presented to T cells by MHC. In the sense of the present invention, an antigen may be the translation product of a provided nucleic acid molecule, preferably an mRNA as defined herein. In this context, fragments, variants and derivatives of peptides and proteins that comprise at least one epitope are also understood as antigens.

[0052] Epitope (also referred to as "antigenic determinant"): A T cell epitope or portion of a protein, in the context of the present invention, may comprise a fragment, preferably about 6 to about 20 amino acids or even longer, e.g., a fragment, preferably about 8 to about 10 amino acids, e.g., 8, 9, or 10 (or even 11 or 12) amino acids, that is processed and presented by MHC class I molecules, or a fragment, preferably about 13 amino acids or more, e.g., 13, 14, 15, 16, 17, 18, 19, 20 amino acids or even longer, that is processed and presented by MHC class II molecules, where these fragments may be selected from any portion of the amino acid sequence. These fragments are typically recognized by T cells in the form of a complex consisting of the peptide fragment and the MHC molecule.

[0053] A B-cell epitope is typically a fragment of preferably 5 to 15 amino acids, more preferably 5 to 12 amino acids, even more preferably 6 to 9 amino acids, located on the outer surface of a (native) protein or peptide antigen as defined herein, which can be recognised by an antibody, i.e. in its native form.

[0054] Such epitopes of proteins or peptides may further be selected from any of the variants of such proteins or peptides mentioned herein. In this context, an antigenic determinant may be a conformational or discontinuous epitope, composed of segments of a protein or peptide as defined herein, where the amino acid sequence of the protein or peptide as defined herein is discontinuous but together forms a three-dimensional structure, or it may be a continuous or linear epitope, composed of a single polypeptide chain.

[0055] Vaccine: A vaccine is typically understood to be a prophylactic or therapeutic material that provides at least one antigen or antigenic function that can stimulate the adaptive immune system of the body to produce an adaptive immune response.

[0056] Antigen-conferring mRNA: In the context of the present invention, an antigen-conferring mRNA may typically be an mRNA having at least one open reading frame that can be translated by the cell or organism from which it is provided. The product of this translation is an antigen, preferably a peptide or protein that can act as an immunogen. The product may also be a fusion protein composed of two or more immunogens, for example, a fusion protein composed of two or more epitopes, peptides or proteins derived from the same or different viral proteins, where the epitopes, peptides or proteins may be linked by a linker sequence.

[0057] Artificial mRNA (sequence): An artificial mRNA (sequence) can typically be understood as an mRNA molecule that does not occur in nature. In other words, an artificial mRNA molecule can be understood as a non-natural mRNA molecule. Such an mRNA molecule can be non-natural due to its individual sequence (not occurring in nature) and / or due to other modifications, such as non-natural structural modifications of nucleotides. Typically, an artificial mRNA molecule can be designed and / or created by genetic engineering methods to correspond to a desired artificial nucleotide sequence (heterologous sequence). In this context, an artificial sequence is usually a sequence that may not occur in nature, i.e., it differs from the wild-type sequence by at least one nucleotide. The term "wild-type" can be understood as a naturally occurring sequence. Furthermore, the term "artificial nucleic acid molecule" is not limited to meaning "one single molecule," but is typically understood to include a collection of identical molecules. It can therefore relate to multiple identical molecules contained in an aliquot.

[0058] Bicistronic / multicistronic mRNA: An mRNA that can typically have two (bicistronic) or more (multicistronic) open reading frames (ORFs) (coding regions or sequences). In this context, an open reading frame is a sequence of several nucleotide triplets (codons) that can be translated into a peptide or protein. When such an mRNA is translated, two (bicistronic) or more (multicistronic) separate translation products are generated (provided that the ORFs are not identical). For expression in eukaryotes, such an mRNA can contain, for example, an internal ribosome entry site (IRES) sequence.

[0059] Monocistronic mRNA: A monocistronic mRNA may typically be an mRNA that contains only one open reading frame (coding sequence or region). In this context, an open reading frame is a sequence of several nucleotide triplets (codons) that can be translated into a peptide or protein.

[0060] 5'-CAP structure: 5'-CAP is a modified nucleotide (CAP analog), particularly a guanine nucleotide, that is typically added to the 5' end of an mRNA molecule. Preferably, the 5'-CAP is added using a 5'-5' triphosphate linkage (also known as m7GpppN). Further examples of 5'-CAP structures include glyceryl, inverted deoxyabasic residue (moiety), 4',5' methylene nucleotide, 1-(β-D-erythrofuranosyl) nucleotide, 4'-thionucleotide, carbocyclic nucleotide, 1,5-anhydrohexitol nucleotide, L-nucleotide, α-nucleotide, modified base nucleotide, threopentofuranosyl nucleotide, acyclic 3',4'-seconucleotide, acyclic 3,4-dihydroxybutyl nucleotide, acyclic 3,5 dihydroxypentyl nucleotide, 3'-3'-inverted nucleotide moiety, 3'-3'-inverted abasic moiety, 3'-2'-inverted nucleotide moiety, 3'-2'-inverted abasic moiety, 1,4-butanediol phosphate, 3'-phosphoramidate, hexyl phosphate, aminohexyl phosphate, 3'-phosphate, 3' phosphorothioate, phosphorodithioate, or a bridged or non-bridged methylphosphonate moiety. These modified 5'-CAP structures can be used in the context of the present invention to modify the mRNA sequence of the composition of the present invention. Additional modified 5'-CAP structures that can be used in the context of the present invention are CAP1 (additional methylation of the ribose of the nucleotide adjacent to m7GpppN), CAP2 (additional methylation of the ribose of the second nucleotide downstream of m7GpppN), cap3 (additional methylation of the ribose of the third nucleotide downstream of m7GpppN), cap4 (additional methylation of the ribose of the fourth nucleotide downstream of m7GpppN), ARCA (anti-reverse CAP analog), modified ARCA (e.g., phosphothioate-modified ARCA), inosine, N1-methyl-guanosine, 2'-fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine.

[0061] In the context of the present invention, 5'-CAP structures may also be formed by chemical RNA synthesis or RNA in vitro transcription (co-transcriptional capping) using cCAP analogs, or CAP structures may be formed in vitro using capping enzymes (e.g., commercially available capping kits).

[0062] CAP analog: A CAP analog refers to a non-polymerizable dinucleotide that has the CAP function in that when incorporated into the 5' end of an RNA molecule, it promotes translation or localization and / or prevents degradation of the RNA molecule. Non-polymerizable means that the CAP analog can only be incorporated into the 5' end because it does not have a 5' triphosphate and therefore cannot be extended in the 3' direction by template-dependent RNA polymerase.

[0063] CAP analogs include, but are not limited to, chemical structures selected from the group consisting of m7GpppG, m7GpppA, m7GpppC; unmethylated CAP analogs (e.g., GpppG); dimethylated CAP analogs (e.g., m2,7GpppG), trimethylated CAP analogs (e.g., m2,2,7GpppG), dimethylated symmetric CAP analogs (e.g., m7Gpppm7G), or anti-reverse CAP analogs (e.g., ARCA; m7,2'OmeGpppG, m7,2'dGpppG, m7,3'OmeGpppG, m7,3'dGpppG, and their tetraphosphate derivatives) (Stepinski et al., 2001. RNA 7(10):1486-95).

[0064] Additional CAP analogs have been previously described (U.S. Pat. No. 7,074,596, WO 2008 / 016473, WO 2008 / 157688, WO 2009 / 149253, WO 2011 / 015347, and WO 2013 / 059475). More recently, the synthesis of N7-(4-chlorophenoxyethyl) substituted dinucleotide CAP analogs has been described (Kore et al. (2013) Bioorg. Med. Chem. 21(15):4570-4).

[0065] Poly(C) sequence: A poly(C) sequence is typically a long sequence of cytosine nucleotides, typically about 10 to about 200 cytosine nucleotides, preferably about 10 to about 100 cytosine nucleotides, more preferably about 10 to about 70 cytosine nucleotides, or even more preferably about 20 to about 50, or even about 20 to about 30 cytosine nucleotides. The poly(C) sequence may preferably be located on the 3' side of a coding region contained in a nucleic acid.

[0066] Poly(A) tail / sequence: A poly(A) tail, also referred to as a "3'-poly(A) tail or poly(A) sequence," is typically a long adenosine nucleotide sequence of up to about 400 adenosine nucleotides, e.g., about 25 to about 400, preferably about 50 to about 400, more preferably about 50 to about 300, even more preferably about 50 to about 250, and most preferably about 60 to about 250 adenosine nucleotides, added to the 3' end of RNA. Furthermore, a poly(A) sequence or poly(A) tail may be generated in vitro by enzymatic polyadenylation of RNA using, for example, poly(A) polymerase derived from Escherichia coli (E. coli) or yeast.

[0067] Polyadenylation: Polyadenylation is typically understood as the addition of a poly(A) sequence to a nucleic acid molecule, such as an RNA molecule, for example, a premature mRNA. Polyadenylation can be induced by a so-called polyadenylation signal. This signal is preferably located within the nucleotide stretch to be polyadenylated at the 3' end of the nucleic acid molecule, such as an RNA molecule. The polyadenylation signal typically comprises a hexamer consisting of adenine and uracil / thymine nucleotides, preferably the hexamer sequence AAUAAA. Other sequences, preferably hexamer sequences, are also contemplated. Polyadenylation typically occurs during the processing of pre-mRNA (also called premature mRNA). Typically, RNA maturation (from pre-mRNA to mature mRNA) includes a polyadenylation step.

[0068] 3'-Untranslated Region (3'-UTR): The 3'-UTR is typically a portion of an mRNA located between the protein-coding region (i.e., open reading frame) and the poly(A) sequence of the mRNA. The 3'-UTR of an mRNA is not translated into an amino acid sequence. The 3'-UTR sequence is generally encoded by a gene, which is transcribed into the respective mRNA during gene expression. The genomic sequence is first transcribed into a premature mRNA, which optionally contains introns. The premature mRNA is then further processed into a mature mRNA during the maturation process. This maturation process includes 3'-end modification steps, such as a 5'-capping step, excision of optional introns by splicing the premature mRNA, and polyadenylation of the 3' end of the premature mRNA, as well as optional endo- or exonuclease cleavage steps. In the context of the present invention, the 3'-UTR corresponds to the sequence of a mature mRNA that is located 3' to the stop codon of the protein-coding region, preferably immediately 3' to the stop codon of the protein-coding region, and extends to the 5' side of the poly(A) sequence, preferably to the nucleotide immediately 5' to the poly(A) sequence. The term "corresponding to" means that the 3'-UTR sequence may be an RNA sequence as in the mRNA sequence used to define the 3'-UTR sequence, or a DNA sequence corresponding to such an RNA sequence. In the context of the present invention, the term "3'-UTR of a gene," such as "3'-UTR of the albumin gene," refers to a sequence that corresponds to the 3'-UTR of a mature mRNA derived from that gene, i.e., an mRNA obtained by transcription of that gene and maturation of the premature mRNA. The term "3'-UTR of a gene" encompasses both DNA and RNA sequences of the 3'-UTR.

[0069] 5'-untranslated region (5'-UTR): 5'-UTR is typically understood to be a specific section of messenger RNA (mRNA). It is located 5' to the open reading frame of the mRNA. Typically, the 5'-UTR begins at the transcription initiation site and ends one nucleotide before the start codon of the open reading frame. The 5'-UTR may contain elements, also called regulatory elements, that control gene expression. Such regulatory elements may be, for example, a ribosome binding site or a 5'-terminal oligopyrimidine tract. The 5'-UTR may be post-transcriptionally modified, for example, by the addition of a 5'-CAP. In the context of the present invention, the 5'-UTR corresponds to the sequence located between the 5'-CAP and the start codon of the mature mRNA. Preferably, the 5'-UTR corresponds to the sequence extending from the nucleotide located 3' to the 5'-CAP, preferably the nucleotide located immediately 3' to the 5'-CAP, to the nucleotide located 5' to the start codon of the protein-coding region, preferably the nucleotide located immediately 5' to the start codon of the protein-coding region. The nucleotide located immediately 3' to the 5'-CAP of the mature mRNA typically corresponds to the transcription start site. The term "corresponding to" means that the 5'-UTR sequence may be an RNA sequence, such as in the mRNA sequence used to define the 5'-UTR sequence, or a DNA sequence corresponding to such an RNA sequence. In the context of the present invention, the term "5'-UTR of a gene," such as "5'-UTR of a TOP gene," refers to a sequence corresponding to the 5'-UTR of the mature mRNA derived from that gene, i.e., the mRNA obtained by transcription of that gene and maturation of the premature mRNA. The term "5'-UTR of a gene" encompasses both DNA and RNA sequences of the 5'-UTR.

[0070] 5'-Terminal Oligopyrimidine Tract (TOP): A 5'-Terminal Oligopyrimidine Tract (TOP) is a stretch of pyrimidine nucleotides typically located in the 5'-terminal region of a nucleic acid molecule, such as the 5'-terminal region of a certain mRNA molecule or the 5'-terminal region of a functional entity of a certain gene, e.g., the 5'-terminal region of a transcribed region. This sequence usually begins with a cytidine corresponding to the transcription start site and is usually followed by a stretch of about 3 to 30 pyrimidine nucleotides. For example, a TOP can contain 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or even more nucleotides. The pyrimidine stretch, and thus the 5'-TOP, ends one nucleotide 5' to the first purine nucleotide located downstream of the TOP. Messenger RNAs containing a 5'-terminal oligopyrimidine tract are often referred to as TOP mRNAs. Therefore, genes that provide such messenger RNAs are called TOP genes. TOP sequences are found, for example, in genes and mRNAs encoding peptide elongation factors and ribosomal proteins.

[0071] TOP motif: In the context of the present invention, a TOP motif is a nucleic acid sequence corresponding to a 5'-TOP as defined above. Accordingly, a TOP motif in the context of the present invention is a stretch of pyrimidine nucleotides, preferably 3 to 30 nucleotides in length. Preferably, a TOP motif consists of at least 3 pyrimidine nucleotides, preferably at least 4 pyrimidine nucleotides, preferably at least 5 pyrimidine nucleotides, more preferably at least 6 nucleotides, more preferably at least 7 nucleotides, and most preferably at least 8 pyrimidine nucleotides, the stretch of pyrimidine nucleotides preferably starting at its 5'-end with a cytosine nucleotide. In TOP genes and TOP mRNAs, the TOP motif preferably starts at its 5'-end from the transcription start site and ends one nucleotide 5' to the first purine residue in said gene or mRNA. A TOP motif in the sense of the present invention is preferably located at the 5'-end of a sequence corresponding to a 5'-UTR or at the 5'-end of a sequence encoding a 5'-UTR. Preferably, therefore, in the sense of the present invention, a stretch of 3 or more pyrimidine nucleotides is called a "TOP motif" when it is located at the 5'-end of the respective sequence, such as a nucleic acid sequence derived from an mRNA of the present invention, a 5'-UTR element of an mRNA of the present invention, or the 5'-UTR of a TOP gene as described herein. In other words, a stretch of 3 or more pyrimidine nucleotides that is not located at the 5'-end of the 5'-UTR or 5'-UTR element, but is located within the 5'-UTR or 5'-UTR element, is preferably not referred to as a "TOP motif".

[0072] TOP gene: TOP genes are typically characterized by the presence of a 5'-terminal oligopyrimidine tract. Furthermore, many TOP genes are characterized by growth-related translational regulation. However, TOP genes with tissue-specific translational regulation are also known. As defined above, the 5'-UTR of a TOP gene corresponds to the sequence of the 5'-UTR of the mature mRNA derived from the TOP gene, preferably extending from the nucleotide located 3' to the 5'-CAP to the nucleotide located 5' to the start codon. The 5'-UTR of a TOP gene typically does not contain any start codon, and preferably does not contain an upstream AUG (uAUG) or an upstream open reading frame (uORF). In this context, upstream AUG and upstream open reading frame are typically understood to be the AUG and open reading frame located 5' to the start codon (AUG) of the open reading frame to be translated. The 5'-UTR of a TOP gene is generally rather short. The length of the 5'-UTR of a TOP gene may vary between 20 nucleotides and up to 500 nucleotides, and is typically less than about 200 nucleotides, preferably less than about 150 nucleotides, and more preferably less than about 100 nucleotides. Exemplary 5'-UTRs of TOP genes within the meaning of the present invention are nucleic acid sequences extending from the 5th nucleotide in the sequences according to SEQ ID NOs: 1 to 1363, 1395, 1421, and 1422 of WO 2013 / 143700, or homologs or variants thereof (the disclosure of which is hereby incorporated by reference), to the nucleotide located immediately 5' to the start codon (e.g., ATG). In this context, a particularly preferred fragment of the 5'-UTR of a TOP gene is a 5'-UTR of a TOP gene lacking the 5'-TOP motif. The term "5'-UTR of a TOP gene" preferably refers to the 5'-UTR of a naturally occurring TOP gene.

[0073] Fragments of nucleic acid sequences, in particular mRNA: A fragment of a nucleic acid sequence consists of a contiguous nucleotide stretch that corresponds to a contiguous nucleotide stretch in the full-length nucleic acid sequence that represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full-length nucleic acid sequence on which the nucleic acid sequence of the fragment is based. Such fragments are preferably functional fragments of the full-length nucleic acid sequence in the sense of the present invention.

[0074] In this context, a "fragment of a nucleic acid sequence", e.g., a fragment of an mRNA sequence, is preferably a nucleic acid sequence encoding a fragment of a protein or a variant thereof as described herein. More preferably, the expression "fragment of a nucleic acid sequence" refers to a nucleic acid sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, and most preferably at least 95% or even 97% sequence identity to the respective full-length nucleic acid sequence.

[0075] Nucleic acid sequence, particularly mRNA, variants: A variant of a nucleic acid sequence refers to a variant of the nucleic acid sequence that forms the basis of the nucleic acid sequence. For example, a variant nucleic acid sequence may exhibit one or more nucleotide deletions, insertions, additions, and / or substitutions compared to the nucleic acid sequence from which the variant is derived. Preferably, a variant of a nucleic acid sequence is at least 40%, preferably at least 50%, more preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, even more preferably at least 90%, and most preferably at least 95% identical to the nucleic acid sequence from which the variant is derived. Preferably, the variant is a functional variant. A "variant" of a nucleic acid sequence may have at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% nucleotide identity over a stretch of 10, 20, 30, 50, 75, or 100 nucleotides of the nucleic acid sequence in question.

[0076] Stabilized nucleic acids, preferably mRNA: Stabilized nucleic acids, preferably mRNA, typically exhibit modifications that increase resistance to in vivo degradation (e.g., degradation by exonucleases or endonucleases) and / or ex vivo degradation (e.g., due to manufacturing steps prior to vaccine administration, e.g., during preparation of the vaccine solution to be administered). Stabilization of RNA can be achieved, for example, by providing a 5'-CAP structure, a polyA tail, or any other UTR modification. This can also be achieved by chemical modification or modification of the G / C content of the nucleic acid. A variety of other methods are known in the art and can be contemplated in the context of the present invention.

[0077] RNA in vitro transcription: The term "RNA in vitro transcription" or "in vitro transcription" refers to a process by which RNA is synthesized in a cell-free system (in vitro). DNA, particularly plasmid DNA, is used as a template for the production of RNA transcripts. RNA may be obtained by DNA-dependent in vitro transcription of a suitable DNA template, which, according to the present invention, is preferably a linearized plasmid DNA template. The promoter controlling the in vitro transcription may be any promoter for any DNA-dependent RNA polymerase. Specific examples of DNA-dependent RNA polymerases are T7, T3, and SP6 RNA polymerases. DNA templates for in vitro RNA transcription may be obtained by cloning nucleic acids, particularly cDNAs corresponding to the respective RNAs to be in vitro transcribed, and introducing them into a suitable vector for in vitro transcription, such as plasmid DNA. In a preferred embodiment of the present invention, the DNA template is linearized with a suitable restriction enzyme before being in vitro transcribed. cDNA may be obtained by reverse transcription of mRNA or chemical synthesis. Furthermore, DNA templates for in vitro RNA synthesis may also be obtained by gene synthesis.

[0078] In vitro transcription methods are known in the art (see, e.g., Geall et al. (2013) Semin. Immunol. 25(2):152-159; Brunelle et al. (2013) Methods Enzymol. 530:101-14). Reagents used in the methods typically include: 1) a linearized DNA template containing a promoter sequence with high binding affinity for its respective RNA polymerase, such as a bacteriophage-encoded RNA polymerase; 2) ribonucleoside triphosphates (NTPs) of four bases (adenine, cytosine, guanine, and uracil); 3) optionally a CAP analog as defined above (e.g., m7G(5')ppp(5')G(m7G)); 4) a DNA-dependent RNA polymerase (e.g., T7, T3, or SP6 RNA polymerase) capable of binding to a promoter sequence within a linearized DNA template; 5) optionally, a ribonuclease (RNase) inhibitor to inactivate any contaminating RNases; 6) optionally, a pyrophosphatase to degrade pyrophosphates that may inhibit transcription; 7) MgCl2, which provides Mg2+ ions as a cofactor for the polymerase; 8) A buffer that maintains a suitable pH value, which also contains optimal concentrations of antioxidants (e.g., DTT) and / or polyamines such as spermidine.

[0079] Full-length protein: As used herein, the term "full-length protein" typically refers to a protein that includes substantially the entire amino acid sequence of a naturally occurring protein. Nevertheless, amino acid substitutions resulting from, for example, mutation of the protein are also encompassed by the term full-length protein.

[0080] Fragment of a protein: A "fragment" of a protein or peptide in the context of the present invention may typically comprise a protein or peptide sequence as defined herein, which, with respect to its amino acid sequence (or its encoding nucleic acid molecule), is N-terminally and / or C-terminally truncated compared to the amino acid sequence of the original (native) protein (or its encoding nucleic acid molecule). Such truncation may therefore occur either at the amino acid level or, correspondingly, at the nucleic acid level. Sequence identity with respect to such fragments as defined herein therefore preferably refers to the entire protein or peptide as defined herein, or to the entire (encoding) nucleic acid molecule of such protein or peptide.

[0081] In this context, a fragment of a protein may typically comprise an amino acid sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90% and most preferably at least 95% or even 97% sequence identity to the amino acid sequence of the respective naturally occurring full-length protein.

[0082] A fragment of a protein or peptide, in the context of the present invention, may further comprise a protein or peptide sequence as defined herein, for example at least 5 amino acids in length, preferably at least 6 amino acids, preferably at least 7 amino acids, more preferably at least 8 amino acids, even more preferably at least 9 amino acids; even more preferably at least 10 amino acids; even more preferably at least 11 amino acids; even more preferably at least 12 amino acids; even more preferably at least 13 amino acids; even more preferably at least 14 amino acids; even more preferably at least 15 amino acids; even more preferably at least 16 amino acids; even more preferably at least 17 amino acids; even more preferably at least 18 amino acids; even more preferably at least 19 amino acids; even more preferably at least 20 amino acids; even more preferably at least 25 amino acids; even more preferably at least 30 amino acids; even more preferably at least 35 amino acids; even more preferably at least 50 amino acids; or most preferably at least 100 amino acids in length. For example, such fragments may be about 6 to about 20 amino acids or even longer, e.g., preferably about 8 to about 10 amino acids, e.g., 8, 9, or 10 (or even 6, 7, 11, or 12) amino acids in length, as processed and presented by MHC class I molecules, or preferably about 13 amino acids or longer, e.g., 13, 14, 15, 16, 17, 18, 19, 20 amino acids or even longer, as processed and presented by MHC class II molecules, and these fragments may be selected from any portion of the amino acid sequence. These fragments are typically recognized by T cells in the form of a complex consisting of the peptide fragment and the MHC molecule; i.e., the fragment is typically not recognized in its native form. A fragment of a protein or peptide may comprise at least one epitope of the protein or peptide. Furthermore, domains of a protein, such as the extracellular domain, intracellular domain, or transmembrane domain, and truncated or truncated forms of the protein, may also be understood to include fragments of a protein.

[0083] Protein variants: "Variants" of proteins or peptides, as defined in the context of the present invention, may be generated, which have an amino acid sequence that differs from the original sequence by one or more mutations, such as one or more substituted, inserted, and / or deleted amino acids. Preferably, such fragments and / or variants have the same biological function or specific activity, e.g., its specific antigenic properties, as compared to the full-length native protein. "Variants" of proteins or peptides, as defined in the context of the present invention, may contain one or more conservative amino acid substitutions as compared to their native sequence, i.e., the non-mutated physiological sequence. These amino acid sequences as well as their encoding nucleotide sequences particularly fall under the term variant as defined herein. Substitutions in which amino acids from the same class are exchanged for one another are called conservative substitutions. In particular, these are amino acids with aliphatic side chains, positively or negatively charged side chains, aromatic groups in the side chains, or amino acids whose side chains can enter into hydrogen bridges, e.g., amino acids with side chains bearing hydroxyl functions. This means, for example, that an amino acid with a polar side chain is replaced by another amino acid with a similarly polar side chain, or that an amino acid characterized by a hydrophobic side chain is replaced by another amino acid with a similarly hydrophobic side chain (e.g., serine (threonine) for threonine (serine) or leucine (isoleucine) for isoleucine (leucine)). Insertions and substitutions are possible, in particular, at sequence positions that do not result in modifications of the three-dimensional structure or that do not affect the binding region. Modifications of the three-dimensional structure by one or more insertions or one or more deletions can be easily determined, for example, using CD spectroscopy (circular dichroism spectroscopy) (Urry, 1985, Absorption, Circular Dichroism and ORD of Polypeptides, in: Modern Physical Methods in Biochemistry, Neuberger et al. (ed.), Elsevier, Amsterdam).

[0084] A "variant" of a protein or peptide may have at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% amino acid identity over a stretch of 10, 20, 30, 50, 75 or 100 amino acids with such protein or peptide.

[0085] Furthermore, variants of proteins or peptides as defined herein, which may be encoded by a nucleic acid molecule, may also include sequences in which the nucleotides of the encoding nucleic acid sequence have been exchanged in accordance with the degeneracy of the genetic code, without leading to a change in the respective amino acid sequence of the protein or peptide, i.e. sequences in which the amino acid sequence or at least a part thereof may not differ from the original sequence within the above meaning in terms of one or more mutations.

[0086] Sequence identity: To determine the percentage of identity between two sequences, such as nucleic acid sequences or amino acid sequences as defined herein, preferably the amino acid sequence encoded by the nucleic acid sequence of a polymeric carrier as defined herein, or the amino acid sequence itself, the sequences can be aligned for subsequent comparison. Thus, for example, a position in a first sequence can be compared with the corresponding position in a second sequence. If a position in the first sequence is occupied by the same component (residue) as in the second sequence, the two sequences are identical at that position. Otherwise, the sequences differ at that position. If an insertion occurs in the second sequence compared to the first sequence, a gap can be inserted in the first sequence to allow further alignment. If a deletion occurs in the second sequence compared to the first sequence, a gap can be inserted in the second sequence to allow further alignment. Thus, the percentage of identity between two sequences is a function of the number of identical positions divided by the total number of positions, including positions occupied only in one sequence. The percentage of identity between two sequences can be determined using a mathematical algorithm. A preferred, but non-limiting example of a mathematical algorithm that can be used is the algorithm of Karlin et al. (1993), PNAS USA, 90:5873-5877 or Altschul et al. (1997), Nucleic Acids Res., 25:3389-3402. Such an algorithm is incorporated into the BLAST program. Sequences that are only partially identical to the sequences of the present invention can be identified by this program.

[0087] Derivative of a protein or peptide: A derivative of a peptide or protein is typically understood to be a molecule derived from another molecule, such as said peptide or protein. The "derivative" of a peptide or protein also encompasses a fusion comprising the peptide or protein used in the present invention. For example, the fusion comprises a tag, such as an epitope, such as a FLAG epitope or a V5 epitope. For example, the epitope is a FLAG epitope. Such a tag is useful, for example, for purifying the fusion protein.

[0088] Pharmaceutically effective amount: A pharmaceutically effective amount in the context of the present invention is typically understood as an amount sufficient to induce an immune response.

[0089] Carrier / Polymer Carrier: A carrier in the context of the present invention may typically be a compound that facilitates the transport and / or complexation of another compound. Said carrier may form a complex with said other compound. A polymeric carrier is a carrier made of a polymer.

[0090] Vehicle: An agent, such as a carrier, that may typically be used in a pharmaceutical composition or vaccine to facilitate administration of the components of the pharmaceutical composition or vaccine to an individual.

[0091] Jet injection: The term "jet injection," as used herein, refers to a needle-free injection method in which a fluid containing at least one mRNA sequence of the present invention and, optionally, additional suitable excipients, is forced through an orifice, thus generating a high-pressure, ultra-fine liquid stream capable of penetrating the mammalian skin and, depending on the injection setting, the subcutaneous or muscular tissue. In principle, the liquid stream punctures the skin, from which it is forced into the target tissue. Preferably, jet injection is used for intradermal, subcutaneous, or intramuscular injection of the mRNA sequences of the present invention. In a preferred embodiment, jet injection is used for intramuscular injection of the mRNA sequences of the present invention. In a further preferred embodiment, jet injection is used for intradermal injection of the mRNA sequences of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0092] Detailed Description of the Invention The present invention is based on the inventors' surprising discovery that mRNA encoding at least one antigenic peptide or protein contained in lipid nanoparticles (LNPs) can highly efficiently induce an antigen-specific immune response against the encoded antigenic peptide or protein at extremely low dosages and in an administration regimen that does not require frequent administration.

[0093] Further advantages of the mRNA of the present invention that encodes at least one antigenic peptide or protein contained in a lipid nanoparticle (LNP) include: - Induction of a strong humoral immune response - Induction of B cell memory - Faster immune defense onset - The induced immune response is long-lasting - Induction of broad cellular T cell responses - Induction of a (local, transient) pro-inflammatory environment - Does not induce a systemic cytokine or chemokine response - Well tolerated, no side effects, non-toxic - Advantageous stability characteristics - Formulation compatible with many different antigens: Larger scale antigen cocktails can be achieved based on the same technology - No vector immunization, i.e. the technique can be used to vaccinate the same subject multiple times against several (different) antigens - Speed, adaptability, simplicity and scalability of production is.

[0094] In particular, the present invention relates to mRNA-containing lipid nanoparticles and uses thereof. To be suitable for the present invention, lipid nanoparticles comprise at least: (i) a cationic lipid and / or a PEG lipid, as defined below; and (ii) an mRNA compound containing an mRNA sequence encoding an antigenic peptide or protein; Includes:

[0095] The mRNA-containing lipid nanoparticles may contain additional compounds, such as one or more neutral lipids, steroids, and combinations of the aforementioned compounds. Suitable compounds are described in more detail below.

[0096] The mRNA compound comprising an mRNA sequence encoding an antigenic peptide or protein may be an mRNA molecule. In one embodiment of the present invention, the mRNA compound is natural, unmodified mRNA. In the context of the present invention, natural, unmodified mRNA encompasses mRNA produced in vitro without chemical modification or sequence alteration.

[0097] In an alternative embodiment of the invention, the mRNA compound comprises an artificial mRNA. In the context of the present invention, artificial mRNA encompasses mRNA that has been chemically modified, sequence modified or has a non-natural sequence.

[0098] In a preferred embodiment of the present invention, the mRNA compound does not contain nucleoside modifications, in particular does not contain base modifications. In a further embodiment, the mRNA compound does not contain 1-methylpseudouridine modifications. In a preferred embodiment, the mRNA contains only naturally occurring nucleosides. In a further preferred embodiment, the mRNA compound does not contain any chemical modifications and optionally contains sequence modifications. In a further preferred embodiment of the present invention, the mRNA compound contains only the naturally occurring nucleosides adenine, uracil, guanine and cytosine.

[0099] According to certain embodiments of the present invention, the mRNA sequence is preferably monocistronic, bicistronic, or multicistronic, as defined herein. The coding sequence of a bicistronic or multicistronic mRNA preferably encodes individual peptides or proteins, or fragments or variants thereof, as defined herein. Preferably, the coding sequences encoding two or more peptides or proteins may be separated in a bicistronic or multicistronic mRNA by at least one IRES (internal ribosome entry site) sequence, as defined below. Thus, the term "encoding two or more peptides or proteins" may mean, but is not limited to, that a bicistronic or even multicistronic mRNA may encode, for example, at least two, three, four, five, six, or more (preferably different) peptides or proteins, or fragments or variants thereof, within the definition provided herein. More preferably, but not exclusively, a bicistronic or even multicistronic mRNA may encode, for example, at least two, three, four, five, six or more (preferably different) peptides or proteins as defined herein, or fragments or variants thereof as defined herein. In this context, a so-called IRES (Internal Ribosome Entry Site) sequence as defined above may function as a single ribosome binding site, but may also serve to provide a bicistronic or even multicistronic mRNA as defined above that encodes several peptides or proteins that are translated independently of each other by the ribosome. Examples of IRES sequences that may be used according to the present invention are those from picornaviruses (e.g. FMDV), pestiviruses (CFFV), polioviruses (PV), encephalomyocarditis virus (ECMV), foot and mouth disease virus (FMDV), hepatitis C virus (HCV), classical swine fever virus (CSFV), mouse leukoma virus (MLV), simian immunodeficiency virus (SIV) or cricket paralysis virus (CrPV).

[0100] According to further embodiments, at least one coding region of the mRNA sequence of the present invention may encode at least two, three, four, five, six, seven, eight, or more peptides or proteins (or fragments and derivatives thereof) as defined herein, with or without an amino acid linker sequence, wherein the linker sequence may comprise a non-flexible linker, a flexible linker, a cleavable linker (e.g., a self-cleaving peptide), or a combination thereof, wherein the peptides or proteins may be the same, different, or a combination thereof. A particular peptide or protein combination may be encoded by the mRNA encoding at least two peptides or proteins as described herein (also referred to herein as a "multi-antigen construct / mRNA").

[0101] In certain embodiments of the present invention, the lipid nanoparticles comprise an mRNA compound comprising an mRNA sequence encoding an antigenic peptide or protein, or a fragment, variant, or derivative thereof.

[0102] These antigenic peptides or proteins may be derived from pathogenic antigens, tumor antigens, allergenic antigens or autoimmune autoantigens, preferably as defined herein. In the context of the present invention, antigenic peptides or proteins preferably exclude luciferase.

[0103] Pathogenic antigen: Such pathogenic antigens are derived from pathogenic organisms, particularly bacterial, viral or protozoan (multicellular) pathogenic organisms, that elicit an immune response by a subject, particularly a mammalian subject, more particularly a human. More particularly, the pathogenic antigen is preferably a surface antigen, such as a protein (or a fragment of a protein, e.g., an outer portion of a surface antigen) located on the surface of a virus or bacterial or protozoan organism.

[0104] The pathogenic antigen is preferably a peptide or protein antigen derived from a pathogen associated with an infectious disease, preferably the pathogen Acinetobacter baumannii, Anaplasma, Anaplasma phagocytophilum, Ancylostoma braziliense, Ancylostoma duodenale, Arcanobacterium haemolyticum, Ascaris lumbricoides, Aspergillus, Astroviridae, Babesia, Bacillus anthracis, Bacillus cereus, Bartonella henselae, henselae, BK virus, Blastocystis hominis, Blastomyces dermatitidis, Bordetella pertussis, Borrelia burgdorferi, Borrelia, Borrelia spp, Brucella, Brugia malayi, Bunyaviridae, Burkholderia cepacia and other Burkholderia spp, Burkholderia mallei, Burkholderia pseudomallei pseudomallei, Caliciviridae, Campylobacter, Candida albicans, Candida spp, Chlamydia trachomatis, Chlamydophila pneumoniae, Chlamydophilapsittaci, CJD prion, Clonorchis sinensis, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium perfringens, Clostridium spp, Clostridium tetani, Coccidioides spp, coronavirus, Corynebacterium diphtheriae, Coxiella burnetii, Crimean-Congo hemorrhagic fever virus, Cryptococcus neoformans neoformans, Cryptosporidium, Cytomegalovirus (CMV), Dengue viruses (DEN-1, DEN-2, DEN-3, and DEN-4), Dientamoeba fragilis, Ebola virus (EBOV), Echinococcus, Ehrlichia chaffeensis, Ehrlichia ewingii, Ehrlichia, Entamoeba histolytica, Enterococcus, Enterovirus, enteroviruses, mainly Coxsackie A virus and enterovirus 71 (EV71), Epidermophyton species spp), Epstein-Barr virus (EBV), Escherichia coli O157:H7, O111 and O104:H4, Fasciola hepatica and Fasciola gigantica, FFI prions, Filarioidea, Flaviviruses, Francisella tularensis, Fusobacterium, Geotrichum candidumcandidum, Giardia intestinalis, Gnathostoma spp., GSS prion, Guanarito virus, Haemophilus ducreyi, Haemophilus influenzae, Helicobacter pylori, Henipaviruses (Hendra virus, Nipah virus), Hepatitis A virus, Hepatitis B virus (HBV), Hepatitis C virus (HCV), Hepatitis D virus, Hepatitis E virus, Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), Histoplasma capsulatum, HIV (human immunodeficiency virus), Hortaea wernekii werneckii, human bocavirus (HBoV), human herpesvirus type 6 (HHV-6) and human herpesvirus type 7 (HHV-7), human metapneumovirus (hMPV), human papillomavirus (HPV), human parainfluenza virus (HPIV), Japanese encephalitis virus, JC virus, Junin virus, Kingella kingae, Klebsiella granulomatis, Coulouri virus, Lassa virus, Legionella pneumophila, Leishmania, Leptospira, Listeria monocytogenes, lymphocytic choriomeningitis virus (LCMV), Machupo virus, Malassezia spp. spp), Marburg virus, measles virus, Metagonimus yokagawai, Microsporidia, Molluscum contagiosum virus (MCV), Mumps virus, Mycobacterium leprae and Mycobacterium lepromatosis, Mycobacterium tuberculosis, Mycobacterium ulceransulcerans, Mycoplasma pneumoniae, Naegleria fowleri, Necator americanus, Neisseria gonorrhoeae, Neisseria meningitidis, Nocardia asteroides, Nocardia spp, Onchocerca volvulus, Orientia tsutsugamushi, Orthomyxoviridae (influenza), Paracoccidioides brasiliensis, Paragonimus spp, Paragonimus westermani westermani, Parvovirus B19, Pasteurella, Plasmodium, Pneumocystis jirovecii, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rhinovirus, Rhinoviruses, Rickettsia akari, Rickettsia, Rickettsia prowazekii, Rickettsia rickettsii, Rickettsia typhi, Rift Valley fever virus, Rotavirus, Rubella virus, Sabia virus, Salmonella, Sarcoptes scabiei, SARS coronavirus, Schistosoma, Shigella, Sin Nombre virus, Hantavirus, Sporothrix schenckii, Staphylococcus, Staphylococcus, Streptococcus agalactiaeagalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Strongyloides stercoralis, Taenia, Taenia solium, Tick-borne encephalitis virus (TBEV), Toxocara canis or Toxocara cati, Toxoplasma gondii, Treponema pallidum, Trichinella spiralis, Trichomonas vaginalis, Trichophyton spp., Trichuris trichiura, Trypanosoma brucei, Trypanosoma cruzi cruzi, Ureaplasma urealyticum, varicella zoster virus (VZV), variola major or minor, vCJD prion, Venezuelan equine encephalitis virus, Vibrio cholerae, West Nile virus, Western equine encephalitis virus, Wuchereria bancrofti, yellow fever virus, Yersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis.

[0105] In this context, antigens from pathogens selected from influenza virus, respiratory syncytial virus (RSV), herpes simplex virus (HSV), human papillomavirus (HPV), human immunodeficiency virus (HIV), Plasmodium, Staphylococcus aureus, dengue virus, Chlamydia trachomatis, cytomegalovirus (CMV), hepatitis B virus (HBV), Mycobacterium tuberculosis, rabies virus, and yellow fever virus are particularly preferred.

[0106] Furthermore, the pathogenicity antigens (antigens derived from pathogens associated with infectious diseases) are preferably the following antigens: outer membrane protein A OmpA, biofilm-associated protein Bap, transport protein MucK (Acinetobacter baumannii, Acinetobacter infection); variable surface glycoprotein VSG, microtubule-associated protein MAPP15, trans-sialidase TSA (Trypanosoma brucei, African sleeping sickness (African trypanosomiasis)); HIV p24 antigen, HIV envelope proteins (Gp120, Gp41, Gp160), polyprotein GAG, negative factor protein Nef, transactivator Tat (HIV (human immunodeficiency virus), AIDS (acquired immunodeficiency syndrome)); galactose-repressible adhesion protein GIAP, 29 kDa antigen Eh29, Gal / GalNAc lectin, protein CRT, 125 kDa immunodominant antigen, protein M17, adhesin ADH112, protein STIRP (Entamoeba histolytica, amebiasis); major surface proteins 1 to 5 (MSP1a, MSP1b, MSP2, MSP3, MSP4, MSP5), type IV secretion system system proteins (VirB2, VirB7, VirB11, VirD4) (Anaplasma, anaplasmosis); protective antigen PA, edema factor EF, lethal factor LF, S-layer homology protein SLH (Bacillus anthracis, anthrax); acranolysin, phospholipase D, collagen-binding protein CbpA (Arcanobacterium haemolyticum, hemolytic arkanobacterial infection); nucleocapsid protein NP, glycoprotein precursor GPC, glycoprotein GP1, glycoprotein GP2 (Junín virus, Argentine hemorrhagic fever);Chitin protein layer protein, 14 kDa surface antigen A14, major sperm protein MSP, MSP polymerization-organizing protein MPOP, MSP fiber protein 2 MFP2, MSP polymerization-activating kinase MPAK, ABA-1-like protein ALB, protein ABA-1, cuticulin CUT-1 (Ascaris lumbricoides, ascariasis); 41 kDa allergen Asp v13, allergen Asp f3, major conidial surface protein rodlet A, protease Pep1p, GPI-anchored protein Gel1p, GPI-anchored protein Crf1p (Aspergillus, aspergillosis); family VP26 protein, VP29 protein (Astroviridae, astrovirus infection); rhoptry-related protein 1 RAP-1, merozoite surface antigen MSA-1, MSA-2 (a1, a2, b, c), 12D3, 11C5, 21B4, P29, variant erythrocyte surface antigen VESA1, apical membrane antigen 1 AMA-1 (Babesia, babesiosis); hemolysin, enterotoxin C, PXO1-51, glycolate oxidase, ABC transporter, penicillin-binding protein, zinc transporter family protein, pseudouridine synthase Rsu, plasmid replication protein RepX, oligoendopeptidase F, prophage membrane protein, protein HemK, flagellar antigen H, 28.5 kDa cell surface antigen (Bacillus cereus) cereus, Bacillus cereus infection); large T antigen LT, small T antigen, capsid protein VP1, capsid protein VP2 (BK virus, BK virus infection); 29 kDa protein, caspase-3-like antigen, glycoproteins (Blastocystis hominis, human Blastocystis infection); yeast surface adhesin WI-1 (Blastomyces dermatitidis, blastomycosis); nucleoprotein N, polymerase L, matrix protein Z, glycoprotein GP (Machupo virus, Bolivian hemorrhagic fever);Cell surface protein A OspA, cell surface protein OspB, cell surface protein OspC, decorin-binding protein A DbpA, decorin-binding protein B DbpB, flagellar filament 41 kDa core protein Fla, base membrane protein A precursor BmpA (immunodominant antigen P39), outer surface 22 kDa lipoprotein precursor (antigen IPLA7), variant surface lipoprotein vlsE (Borrelia, Borrelia infection); botulinum neurotoxins BoNT / A1, BoNT / A2, BoNT / A3, BoNT / B, BoNT / C, BoNT / D, BoNT / E, BoNT / F, BoNT / G, recombinant botulinum toxin F Hc domain FHc (Clostridium botulinum) botulinum), botulism (and infant botulism)); nucleocapsid, glycoprotein precursor (Sabia virus, Brazilian hemorrhagic fever); copper / zinc superoxide dismutase SodC, bacterioferritin Bfr, ​​50S ribosomal protein RplL, OmpA-like transmembrane domain-containing protein Omp31, immunogenic 39-kDa protein M5 P39, zinc ABC transporter periplasmic zinc-binding protein znuA, periplasmic immunogenic protein Bp26, 30S ribosomal protein S12 RpsL, glyceraldehyde-3-phosphate dehydrogenase Gap, 25-kDa outer membrane immunogenic protein precursor Omp25, invasion protein B lalB, trigger factor Tig, molecular chaperone DnaK, putative peptidyl-prolyl cis-trans isomerase SurA, lipoprotein Omp19, outer membrane protein MotY Omp16, conserved outer membrane protein D15, malate dehydrogenase Mdh, type IV secretion apparatus component (T4SS) VirJ, lipoprotein of unknown function BAB1_0187 (Brucella, brucellosis);ABC transporter family members (LolC, OppA, and PotF), putative lipoprotein release system transmembrane protein LolC / E, flagellin FliC, Burkholderia intracellular motility A BimA, bacterial elongation factor Tu EF-Tu, 17 kDa OmpA-like protein, boaA-encoded protein, boaB-encoded protein (Burkholderia cepacia and other Burkholderia species, Burkholderia infections); mycolyltransferase Ag85A, heat shock protein Hsp65, protein TB10.4, 19 kDa antigen, protein PstS3, heat shock protein Hsp70 (Mycobacterium ulcerans) ulcerans, Buruli ulcer); norovirus major and minor virus capsid proteins VP1 and VP2, genome polyprotein; sapovirus capsid protein VP1, protein Vp3, genome polyprotein polyprotein) (family Caliciviridae, calicivirus infections (norovirus and sapovirus)); major outer membrane protein PorA, flagellin FlaA, surface antigen CjaA, fibronectin-binding protein CadF, aspartate / glutamate-binding ABC transporter protein Peb1A, protein FspA1, protein FspA2 (Campylobacter, campylobacteriosis); glycolytic enzyme enolase, secreted aspartyl proteinase SAP1-10, glycophosphatidylinositol (GPI)-linked cell wall protein Hyr1, complement receptor 3-related protein CR3-RP, adhesin Als3p, heat shock protein 90kDa hsp90, cell surface hydrophobic protein CSH (typically Candida albicans and other Candida species, candidiasis);17 kDa antigen, protein P26, trimeric autotransporter adhesin TAA, Bartonella adhesin A BadA, variably expressed outer membrane protein Vomps, protein Pap3, protein HbpA, envelope-associated protease HtrA, protein OMP89, protein GroEL, protein LalB, protein OMP43, dihydrolipoamide succinyltransferase SucB (Bartonella henselae, cat scratch disease); amastigotes surface protein-2, amastigotes-specific surface protein SSP4, cruzipain, trans-sialidase TS, trypomastigotes surface glycoprotein TSA-1, complement regulatory protein CRP-10, protein G4, protein G2, accessory rod protein PAR2, accessory rod component Par1, mucin-associated surface protein MPSP (Trypanosoma cruzi) cruzi), Chagas disease (American trypanosomiasis); envelope glycoproteins (gB, gC, gE, gH, gI, gK, gL) (Varicella-zoster virus (VZV), chickenpox); major outer membrane protein MOMP, putative outer membrane protein PMPC, outer membrane complex protein B OmcB, heat shock protein Hsp60 HSP10, protein IncA, protein from type III secretion apparatus, ribonucleotide reductase small chain protein NrdB, plasmid protein Pgp3, chlamydial outer protein N CopN, antigen CT521, antigen CT425, antigen CT043, antigen TC0052, antigen TC0189, antigen TC0582, antigen TC0660, antigen TC0726, antigen TC0816, antigen TC0828 (Chlamydia trachomatis, chlamydia);Low calcium response protein E LCrE, chlamydial outer protein N CopN, serine / threonine protein kinase PknD, acyl carrier protein S-malonyltransferase FabD, single-stranded DNA binding protein Ssb, major outer membrane protein MOMP, outer membrane protein 2 Omp2, polymorphic membrane protein family (Pmp1, Pmp2, Pmp3, Pmp4, Pmp5, Pmp6, Pmp7, Pmp8, Pmp9, Pmp10, Pmp11, Pmp12, Pmp13, Pmp14, Pmp15, Pmp16, Pmp17, Pmp18, Pmp19, Pmp20, Pmp21) (Chlamydophila pneumoniae, Chlamydophila pneumoniae infection); cholera toxin B CTB, toxin coregulatory pilin A TcpA, toxin coregulatory pilin TcpF, toxin coregulatory pilus biogenesis protein (ptrotein) F TcpF, cholera enterotoxin subunit A, cholera enterotoxin subunit B, heat-stable enterotoxin ST, mannose-sensitive hemagglutinin MSHA, outer membrane protein U porin ompU, porin B protein, polymorphic membrane protein D (Vibrio cholerae, cholera); propionyl-CoA carboxylase PCC, 14-3-3 protein, prohibitin, cysteine ​​protease, glutathione transferase, gelsolin, cathepsin L proteinase CatL, tegument protein 20.8 kDa TP20.8, tegument protein 31.8 kDa TP31.8, lysophosphatidic acid phosphatase LPAP (Clonorchis liver fluke) sinensis), Clonorchiasis); surface protein SLP, glutamate dehydrogenase antigen GDH, toxin A, toxin B, cysteine ​​protease Cwp84, cysteine ​​protease Cwp13; Cysteine ​​protease Cwp19, cell wall protein CwpV, flagellar protein FliC, flagellar protein FliD (Clostridium difficile, Clostridium difficile infection); rhinovirus: capsid proteins VP1, VP2, VP3, VP4; coronavirus: spike protein Protein S, envelope protein E, membrane protein M, nucleocapsid protein N (commonly rhinoviruses and coronaviruses, common cold (acute viral nasopharyngitis; acute coryza)); prion protein Prp (CJD prion, Creutzfeldt-Jakob disease (CJD)); envelope protein Gc, envelope protein Gn, nucleocapsid protein (Crimean-Congo hemorrhagic fever virus, Crimean-Congo hemorrhagic fever (CCHF)); virulence-associated DEAD-box RNA helicase VAD1, galactoxylomannan-protein GalXM, glucuronoxylomannan GXM, mannoprotein MP (Cryptococcus neoformans, cryptococcosis); acidic ribosomal protein P2 (CpP2), mucin antigens Muc1, Muc2, Muc3 Muc4, Muc5, Muc6, Muc7, surface adhesion protein CP20, surface adhesion protein CP23, surface protein CP12, surface protein CP21, surface protein CP40, surface protein CP60, surface protein CP15, surface-associated glycopeptide gp40, surface-associated glycopeptide gp15, oocyst wall protein AB, profilin PRF, apyrase ( Cryptosporidium , cryptosporidiosis);Fatty acid and retinol binding protein-1 FAR-1, tissue metalloproteinase inhibitor TIMP (TMP), cysteine ​​proteinase ACEY-1, cysteine ​​proteinase ACCP-1, surface antigen Ac-16, secreted protein 2 ASP-2, metalloproteinase 1 MTP-1, aspartyl protease inhibitor API-1, surface-associated antigen SAA-1, adult-specific secreted factor Xa serine protease inhibitor anticoagulant AP, cathepsin D-like aspartic protease ARR-1 (usually found in the Brazilian hookworm, Ancylostoma braziliense); several other parasites, cutaneous larva migrans (CLM); cathepsin L-like protease, 53 / 25 kDa antigen, 8 kDa family member, cysticercal protein TsAg5 with limited trypsin-like activity, oncocysticercal protein TSOL18, oncocysticercal protein TSOL45-1A, lactate dehydrogenase A LDHA, lactate dehydrogenase B LDHB (Taenia solium, cysticercosis); pp65 antigen, membrane protein pp15, capsid-proximal tegument protein pp150, protein M45, DNA polymerase UL54, helicase UL105, glycoprotein gM, glycoprotein gN, glycoprotein H, glycoprotein B gB, proteins UL83, UL94, and UL99 (cytomegalovirus (CMV), cytomegalovirus infection); capsid protein C, premembrane protein prM, membrane protein M, envelope protein E (domain I, domain II, domain II), protein NS1, protein NS2A, protein NS2B, protein NS3, protein NS4A, protein 2K, protein NS4B, and protein NS5 (dengue virus (DEN-1, DEN-2, DEN-3, and DEN-4) - flavivirus, dengue fever); 39 kDa protein (Dientamoeba fragilis, dienterate amebiasis);Diphtheria toxin precursor Tox, diphtheria toxin DT, pilin-specific sortase SrtA, shaft pilin protein SpaA, apical pilin protein SpaC, minor pilin protein SpaB, surface-associated protein DIP1281 (Corynebacterium diphtheriae, diphtheria); glycoprotein GP, ​​nucleoprotein NP, minor matrix protein VP24, major matrix protein VP40, transcription activator VP30, polymerase cofactor VP35, RNA polymerase L (Ebola virus (EBOV), Ebola hemorrhagic fever); prion protein (vCJD prion, variant Creutzfeldt-Jakob disease (vCJD, nvCJD)); UvrABC system protein B, protein Flp1, protein Protein Flp2, protein Flp3, protein TadA, hemoglobin receptor HgbA, outer membrane protein TdhA, protein CpsRA, regulator CpxR, protein SapA, 18 kDa antigen, outer membrane protein NcaA, protein LspA, protein LspA1, protein LspA2, protein LspB, outer membrane component DsrA, lectin DltA, lipoprotein Hlp, major outer membrane protein OMP, outer membrane protein OmpA2 (Haemophilus ducreyi) ducreyi, chancroid); aspartyl protease 1 Pep1, phospholipase B PLB, α-mannosidase 1 AMN1, glucanosyltransferase GEL1, urease URE, peroxisomal matrix protein Pmp1, proline-rich antigen Pra, human T-cell reactive protein TcrP (Coccidioides immitis and Coccidioides posadasii, coccidioidomycosis);Allergen Tri r 2, heat shock protein 60 Hsp60, fungal actin Act, antigen Tri r2, antigen Tri r4, antigen Tri t1, protein IV, glycerol-3-phosphate dehydrogenase Gpd1, osmoreceptor HwSho1A, osmoreceptor HwSho1B, histidine kinase HwHhk7B, allergen Mala s 1, allergen Mala s 11, thioredoxin Trx Mala s 13, allergen Mala f, allergen Mala s (usually Trichophyton spp., Epidermophyton spp., Malassezia spp., Hortaea wernekii) werneckii, dermatophytosis); protein EG95, protein EG10, protein EG18, protein EgA31, protein EM18, antigen EPC1, antigen B, antigen 5, protein P29, protein 14-3-3, 8 kDa protein, myophilin, heat shock protein 20 HSP20, glycoprotein GP-89, fatty acid binding protein FAPB (Echinococcus, echinococcosis); major surface protein 2 MSP2, major surface protein 4 MSP4, MSP variant SGV1, MSP variant SGV2, outer membrane protein OMP, outer membrane protein 19 OMP-19, major antigen protein MAP1, major antigen protein MAP1-2, major antigen protein MAP1B, major antigen protein MAP1-3, Erum2510-encoded protein, protein GroEL, protein GroES, 30 kDa major outer membrane protein, GE 100 kDa protein, GE 130 kDa protein, GE 160 kDa protein (Ehrlichia, ehrlichiosis); secretory antigen SagA, sagA-like proteins SalA and SalB, collagen adhesin Scm, surface protein Fms1 (EbpA(fm)), Fms5 (EbpB(fm)), Fms9 (EpbC(fm) and Fms10), protein EbpC(fm), 96 kDa immunoprotective glycoprotein G1 (Enterococcus, enterococcal infections);Genome polyprotein, polymerase 3D, viral capsid protein VP1, viral capsid protein VP2, viral capsid protein VP3, viral capsid protein VP4, protease 2A, protease 3C (Enterovirus, enterovirus infection); outer membrane protein OM, 60 kDa outer membrane protein, cell surface antigen OmpA, cell surface antigen OmpB (sca5), 134 kDa outer membrane protein, 31 kDa outer membrane protein, 29.5 kDa outer membrane protein, cell surface protein SCA4, cell surface protein Adr1 (RP827), cell surface protein Adr2 (RP828), cell surface protein SCA1, entry protein invA, cell division protein fts, secretion protein sec 0 family, virulence proteins virB, tlyA, tlyC, parvulin-like protein Plp, preprotein translocase SecA, 120 kDa surface protein antigen SPA, 138 kD complex antigen, major 100 kD protein (protein I), cytoplasmic protein D, protective surface protein antigen SPA (Rickettsia typhi) prowazekii), typhus); Epstein-Barr nuclear antigens (EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA leader protein (EBNA-LP)), latent membrane proteins (LMP-1, LMP-2A, LMP-2B), early antigen EBV-EA, membrane antigen EBV-MA, viral capsid antigen EBV-VCA, alkaline nuclease EBV-AN, glycoprotein H, glycoprotein gp350, glycoprotein gp110, glycoprotein gp42, glycoprotein gH, glycoprotein gL, glycoprotein gB (Epstein-Barr virus (EBV), Epstein-Barr virus infectious mononucleosis); capsid protein (cpasid protein) VP2, capsid protein VP1, major protein NS1 (parvovirus B19, erythema infectiosum (fifth disease)); pp65 antigen, glycoprotein 105, major capsid protein, envelope glycoprotein H, protein U51 (human herpesvirus type 6 (HHV-6) and human herpesvirus type 7 (HHV-7), exanthem subitum);Thioredoxin-glutathione reductase TGR, cathepsins L1 and L2, Kunitz-type protein KTM, leucine aminopeptidase LAP, cysteine ​​proteinase Fas2, saposin-like protein-2 SAP-2, thioredoxin peroxidase TPx, Prx-1, Prx-2, cathepsin I cysteine ​​proteinase CL3, protease cathepsin L CL1, phosphoglycerate kinase PGK, 27 kDa secretory protein, 60 kDa protein HSP35α, glutathione transferase GST, 28.5 kDa envelope antigen 28.5 kDa TA, cathepsin B3 protease CatB3, type I cystatin stefin-1, cathepsin L5, cathepsin L1g, and cathepsin B, fatty acid-binding protein FABP, leucine aminopeptidase LAP (Fasciola hepatica) hepatica and Fasciola gigantica, fascioliasis); prion protein (FFI prion, fatal familial insomnia (FFI)); venom allergen homolog-like protein VAL-1, abundant larval transcript ALT-1, abundant larval transcript ALT-2, thioredoxin peroxidase TPX, vespid allergen homolog VAH, thiordoxin peroxidase 2 TPX-2, antigenic protein SXP (peptides N, N1, N2, and N3), activation-associated protein-1 ASP-1, thioredoxin TRX, transglutaminase BmTGA, glutathione S-transferase GST, myosin, vespid allergen homolog VAH, 175 kDa collagenase, glycine; Glyceraldehyde-3-phosphate dehydrogenase GAPDH, cuticular collagen Col-4, secretory larval acidic protein SLAP, chitinase CHI-1, maltose-binding protein MBP, glycolytic enzyme fructose-1,6-bisphosphate aldolase Fba, tropomyosin TMY-1, nematode-specific gene product OvB20, onchocystatin CPI-2, Cox-2 (Filarioidea, filariasis); phospholipase C PLC, heat-labile enterotoxin B, iota toxin component Ib, protein CPE1281, pyruvate ferredoxin oxidoreductase, elongation factor G EF-G, perfringolysin O Pfo, glyceraldehyde-3-phosphate dehydrogenase GapC, fructose-bisphosphate aldolase Alf2, Clostridium perfringens perfringens enterotoxin CPE, alpha toxin AT, alpha toxoid ATd, epsilon toxoid ETd, protein HP, large cytotoxin TpeL, endo-β-N-acetylglucosaminidase Naglu, phosphoglycerin mutase Pgm (Clostridium perfringens, food poisoning caused by Clostridium perfringens); leukotoxin lktA, adhesion FadA, outer membrane protein RadD, high molecular weight arginine-binding protein (Fusobacterium, Fusobacterium infection); phospholipase C PLC, heat-labile enterotoxin B, iota toxin component Ib, protein CPE1281, pyruvate ferredoxin oxidoreductase, elongation factor G EF-G, perfringolysin O Pfo, glyceraldehyde-3-phosphate dehydrogenase GapC, fructose bisphosphate aldolase Alf2, Clostridium perfringens enterotoxin CPE, alpha toxin AT, alpha toxoid ATd, epsilon toxoid ETd, protein HP, large cytotoxin TpeL, endo-β-N-acetylglucosaminidase Naglu, phosphoglycerin mutase Pgm (usually Clostridium perfringens; other Clostridium species, gas gangrene (Clostridial myonecrosis));Lipase A, lipase B, peroxidase Dec1 (Geotrichum candidum, geotrichum disease); prion protein (GSS prion, Gerstmann-Straussler-Scheinker syndrome (GSS)); cyst wall proteins CWP1, CWP2, CWP3; variant surface proteins VSP, VSP1, VSP2, VSP3, VSP4, VSP5, VSP6; 56 kDa antigen; pyruvate ferredoxin oxidoreductase PFOR; alcohol dehydrogenase E ADHE, α-giardin, α8-giardin, α1-giardin, β-giardin, cysteine ​​protease, glutathione-S-transferase GST, arginine deiminase ADI, fructose-1,6-bisphosphate aldolase FBA, Giardia trophozoite antigen GTA (GTA1, GTA2), ornithine carboxyltransferase OCT, striated fiber-asseblin-like protein SALP, uridine phosphoryl-like protein UPL, α-tubulin, β-tubulin (Giardia intestinalis, giardiasis); ABC transporter family members (LolC, OppA, and PotF), putative lipoprotein release system transmembrane protein LolC / E, flagellin FliC, Burkholderia intracellular motility A BimA, bacterial elongation factor Tu EF-Tu, a 17 kDa OmpA-like protein, encoding the boaA protein (Burkholderia mallei, glanders); cyclophilin CyP, a 24 kDa third stage larval protein GS24, and excretory-secretory products ESP (40, 80, 120, and 208 kDa) (Gnathostoma spinigerum and Gnathostoma hispidum, gnathostomiasis);Pilin protein, minor pilin-related subunit pilC, major pilin subunit and variants pilE, pilS, phase variant protein porA, porin B PorB, protein TraD, Neisseria outer membrane antigen H.8, 70 kDa antigen, major outer membrane protein PI, outer membrane proteins PlA and PlB, W antigen, surface protein A NspA, transferrin-binding protein TbpA, transferrin-binding protein TbpB, PBP2, mtrR-encoded protein, ponA-encoded protein, membrane permease FbpBC, FbpABC protein system, LbpAB protein, outer membrane protein Opa, outer membrane transporter FetA, iron repressible regulator MpeR (Neisseria gonorrhoeae, gonorrhea); outer membrane protein A OmpA, outer membrane protein C OmpC, outer membrane protein K17 OmpK17 (Klebsiella granulomatis, gonorrhea); granulomatis, inguinal granuloma (Donovanosis); fibronectin-binding protein Sfb, fibronectin / fibrinogen-binding protein FBP54, fibronectin-binding protein FbaA, M-protein type 1 Emm1, M-protein type 6 Emm6, immunoglobulin-binding protein 35 Sib35, surface protein R28 Spr28, superoxide dismutase SOD, C5a peptidase ScpA, antigen I / II AgI / II, adhesin AspA, G-related α2-macroglobulin-binding protein GRAB, surface fibrous protein M5 (Streptococcus pyogenes, group A streptococcal infections);C protein β antigen, arginine deiminase protein, adhesin BibA, 105 kDA protein BPS, surface antigen c, surface antigen R, surface antigen X, trypsin-resistant protein R1, trypsin-resistant protein R3, trypsin-resistant protein R4, surface immunogenic protein Sip, surface protein Rib, leucine-rich repeat protein LrrG, serine-rich repeat protein Srr-2, C protein α-antigen Bca, β-antigen Bag, surface antigen ε, α-like protein ALP1, α-like protein ALP5, surface antigen δ, α-like protein ALP2, α-like protein ALP3, α-like protein ALP4, Cβ-protein Bac (Streptococcus agalactiae, group B streptococcal infections); transferrin-binding protein 2 Tbp2, phosphatase P4, outer membrane protein P6, peptidoglycan-associated lipoprotein Pal, protein D, protein E, adhesion and invasion protein Hap, outer membrane protein 26 Omp26, outer membrane protein P5 (fimbrin), outer membrane protein D15, outer membrane protein OmpP2, 5'-nucleotidase NucA, outer membrane protein P1, outer membrane protein P2, outer membrane lipoprotein Pcp, lipoprotein E, outer membrane protein P4, fuculinase FucK, [Cu,Zn]-superoxide dismutase SodC, protease HtrA, protein O145, α-galactosylceramide (Haemophilus influenzae) influenzae, Haemophilus influenzae infection); polymerase 3D, viral capsid protein VP1, viral capsid protein VP2, viral capsid protein VP3, viral capsid protein VP4, protease 2A, protease 3C (enteroviruses, mainly Coxsackie A virus and enterovirus 71 (EV71), hand, foot, and mouth disease (HFMD)); RNA polymerase L, protein L, glycoprotein Gn, glycoprotein Gc, nucleocapsid protein S, envelope glycoprotein G1, nucleoprotein NP, protein N, polyprotein M (Sin Nombre virus, hantavirus, hantavirus pulmonary syndrome (HPS));Heat shock protein HspA, heat shock protein HspB, citrate synthase GltA, protein UreB, heat shock protein Hsp60, neutrophil-activating protein NAP, catalase KatA, vacuolating cytotoxin VacA, urease α-urea, urease β-Ureb, protein Cpn10, protein groES, heat shock protein Hsp10, protein MopB, cytotoxicity-associated 10 kDa protein CAG, 36 kDa antigen, β-lactamase HcpA, β-lactamase HcpB (Helicobacter pylori, Helicobacter pylori infection); integral membrane protein, aggregation-prone protein, O antigen, toxin antigen Stx2B, toxin antigen Stx1B, adhesion antigen fragment Int28, protein EspA, protein EspB, intimin, protein Tir, protein IntC300, protein Eae (Escherichia coli) coli O157:H7, O111, and O104:H4, hemolytic uremic syndrome (HUS); RNA polymerase L, protein L, glycoprotein Gn, glycoprotein Gc, nucleocapsid protein S, envelope glycoprotein G1, nucleoprotein NP, protein N, polyprotein M (Bunyaviridae, hemorrhagic fever with renal syndrome (HFRS)); glycoprotein G, matrix protein M, nucleoprotein N, fusion protein F, polymerase L, protein W, protein C, phosphoprotein p, nonstructural protein V (Henipavirus (Hendra virus, Nipah virus), Henipavirus infection); polyprotein, glycoprotein Gp2, hepatitis A surface antigen HBAg, protein 2A, viral protein VP1, viral protein VP2, viral protein VP3, viral protein VP4, protein P1B, protein P2A, protein P3AB, protein P3D (hepatitis A virus, Hepatitis A);Hepatitis B surface antigen HBsAg, hepatitis B core antigen HbcAg, polymerase, protein Hbx, preS2 middle surface protein, surface protein L, large S protein, viral protein VP1, viral protein VP2, viral protein VP3, viral protein VP4 (hepatitis B virus (HBV), hepatitis B); envelope glycoproteins E1 gp32 gp35, envelope glycoproteins E2 NS1 gp68 gp70, capsid protein C, core protein Core, polyprotein, viral protein VP1, viral protein VP2, viral protein VP3, viral protein VP4, antigen G, protein NS3, protein NS5A (hepatitis C virus, hepatitis C); viral protein VP1, viral protein VP2, viral protein VP3, viral protein VP4, large hepatitis delta antigen (hepaptitis delta antigen), small hepatitis delta antigen (hepaptitis delta antigen) (hepatitis D virus, hepatitis D); viral protein VP1, viral protein VP2, viral protein VP3, viral protein VP4, capsid protein E2 (hepatitis E virus, hepatitis E); glycoprotein L UL1, uracil-DNA glycosylase UL2, protein UL3, protein UL4, DNA replication protein UL5, portal protein UL6, virion maturation protein UL7, DNA helicase UL8, replication origin binding protein UL9, glycoprotein M UL10, protein UL11, alkaline exonuclease UL12, serine-threonine protein kinase UL13, tegument protein UL14; , terminase UL15, tegument protein UL16, protein UL17, capsid protein VP23 UL18, major capsid protein VP5 UL19, membrane protein UL20, tegument protein UL21, glycoprotein H (UL22), thymidine kinase UL23, protein UL24, protein UL25, capsid protein P40 (UL26, VP24, VP22A), glycoprotein B (UL27), ICP18.5 protein (UL28), major DNA-binding protein ICP8 (UL29), DNA polymerase UL30, nuclear matrix protein UL31, envelope glycoprotein UL32, protein UL33, inner nuclear membrane protein U L34, capsid protein VP26 (UL35), large tegument protein UL36, capsid assembly protein UL37, VP19C protein (UL38), ribonucleotide reductase (large subunit) UL39, ribonucleotide reductase (small subunit) UL40, tegument protein / virion host shutoff VHS protein (UL41), DNA polymerase processivity factor UL42, membrane protein UL43, glycoprotein C (UL44), membrane protein UL45, tegmen tegument protein VP11 / 12 (UL46), tegument protein VP13 / 14 (UL47), virion maturation protein VP16 (UL48, α-TIF), envelope protein UL49, dUTP diphosphatase UL50, tegument protein UL51, DNA helicase / primase complex protein UL52, glycoprotein K (UL53), transcriptional regulatory protein IE63 (ICP27, UL54), protein UL55, protein UL56, viral replication protein ICP22 (IE68, U S1), protein US2, serine / threonine protein kinase US3, glycoprotein G (US4), glycoprotein J (US5), glycoprotein D (US6), glycoprotein I (US7), glycoprotein E (US8), tegument protein US9, capsid / tegument protein US10, Vmw21 protein (US11), ICP47 protein (IE12, US12), major transcriptional activator ICP4 (IE175, RS1), E3 ubiquitin ligase ICP0 (IE110), and latency-associated protein 1.LRP1, latency-associated protein 2; LRP2, neurovirulence factor RL1 (ICP34.5), latency-associated transcript LAT (herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), herpes simplex); heat shock protein Hsp60, cell surface protein H1C, dipeptidyl peptidase type IV DppIV, M antigen, 70 kDa protein, 17 kDa histone-like protein (Histoplasma capsulatum, histoplasmosis); fatty acid and retinol binding protein-1 FAR-1, tissue inhibitor of metalloproteinase (TIMP), cysteine ​​proteinase ACEY-1, cysteine ​​proteinase ACCP-1, surface antigen Ac-16, secretory protein 2 ASP-2, metalloproteinase 1 MTP-1, aspartyl protease inhibitor API-1, surface-associated antigen SAA-1, surface-associated antigen SAA-2, adult-specific secretory factor Xa, serine protease inhibitor anticoagulant AP, cathepsin D-like aspartic protease ARR-1, glutathione S-transferase GST, aspartic protease APR-1, acetylcholinesterase AChE (from Ancylostoma duodenale and Necator americanus, hookworm infection); protein NS1, protein NP1, protein VP1, protein VP2, protein VP3 (human bocavirus (HBoV), human bocavirus infection); major surface protein 2 MSP2, major surface protein 4 MSP4, MSP variant SGV1, MSP variant SGV2, outer membrane protein OMP, outer membrane protein 19 OMP-19, major antigen protein MAP1, major antigen protein MAP1-2, major antigen protein MAP1B, major antigen protein MAP1-3, Erum2510-encoded protein, protein GroEL, protein GroES, 30 kDA major outer membrane protein, GE 100 kDa protein, GE 130 kDa protein, GE 160 kDa protein (Ehrlichia ewingii, human ewingii ehrlichiosis)ehrlichiosis); major surface proteins 1-5 (MSP1a, MSP1b, MSP2, MSP3, MSP4, MSP5), type IV secretion system proteins VirB2, VirB7, VirB11, VirD4 (Anaplasma phagocytophilum, human granulocytic anaplasmosis (HGA)); protein NS1, small hydrophobic protein NS2, SH protein, fusion protein F, glycoprotein G, matrix protein M, matrix protein M2-1, matrix protein M2-2, phosphoprotein P, nucleoprotein N, polymerase L (human metapneumovirus (hMPV), human metapneumovirus infection); major surface protein 2 MSP2, major surface protein 4 MSP4, MSP variant SGV1, MSP variant SGV2, outer membrane protein OMP, outer membrane protein 19 OMP-19, major antigen protein MAP1, major antigen protein MAP1-2, major antigen protein MAP1B, major antigen protein MAP1-3, Erum2510-encoded protein, protein GroEL, protein GroES, 30 kDA major outer membrane protein, GE 100 kDa protein, GE 130 kDa protein, GE 160 kDa protein (Ehrlichia chaffeensis)chaffeensis, human monocytic ehrlichiosis); replication protein E1, regulatory protein E2, protein E3, protein E4, protein E5, protein E6, protein E7, protein E8, major capsid protein L1, minor capsid protein L2 (human papillomavirus (HPV), human papillomavirus (HPV) infection); fusion protein F, hemagglutinin-neuraminidase HN, glycoprotein G, matrix protein M, phosphoprotein P, nucleoprotein N, polymerase L (human parainfluenza virus (HPIV), human parainfluenza virus infection); hemagglutinin (HA), neuraminidase nucleoprotein (NP), M1 protein, M2 protein, NS1 protein, NS2 protein (NEP protein: nuclear export protein), PA protein, PB1 protein (polymerase basic 1 protein), PB1-F2 protein, and PB2 protein (Orthomyxoviridae, influenza virus (flu)); genome polyprotein, protein E, protein M, capsid protein C (Japanese encephalitis virus, JE); RTX toxin, type IV pilus, major pilus subunit PilA, regulatory transcription factors PilS and PilR, protein sigma 54, outer membrane protein (Kingella kingae) kingae, Kingella kingae infection); prion protein (kuru prion, kuru); nucleoprotein N, polymerase L, matrix protein Z, glycoprotein GP (Lassa virus, Lassa fever); peptidoglycan-associated lipoprotein PAL, 60 kDa chaperonin Cpn60 (groEL, HspB), type IV pilin PilE, outer membrane protein MIP, major outer membrane protein Momps, zinc metalloproteinase MSP (Legionella pneumophila, Legionnaires' disease, Pontiac fever); P4 nuclease, protein WD, ribonucleotide reductase M2, surface membrane glycoprotein Pg46, cysteine ​​proteinase CP, glucose-regulated protein 78GRP-78, stage-specific S antigen-like protein A2, ATPase F1, β-tubulin, heat shock protein 70 Hsp70, KMP-11, glycoprotein GP63, protein BT1, nucleoside hydrolase NH, cell surface protein B1, ribosomal protein P1-like protein P1, sterol 24-c-methyltransferase SMT, LACK protein, histone H1, SPB1 protein, thiol-specific antioxidant TSA, protein antigen STl1, signal peptidase SP, histone H2B, surface antigen PSA-2, cysteine ​​proteinase b Cpb (Leishmania, leishmaniasis); major membrane protein I, serine-rich antigen-45 kDa, 10 kDa caperonin GroES, HSP kDa antigen, aminooxononanoic acid synthase AONS, protein recombinase A RecA, acetyl-coenzyme A / propionyl-coenzyme A carboxylase α, alanine racemase, 60 kDa chaperonin 2, ESAT-6-like protein EcxB (L-ESAT-6), protein Lsr2, protein ML0276, heparin-binding hemagglutinin HBHA, heat shock protein 65 Hsp65, mycP1 or ML0041-encoded protein, htrA2 or ML0176-encoded protein, htrA4 or ML2659-encoded protein, gcp or ML0379-encoded protein, clpC or ML0235-encoded protein (Mycobacterium leprae and Mycobacterium lepromatosis) lepromatosis); outer membrane protein LipL32, membrane protein LIC10258, membrane protein LP30, membrane protein LIC12238, Ompa-like protein Lsa66, surface protein LigA, surface protein LigB, major outer membrane protein OmpL1, outer membrane protein LipL41, protein LigAni, surface protein LcpA, adhesion protein LipL53, outer membrane protein UpL32, surface protein Lsa63, flagellin FlaB1, membrane lipoprotein (membranelipoprotein LipL21, membrane protein pL40, leptospiral surface adhesin Lsa27, outer membrane protein OmpL36, outer membrane protein OmpL37, outer membrane protein OmpL47, outer membrane protein OmpL54, acyltransferase LpxA (Leptospira, leptospirosis); listeriolysin O precursor Hly (LLO), invasion-associated protein Iap (P60), listeriolysin regulatory protein PrfA, zinc metalloproteinase Mpl, phosphatidylinositol-specific phospholipase C PLC (PlcA, PlcB), O-acetyltransferase Oat, ABC transporter permease Im.G_1771, adhesion protein LAP, LAP receptor Hsp60, adhesin LapB, hemolysin listeriolysin OLLO, protein ActA, internalin A InlA, protein lnlB (Listeria monocytogenes) monocytogenes), listeriosis); cell surface protein A OspA, cell surface protein OspB, cell surface protein OspC, decorin-binding protein A DbpA, decorin-binding protein B DbpB, flagellar filament 41 kDa core protein Fla, base membrane protein A BmpA (immunodominant antigen P39), outer surface 22 kDa lipoprotein precursor (antigen IPLA7), variant surface lipoprotein vlsE (usually found in Borrelia burgdorferi (Bo Borrelia burgdorferi and other Borrelia species, Lyme disease (Lyme borreliosis); venom allergen homolog-like protein VAL-1, abundant larval transcript ALT-1, abundant larval transcript ALT-2, thioredoxin peroxidase TPX, hornet allergen homolog VAH, thiordoxin peroxidase 2 TPX-2, antigenic protein SXP (peptides N, N1, N2, and N3), activation-associated protein-1 ASP-1, thioredoxin TRX, transglutaminase BmTGA, glutathione-S-transferase GST, myosin, vespid allergen homolog VAH, 175 kDa collagenase, glyceraldehyde-3-phosphate dehydrogenase GAPDH, cuticular collagen Col-4, secretory larval acidic protein SLAP, chitinase CHI-1, maltose-binding protein MBP, glycolytic enzyme fructose-1,6-bisphosphate aldolase Fba, tropomyosin TMY-1, nematode-specific gene product OvB20, onchocystatin CPI-2, protein Cox-2 (Wuchereria bancrofti and Brugia malayi) malayi), lymphatic filariasis (elephantiasis); glycoprotein GP, ​​matrix protein Z, polymerase L, nucleoprotein N (lymphocytic choriomeningitis virus (LCMV), lymphocytic choriomeningitis);Thrombospondin-related anonymous protein TRAP, SSP2 sporozoite surface protein 2, apical membrane antigen 1 AMA1, rhoptry membrane antigen RMA1, acidic-basic repeat antigen ABRA, traversing cell protein PF, protein Pvs25, merozoite surface protein 1 MSP-1, merozoite surface protein 2 MSP-2, ring body infected erythrocyte surface antigen RESA, liver stage antigen 3 LSA-3, protein Eba-175, serine repeat antigen 5 SERA-5, circumsporozoite protein CS, merozoite surface protein 3 MSP3, merozoite surface protein 8 MSP8, enolase PF10, hepatocyte erythrocyte protein 17 kDa HEP17, erythrocyte membrane protein 1 EMP1, protein Kβ merozoite surface protein 4 / 5 MSP4 / 5, heat shock protein Hsp90, glutamate-rich protein GLURP, merozoite surface protein 4 MSP-4, protein STARP, circumsporozoite protein-related antigen precursor CRA (Plasmodium, malaria); nucleoprotein N, membrane-associated protein VP24, minor nucleoprotein VP30, polymerase cofactor VP35, polymerase L, matrix protein VP40, envelope glycoprotein GP (Marburg virus, Marburg fever (MHF)); protein C, matrix protein M, phosphoprotein P, nonstructural protein V, hemagglutinin glycoprotein H, polymerase L, nucleoprotein N, fusion protein F (measles virus, measles); ABC transporter family members (LolC, OppA, and PotF), putative lipoprotein release system transmembrane protein LolC / E, flagellin FliC, Burkholderia intracellular motility A BimA, bacterial elongation factor Tu EF-Tu, 17 kDa OmpA-like protein, boaA-encoded protein, boaB-encoded protein (Burkholderia pseudomallei), melioidosis (Whitmoor's disease);Pilin protein, minor pilin-related subunit pilC, major pilin subunit and variants pilE, pilS, phase variant protein porA, porin B PorB, protein TraD, Neisseria outer membrane antigen H.8, 70 kDa antigen, major outer membrane protein PI, outer membrane proteins PlA and PlB, W antigen, surface protein A NspA, transferrin-binding protein TbpA, transferrin-binding protein TbpB, PBP2, mtrR-encoded protein, ponA-encoded protein, membrane permease FbpBC, FbpABC protein system, LbpAB protein, outer membrane protein Opa, outer membrane transporter FetA, iron repression regulator MpeR, factor H-binding protein fHbp, adhesin NadA, protein NhbA, repressor FarR (Neisseria meningitidis, meningococcal disease); 66 kDa protein, 22 kDa protein (usually Metagonimus yokagawai, Metagonimia); Polar tube proteins (34, 75, and 170 kDa in Glugea, 35, 55, and 150 kDa in Encephalitozoon), Kinesin-related proteins, RNA polymerase II largest subunit, similar to integral membrane protein YIPA, anti-silencing protein 1, heat shock transcription factor HSF, protein kinase, thymidine kinase, NOP-2-like nucleolar protein (Microsporidia, Microsporidia); CASP8 and FADD-like apoptosis regulator, glutathione peroxidase GPX1, RNA helicase NPH-II NPH2, poly(A) polymerase catalytic subunit PAPL, major envelope protein P43K, early transcription factor 70 kDa subunit VETFS, early transcription factor 82 kDa subunit VETFL, metalloendopeptidase type G1, nucleoside triphosphatase I NPH1, replication protein A28-like MC134L, RNA polymerase 7 kDa subunit RPO7 (molluscum contagiosum virus (MCV), molluscum contagiosum (MC));Matrix protein M, phosphoprotein P / V, small hydrophobic protein SH, nucleoprotein N, protein V, fusion glycoprotein F, hemagglutinin-neuraminidase HN, RNA polymerase L (mumps virus, mumps); outer membrane protein OM, cell surface antigen OmpA, cell surface antigen OmpB (sca5), cell surface protein SCA4, cell surface protein SCA1, cytoplasmic protein D, crystalline surface protein SLP, protective surface protein antigen SPA (Rickettsia typhi, Murine typhus); adhesin P1, adhesin P30, protein p116, protein P40, cytoskeletal protein HMW1, cytoskeletal protein HMW2, cytoskeletal protein HMW3, MPN152-encoded protein, MPN426-encoded protein, MPN456-encoded protein, MPN-500-encoded protein (Mycoplasma pneumoniae) pneumoniae, Mycoplasma pneumoniae); NocA, iron-dependent regulatory protein; VapA, VapD, VapF, VapG, caseinolytic proteases, filament tip-associated 43 kDa protein, protein P24, protein P61, 15 kDa protein, 56 kDa protein (usually Nocardia asteroides and other Nocardia species, nocardiosis);Venom allergen homolog-like protein VAL-1, abundant larval transcript ALT-1, abundant larval transcript ALT-2, thioredoxin peroxidase TPX, hornet allergen homolog VAH, thiordoxin peroxidase 2 TPX-2, antigen protein SXP (peptides N, N1, N2, and N3), activation-associated protein-1 ASP-1, thioredoxin TRX, transglutaminase BmTGA, glutathione-S-transferase GST, myosin, vespid allergen homolog VAH, 175 kDa collagenase, glyceraldehyde-3-phosphate dehydrogenase GAPDH, cuticular collagen Col-4, secretory larval acidic protein SLAP, chitinase CHI-1, maltose-binding protein MBP, glycolytic enzyme fructose-1,6-bisphosphate aldolase Fba, tropomyosin TMY-1, nematode-specific gene product OvB20, onchocystatin CPI-2, Cox-2 (Onchocerca volvulus) volvulus, onchocerciasis (river blindness); 43 kDa secreted glycoprotein, glycoprotein gp0, glycoprotein gp75, antigen Pb27, antigen Pb40, heat shock protein Hsp65, heat shock protein Hsp70, heat shock protein Hsp90, protein P10, triosephosphate isomerase TPI, N-acetylglucosamine-binding lectin paracoccin, 28 kDa protein Pb28 (Paracoccidioides brasiliensis, paracoccidioidomycosis (South American blastomycosis)); 28 kDa cruzipain-like cysteine ​​protease Pw28CCP (typically Paragonimus westermani and other Paragonimus species, paragonimiasis);Outer membrane protein OmpH, outer membrane protein Omp28, protein PM1539, protein PM0355, protein PM1417, repair protein MutL, protein BcbC, protein (prtein) PM0305, formate dehydrogenase-N, protein PM0698, protein PM1422, DNA gyrase, lipoprotein PlpE, adhesion protein Cp39, heme acquisition system receptor HasR, 39 kDa coat protein, iron-regulated OMP IROMP, outer membrane protein OmpA87, pilus protein Ptf, pilus subunit protein PtfA, transferrin-binding protein Tbpl, esterase enzyme MesA, Pasteurella multocida multocida toxin PMT, adhesive protein Cp39 (Pasteurella, pasteurellosis); filamentous hemagglutinin FhaB, adenylate cyclase CyaA, pertussis toxin subunit 4 precursor PtxD, pertactin precursor Prn, toxin subunit 1 PtxA, protein Cpn60, protein brkA, pertussis toxin subunit 2 precursor PtxB, pertussis toxin subunit 3 precursor PtxC, pertussis toxin subunit 5 precursor PtxE, pertactin Prn, protein Fim2, protein Fim3; (Bordetella pertussis, pertussis (whooping cough));"F1 capsule antigen, virulence-associated V antigen, secreted effector protein LcrV, V antigen, outer membrane protease Pla, secreted effector protein YopD, putative secreted protein-tyrosine phosphatase Yoph, needle complex major subunit YscF, protein kinase YopO, putative autotransporter protein YapF, inner membrane ABC transporter YbtQ (Irp7), putative carbohydrate-binding protein YPO0612, heat shock protein 90 HtpG, putative sulfatase protein YdeN, outer membrane lipoprotein carrier protein LolA, secretion chaperone YerA, putative lipoprotein YPO0420, hemolysin activator protein HpmB, pesticin / yersiniabactin outer membrane receptor Psn, secreted effector protein YopE, secreted effector protein YopF, secreted effector protein YopK, outer membrane protein YopN, outer membrane protein YopM, coagulase / fibrinolysin precursor Pla;” (Yersinia pestis, plague); protein PhpA, surface adhesin PsaA; pneumolysin Ply, ATP-dependent protease Clp, lipoic acid-protein ligase; LplA, cell wall surface anchor protein psrP, sortase SrtA, glutamyl-tRNA synthetase GltX, choline-binding protein A CbpA, pneumococcal surface protein A PspA, pneumococcal surface protein C PspC, 6-phosphogluconate dehydrogenase Gnd, iron-binding protein PiaA, murein hydrolase LytB, protein LytC, protease A1 (Streptococcus pneumoniae, pneumococcal infection); major surface protein B, kexin-like protease KEX1, protein A12, 55 kDa antigen P55, major surface glycoprotein Msg (Pneumocystis jirovecii) jirovecii, Pneumocystis pneumonia (PCP); genome polyprotein, polymerase 3D, viral capsid protein VP1, viral capsid protein VP2, viral capsid protein VP3, viral capsid protein VP4, protease 2A, protease 3C (poliovirus, poliomyelitis); protein Nfa1, exendin-3, secretory lipase, cathepsin B-like protease, cysteine ​​protease, cathepsin, peroxiredoxin, protein Cry1Ac (typically, Naegleria fowleri, primary amebic meningoencephalitis (PAM)); agnoprotein, large T antigen, small T antigen, major capsid protein VP1, minor capsid protein Vp2 (JC virus, progressive multifocal leukoencephalopathy); low calcium response protein E, LCrE, chlamydial outer protein N CopN, serine / threonine protein kinase PknD, acyl carrier protein S-malonyltransferase FabD, single-stranded DNA binding protein Ssb, major outer membrane protein MOMP, outer membrane protein 2 Omp2, polymorphic membrane protein family (Pmp1, Pmp2, Pmp3, Pmp4, Pmp5, Pmp6, Pmp7, Pmp8, Pmp9, Pmp10, Pmp11, Pmp12, Pmp13, Pmp14, Pmp15, Pmp16, Pmp17, Pmp18, Pmp19, Pmp20, Pmp21) (Chlamydophila psittaci, psittacosis);Outer membrane protein P1, heat shock protein B HspB, peptide ABC transporter, GTP-binding protein, protein IcmB, ribonuclease R, phosphatase SixA, protein DsbD, outer membrane protein TolC, DNA-binding protein PhoB, ATPase DotB, heat shock protein B HspB, membrane protein Com1, 28 kDa protein, DNA-3-methyladenine glycosidase I, outer membrane protein OmpH, outer membrane protein AdaA, glycine cleavage system T protein (Q), Coxiella burnetii, Q fever); nucleoprotein N, large structural protein L, phophoprotein P, matrix protein M, glycoprotein G (rabies virus, rabies); fusion protein F, nucleoprotein N, matrix protein M, matrix protein M2-1, matrix protein M2-2, phophoprotein P, small hydrophobic protein SH, major surface glycoprotein G, polymerase L, nonstructural protein 1 NS1, nonstructural protein 2 NS2 (respiratory syncytial virus (RSV), respiratory syncytial virus infection); genome polyprotein, polymerase 3D, viral capsid protein VP1, viral capsid protein VP2, viral capsid protein VP3, viral capsid protein VP4, protease 2A, protease 3C (rhinovirus, rhinovirus infection); outer membrane protein OM, cell surface antigen OmpA, cell surface antigen OmpB (sca5), cell surface protein SCA4, cell surface protein SCA1, protein PS120, cytoplasmic protein D, protective surface protein antigen SPA (Rickettsia, rickettsial infection); outer membrane protein OM, cell surface antigen OmpA, cell surface antigen OmpB (sca5), cell surface protein SCA4, cell surface protein SCA1, cytoplasmic protein D (Rickettsia akari), rickettsialpox); envelope glycoprotein GP, ​​polymerase L, nucleoprotein N, nonstructural protein NSS (Rift Valley fever virus, Rift Valley fever (RVF));Outer membrane protein OM, cell surface antigen OmpA, cell surface antigen OmpB (sca5), cell surface protein SCA4, cell surface protein SCA1, cytoplasmic protein D (Rickettsia rickettsii, Rocky Mountain spotted fever (RMSF)); nonstructural protein 6 NS6, nonstructural protein 2 NS2, middle capsid protein VP6, inner capsid protein VP2, nonstructural protein 3 NS3, RNA-specific RNA polymerase L, protein VP3, nonstructural protein 1 NS1, nonstructural protein 5 NS5, outer capsid glycoprotein VP7, nonstructural glycoprotein 4 NS4, outer capsid protein VP4; (rotavirus, rotavirus infection); polyprotein P200, glycoprotein E1, glycoprotein E2, protein NS2, capsid protein C (rubella virus, rubella); chaperonin GroEL (MopA), inositol phosphate phosphatase SopB, heat shock protein HslU, chaperone protein DnaJ, protein TviB, protein iron, flagellin FliC, entry protein SipC, glycoprotein gp43, outer membrane protein LamB, outer membrane protein PagC, outer membrane protein TolC, outer membrane protein NmpC, outer membrane protein FadL, transport protein SadA, transferase WgaP , effector proteins SifA, SteC, SseL, SseJ, and SseF (Salmonella, salmonellosis); protein 14, nonstructural protein NS7b, nonstructural protein NS8a, protein 9b, protein 3a, nucleoprotein N, nonstructural protein NS3b, nonstructural protein NS6, protein 7a, nonstructural protein NS8b, membrane protein M, envelope small membrane protein EsM, replicase polyprotein 1a, spike glycoprotein S, replicase polyprotein 1ab; SARS coronavirus, SARS (severe acute respiratory syndrome); serine protease, atypical Sarcoptes antigen 1 ASA1, glutathione S-transferase GST, cysteine ​​protease, serine protease, apolipoprotein (Sarcoptes scabiei, scabies);Glutathione S-transferase GST, paramyosin, hemoglubinase SM32, major egg antigen, 14 kDa fatty acid-binding protein Sm14, major larval surface antigen P37, 22.6 kDa tegument antigen, calpain CANP, triphospate isomerase Tim, surface protein 9B, outer capsid protein VP2, 23 kDa integral membrane protein Sm23, Cu / Zn-superoxide dismutase, glycoprotein Gp, myosin (Schistosoma, Schistosomiasis haematobium); 60 kDa chaperonin, 56 kDa type-specific antigen, pyruvate phosphate dikinase, 4-hydroxybenzoate octaprenyltransferase (Rickettsia tsutsugamushi) tsutsugamushi, scrub typhus); dehydrogenase GuaB, invasion protein Spa32, invasin IpaA, invasin IpaB, invasin IpaC, invasin IpaD, invasin IpaH, invasin IpaJ (Shigella, shigellosis (bacillary dysentery)); protein P53, virion protein US10 homolog, transcriptional regulator IE63, transcriptional transactivator IE62, protease P33, alpha transinducer 74 kDa protein, deoxyuridine 5'-triphosphate nucleotidyl hydrolase, transcriptional transactivator IE4, membrane protein UL43 homolog, nuclear phosphoprotein UL3 homolog, nuclear protein UL4 homolog, origin binding protein, membrane protein 2, phosphoprotein 32, protein 57, DNA polymerase processivity factor, portal protein 54, DNA primase, tegument protein UL14 homolog, tegument protein UL21 homolog, tegument protein UL55 homolog, tripartite terminase subunit UL33 homolog, tripartite terminase subunit UL15 homolog, capsid binding protein 44, virion packaging protein 43 (varicella-zoster virus (VZV), varicella zoster (herpes zoster));Truncated 3-β-hydroxy-5-enesteroid dehydrogenase homolog, virion membrane protein A13, protein A19, protein A31, truncated protein A35 homolog, protein A37.5 homolog, protein A47, protein A49, protein A51, semaphorin-like protein A43, serine proteinase inhibitor 1, serine proteinase inhibitor 2, serine proteinase inhibitor 3, protein A6, protein B15, protein C1, protein C5, protein C6, protein F7, protein F8, protein F9, protein F11, protein F14, protein F15, protein F16 (variola major or minor, smallpox); adhesin / glycoprotein gp70, protease (Sporothrix schenckii) schenckii, sporotrichosis); heme-iron-binding protein IsdB, collagen adhesin Cna, clumping factor A ClfA, protein MecA, fibronectin-binding protein A FnbA, enterotoxin type A EntA, enterotoxin type B EntB, enterotoxin type C EntC1, enterotoxin type C EntC2, enterotoxin type D EntD, enterotoxin type E EntE, toxic shock syndrome toxin-1 TSST-1, staphylokinase, penicillin-binding protein 2a PBP2a (MecA), secretory antigen SssA (Staphylococcus, staphylococcal food poisoning); heme-iron-binding protein IsdB, collagen adhesin Cna, clumping factor A ClfA, protein MecA, fibronectin-binding protein A FnbA, enterotoxin type A EntA, enterotoxin type B EntB, enterotoxin type C EntC1, enterotoxin type C EntC2, enterotoxin type D EntD, enterotoxin type E EntE, toxic shock syndrome toxin-1 TSST-1, staphylokinase, penicillin-binding protein 2a PBP2a (MecA), secreted antigen SssA (Staphylococcus, e.g., Staphylococcus aureus, staphylococcal infections);Antigen Ss-IR, antigen NIE, strongylastacin, Na+-K+ATPase Sseat-6, tropomysin SsTmy-1, protein LEC-5, 41kDa antigen P5, 41kDa larval protein, 31kDa larval protein, 28kDa larval protein (Strongyloides stercoralis, strongyloidiasis); glycerophosphodiester phosphodiesterase GlpQ (Gpd), outer membrane protein TmpB, protein Tp92, antigen TpF1, repeat protein Tpr, lipid; Repeat protein F TprF, repeat protein G TprG, repeat protein I TprI, repeat protein J TprJ, repeat protein K TprK, treponemal membrane protein A TmpA, lipoprotein, 15 kDa Tpp15, 47 kDa membrane antigen, miniferritin TpF1, adhesin Tp0751, lipoprotein TP0136, protein TpN17, protein TpN47, outer membrane protein TP0136, outer membrane protein TP0155, outer membrane protein TP0326, outer membrane protein TP0483, outer membrane protein TP0956 (Treponema pallidum) pallidum, syphilis); cathepsin L-like protease, 53 / 25 kDa antigen, 8 kDa family member, cysticercal protein TsAg5 with limited trypsin-like activity, oncophora protein TSOL18, oncophora protein TSOL45-1A, lactate dehydrogenase A LDHA, lactate dehydrogenase B LDHB (Taenia, cestode disease); tetanus toxin TetX, tetanus toxin C TTC, 140 kDa S-layer protein, flavoprotein β-subunit CT3, phospholipase (lecithinase), phosphocarrier protein HPr (Clostridium tetani) tetani), tetanus (tetanus emergency); genomic polyprotein, protein E, protein M, capsid protein C (tick-borne encephalitis virus (TBEV), tick-borne encephalitis); 58 kDa antigen, 68 kDa antigen, Toxocara larvae excretory-secretory antigen TES, 32 kDa glycoprotein, glycoprotein TES-70, glycoprotein GP31, excretory-secretory antigen TcES-57, periintestinal fluid antigen Pe, soluble extract antigen Ex, excretory / secretory larval antigen ES, antigen TES-120, polyprotein allergen TBA-1, cathepsin L-like cysteine ​​protease c-cpl-1, 26 kDa protein (Toxocara canis or Toxocara cati, toxocariasis (ocular larva migrans (OLM) and visceral larva migrans (VLM)));Microneme proteins (MIC1, MIC2, MIC3, MIC4, MIC5, MIC6, MIC7, MIC8), rhoptry protein Rop2, rhoptry proteins (Rop1, Rop2, Rop3, Rop4, Rop5, Rop6, Rop7, Rop16, Rjop17), protein SR1, surface antigen P22, major antigen p24, major surface antigen p30, dense granule proteins (GRA1, GRA2, GRA3, GRA4, GRA5, GRA6, GRA7, GRA8, GRA9, GRA10), 28 kDa antigen, surface antigen SAG1, SAG2-related antigen, nucleoside triphosphatase 1, nucleoside triphosphatase 2, protein Stt3, HesB-like domain-containing protein, rhomboid-like protease 5, toxomepsin 1 (Toxoplasma gondii) gondii, toxoplasmosis); 43 kDa secreted glycoprotein, 53 kDa secreted glycoprotein, paramyosin, antigen Ts21, antigen Ts87, antigen p46000, TSL-1 antigen, caveolin-1 CAV-1, 49 kDa newborn larval antigen, prosaposin homolog, serine protease, serine proteinase inhibitor, 45 kDa glycoprotein Gp45 (Trichinella spiralis, trichinellosis); Myb-like transcription factors (Myb1, Myb2, Myb3), adhesion protein AP23, adhesion protein AP33, adhesin protein AP33-3, adhesin AP51, adhesin AP65, adhesion protein AP65-1, α-actinin, kinesin-related protein, teneurin, 62 kDa proteinase, subtilisin-like serine protease SUB1, cysteine ​​proteinase gene 3 CP3, α-enolase Eno1, cysteine ​​proteinase CP30, heat shock proteins (Hsp70, Hsp60), immunogenic protein P270 (Trichomonas vaginalis, trichomoniasis); β-tubulin, 47 kDa protein, secretory leukocyte-like proteinase-1 SLP-1, 50 kDa protein TT50, 17 kDa antigen, 43 / 47 kDa protein (Trichuris trichiura, trichuriasis (whipworm infection));Protein ESAT-6 (EsxA), 10 kDa filtrate antigen EsxB, secretory antigen 85-B FBPB, fibronectin-binding protein A FbpA (Ag85A), serine protease PepA, PPE family protein PPE18, fibronectin-binding protein D FbpD, immunogenic protein MPT64, secretory protein MPT51, catalase-peroxidase peroxynitritase T KATG, periplasmic phosphate-binding lipoprotein PSTS3 (PBP-3, Phos-1), iron-regulated heparin-binding hemagglutinin Hbha, PPE family protein PPE14, PPE family protein PPE68, protein Mtb72F, protein Apa, immunogenic protein MPT63, periplasmic phosphate-binding lipoprotein PSTS1 (PBP-1), molecular chaperone DnaK, cell surface lipoprotein Mpt83, lipoprotein P23, phosphate transport system permease protein pstA, 14 kDa antigen, fibronectin-binding protein C FbpC1, alanine dehydrogenase TB43, glutamine synthetase 1, ESX-1 protein, protein CFP10, TB10.4 protein, protein MPT83, protein MTB12, protein MTB8, Rpf-like protein, protein MTB32, protein MTB39, crystallin, heat shock protein HSP65, protein PST-S (usually found in Mycobacterium tuberculosis) tuberculosis, tuberculosis); outer membrane protein FobA, outer membrane protein FobB, intracellular growth locus lglC1, intracellular growth locus IglC2, aminotransferase Wbtl, chaperonin GroEL, 17 kDa major membrane protein TUL4, lipoprotein LpnA, chitinase family 18 protein, isocitrate dehydrogenase, Nif3 family protein, type IV fimbria glycosylation protein, outer membrane protein tolC, FAD-binding family protein, type IV fimbria multimeric outer membrane protein, two-component sensor protein KdpD, chaperone protein DnaK, protein TolQ (Francisella tularensis, tularemia);"MB antigen, urease, protein GyrA, protein GyrB, protein ParC, protein ParE, lipid-associated membrane protein LAMP, thymidine kinase TK, phospholipase PL-A1, phospholipase PL-A2, phospholipase PL-C, surface-expressed 96 kDa antigen;" (Ureaplasma urealyticum urealyticum, Ureaplasma urealyticum infection); nonstructural polyprotein, structural polyprotein, capsid protein CP, protein E1, protein E2, protein E3, protease P1, protease P2, protease P3 (Venezuelan equine encephalitis virus, Venezuelan equine encephalitis); glycoprotein GP, ​​matrix protein Z, polymerase L, nucleoprotein N (Guanarito virus, Venezuelan hemorrhagic fever); polyprotein, protein E, protein M, capsid protein C, protease NS3, protein NS1, protein NS2A, protein AS2B, protein (brotein) NS4A, protein NS4B, protein NS5 (West Nile virus, West Nile fever); capsid protein protein)CP, protein E1, protein E2, protein E3, protease P2 (Western equine encephalitis virus, Western equine encephalitis); genome polyprotein, protein E, protein M, capsid protein C, protease NS3, protein NS1, protein NS2A, protein AS2B, protein NS4A, protein NS4B, protein NS5 (Yellow fever virus, Yellow fever);Putative Yop targeting protein YobB, effector protein YopD, effector protein YopE, protein Yoph, effector protein YopJ, protein translocation protein YopK, effector protein YopT, protein YpkA, flagellar biosynthesis protein FlhA, peptidase M48, potassium efflux system KefA, transcriptional regulator RovA, adhesin Ifp, translocator protein LcrV, protein PcrV, invasin Inv, outer membrane protein OmpF-like porin, adhesin YadA, protein kinase C, phospholipase C1, protein PsaA, mannosyltransferase-like protein WbyK, protein YscU, antigen YPMa (Yersinia pseudotuberculosis) pseudotuberculosis, Yersinia pseudotuberculosis infection); effector protein YopB, 60 kDa chaperonin, protein WbcP, tyrosine protein phosphatase Yoph, protein YopQ, enterotoxin, galactoside permease, reductase NrdE, protein YasN, invasin Inv, adhesin YadA, outer membrane porin F OmpF, protein UspA1, protein EibA, protein Hia, cell surface protein Ail, chaperones SycD, protein LcrD, protein LcrG, protein LcrV, protein SycE, protein YopE, regulator protein TyeA, protein YopM, protein YopN, protein YopO, protein YopT, protein YopD, protease ClpP, protein MyfA, protein FilA, and protein PsaA (Yersinia enterocolitica, yersiniosis);

[0107] In the preceding paragraph, parentheses indicate the particular pathogen or pathogen family from which the antigen is derived and the infectious disease with which that pathogen is associated.

[0108] influenza: In particularly preferred embodiments of the first aspect of the invention, the mRNA compound comprises an mRNA sequence comprising a coding region encoding at least one antigenic peptide or protein derived from influenza virus hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix protein 1 (M1), matrix protein 2 (M2), nonstructural protein 1 (NS1), nonstructural protein 2 (NS2), nuclear export protein (NEP), polymerase acidic protein (PA), polymerase basic protein PB1, PB1-F2, or polymerase basic protein 2 (PB2), or a fragment or variant thereof.

[0109] In this regard, the amino acid sequence of the at least one antigenic peptide or protein may be selected from any peptide or protein or fragment or variant derived from influenza virus hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix protein 1 (M1), matrix protein 2 (M2), nonstructural protein 1 (NS1), nonstructural protein 2 (NS2), nuclear export protein (NEP), polymerase acidic protein (PA), polymerase basic protein PB1, PB1-F2, or polymerase basic protein 2 (PB2), or any synthetically engineered influenza virus peptide or protein.

[0110] In a preferred embodiment of the invention, the coding region encodes at least one antigenic peptide or protein derived from influenza virus hemagglutinin (HA) and / or neuraminidase (NA), or a fragment or variant thereof, wherein the hemagglutinin (HA) and neuraminidase (NA) may be selected from the same influenza virus or from different influenza viruses.

[0111] In this regard, it is particularly preferred that at least one coding region encodes at least one full-length protein or a variant thereof of influenza virus hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix protein 1 (M1), matrix protein 2 (M2), nonstructural protein 1 (NS1), nonstructural protein 2 (NS2), nuclear export protein (NEP), polymerase acidic protein (PA), polymerase basic protein PB1, PB1-F2, or polymerase basic protein 2 (PB2).

[0112] In a particularly preferred embodiment, the at least one coding region encodes at least one full-length protein of hemagglutinin (HA) and / or at least one full-length protein of neuraminidase (NA) of an influenza virus or a variant thereof.

[0113] The term "full-length protein" as used herein typically refers to a protein that contains substantially the entire amino acid sequence of a naturally occurring protein. As used herein, the term "full-length protein" preferably relates to the full-length sequence of a protein as shown in the sequence listing of the present invention, i.e., the amino acid sequence as defined by any one of the SEQ ID NOs: 1 to 30504, SEQ ID NO: 224269, or SEQ ID NO: 224309 listed in the sequence listing, or the amino acid sequence provided under the respective accession number in the database.

[0114] Preferred sequences of the present invention: In this regard, at least one coding sequence of the mRNA sequence of the present invention may comprise: The hemagglutinin (HA) protein of influenza A virus; or The hemagglutinin (HA) protein of influenza B virus; or The neuraminidase (NA) protein of influenza A virus; or Influenza B virus neuraminidase (NA) protein at least one antigenic peptide or protein derived from; or or a fragment or variant thereof, wherein the influenza A virus hemagglutinin (HA) protein or influenza B virus hemagglutinin (HA) protein or influenza A virus neuraminidase (NA) protein or influenza B virus neuraminidase (NA) protein is selected from the hemagglutinin (HA) protein or neuraminidase (NA) protein as listed in the sequence listing of the present invention.

[0115] The Sequence Listing discloses all influenza A or B virus hemagglutinin (HA) proteins and all influenza A or B virus neuraminidase (NA) proteins that are preferred in the present invention. Each preferred antigenic peptide or protein and its coding sequence is identified by a numerical heading. <223> In other words, each preferred hemagglutinin (HA) or neuraminidase (NA) sequence from an influenza A or B virus can be identified by the data elements shown in the numerical headings: <223> The sequences can be identified by their specific database accession number (ie, GenBank protein or nucleic acid accession number) by browsing the sequence listing entries at

[0116] That is, each preferred sequence is represented by its GenBank protein or nucleic acid accession number, which is in turn represented in the sequence listing by seven individual preferred SEQ ID NOs (protein, nucleic acid wild type, nucleic acid optimized 1-5). <223> It is clear from

[0117] That is, the numerical headings in the sequence listing <223> The first consecutive entry for a particular GenBank protein or nucleic acid accession number in the table below indicates the SEQ ID NO corresponding to the respective amino acid sequence (i.e., the wild-type SEQ ID NO of the protein sequence).

[0118] Furthermore, in the sequence listing, the numerical headings <223> The second consecutive entry of a GenBank protein or nucleic acid accession number in corresponds to the nucleic acid sequence of the wild-type mRNA encoding that protein (i.e., the nucleotide sequence wild-type SEQ ID NO:).

[0119] Furthermore, in the sequence listing, the numerical headings <223> The next five consecutive entries of a GenBank protein or nucleic acid accession number in the Sequence Listing provide SEQ ID NOs (i.e., SEQ ID NOs of the optimized nucleotide sequences) corresponding to five different modified / optimized nucleic acid sequences of the sequences as described herein that preferably encode proteins having the amino acid sequence as defined by the first consecutive entry for that particular GenBank protein or nucleic acid accession number in the Sequence Listing.

[0120] Thus, reference to a particular GenBank protein or nucleic acid accession number is equivalent to a reference to the series of seven sequences as described above (protein=1, nucleic acid=2, optimized sequences=3-7).

[0121] For example, the numerical headings listed in the sequence listing, i.e., SEQ ID NO: 1 <223> The first GenBank protein or nucleic acid accession number in the sequence listing is AAA16879. When accession number AAA16879 is searched for in the sequence listing, it is clear that seven SEQ ID NOs: SEQ ID NO: 1, SEQ ID NO: 32013, SEQ ID NO: 64025, SEQ ID NO: 96037, SEQ ID NO: 128049, SEQ ID NO: 160061, and SEQ ID NO: 192073 are associated with this accession number, as described above.

[0122] As explained above, For SEQ ID NO: 1, the numeric heading <223> , which reads "Protein sequence derived from and / or modified from hemagglutinin_influenza A_AAA16879 (wt)"; For sequence number 32013, see the numeric heading <223> , which reads "CDS sequence derived from and / or modified from hemagglutinin_influenza A_AAA16879 (wt)"; For sequence number 64025, see the numeric heading <223> , which reads "CDS sequence (opt1) derived from and / or modified from hemagglutinin_influenza A_AAA16879"; For sequence number 96037, see the numeric heading <223> , which reads "CDS sequence derived from and / or modified from hemagglutinin_influenza A_AAA16879 (opt2)"; For sequence number 128049, see the numeric heading <223> , which reads "CDS sequence derived from and / or modified from hemagglutinin_influenza A_AAA16879 (opt3)"; For sequence number 160061, use the numeric heading <223> "CDS sequence (opt4) derived from and / or modified from hemagglutinin_influenza A_AAA16879"; and For sequence number 192073, see the numeric heading <223> It says "CDS sequence (opt5) derived from and / or modified from hemagglutinin_influenza A_AAA16879."

[0123] Thus, reference to AAA16879 is equivalent to reference to the seven sequences as set forth above (protein = sequence 1, nucleic acid = sequence 2, five different optimized sequences = sequences 3-7).

[0124] A second example is the numerical heading listed in the sequence listing, i.e., SEQ ID NO:2. <223> The second GenBank protein or nucleic acid accession number is "AAA16880" in the sequence listing. Accession number AAA16880 is linked to these seven sequences in the sequence listing: SEQ ID NO:2 (protein), 32014 (nucleic acid wild type), 64026 (optimized 1), 96038 (optimized 2), 128050 (optimized 3), 160062 (optimized 4), and 192074 (optimized 5). Thus, reference to AAA16880 is equivalent to reference to the seven sequences as set forth above.

[0125] A further explanation of this situation can be seen in the exemplary Figures 20 to 24, which show the structure of the sequence listing by taking as examples the hemagglutinin (HA) and neuraminidase (NA) proteins of influenza A and B viruses and the glycoproteins of the rabies virus: - an exemplary influenza A virus hemagglutinin (HA) protein (Figure 20); - the hemagglutinin (HA) protein of an exemplary influenza B virus (Figure 21); - an exemplary influenza A virus neuraminidase (NA) protein (Figure 22); - an exemplary influenza B virus neuraminidase (NA) protein (Figure 23); - Exemplary rabies virus glycoproteins (Figure 24).

[0126] In this specification, reference is made to the contents of Figures 20 to 24 of the specification of PCT / EP2016 / 075843 filed on October 26, 2016, i.e., the application claiming priority to this international patent application (which is incorporated herein by reference).

[0127] In specific embodiments, the influenza virus peptide or protein is derived from an influenza A, B, or C virus (strain).

[0128] The influenza A virus may be selected from influenza A viruses characterized by a hemagglutinin (HA) selected from the group consisting of H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17 and H18. Preferably, the influenza A virus is selected from influenza viruses characterized by a hemagglutinin (HA) selected from the group consisting of H1, H3, H5 or H9.

[0129] Furthermore, influenza A viruses characterized by a neuraminidase (NA) selected from the group consisting of N1, N2, N3, N4, N5, N6, N7, N8, N9, N10, and N11 are particularly preferred. Most preferably, the influenza A viruses are characterized by a neuraminidase (NA) selected from the group consisting of N1, N2, and N8.

[0130] In particularly preferred embodiments, the influenza A virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N8, and H10N7, preferably H1N1, H3N2, H5N1, and H5N8.

[0131] In this context, it is particularly preferred that at least one coding region of the mRNA sequence of the invention encodes at least one antigenic peptide or protein derived from hemagglutinin (HA) and / or at least one antigenic peptide or protein derived from neuraminidase (NA) of an influenza A virus selected from the group consisting of H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N8 and H10N7, preferably H1N1, H3N2, H5N1, H5N8.

[0132] In the context of the present invention, a fragment of a protein or variant thereof encoded by at least one coding region of an mRNA sequence according to the present invention may typically comprise an amino acid sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90% and most preferably at least 95% or even 97% sequence identity to the amino acid sequence of the respective naturally occurring full-length protein or variant thereof, preferably according to SEQ ID NOs: 1-30504.

[0133] In a specific embodiment, the antigenic peptide or protein is derived from the hemagglutinin (HA) protein of influenza A virus according to SEQ ID NOs: 1-14031.

[0134] In this regard, it is further preferred that at least one coding sequence of the mRNA sequences of the invention encodes at least one antigenic peptide or protein derived from the influenza A virus hemagglutinin (HA) protein, or a fragment or variant thereof, wherein the influenza A virus hemagglutinin (HA) protein is selected from the hemagglutinin (HA) proteins listed in the Sequence Listing (see SEQ ID NOs: 1-32012 or SEQ ID NO: 224269 or SEQ ID NO: 224309 and the description in the section "Preferred Sequences of the Invention"), wherein each hemagglutinin (HA) is identified by the database accession number of the corresponding protein (Sequence Listing numeric headings indicating protein or nucleic acid accession numbers (GenBank) <223> (See ). For each protein or nucleic acid accession number (GenBank), search further into the sequence listing by numeric heading. <223> The following SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, <223> The following five SEQ ID NOs, each with a respective protein or nucleic acid accession number, correspond to five modified / optimized nucleic acid sequences of mRNA as described herein that preferably encode proteins having the respective amino acid sequences set forth above (first entry with the respective protein or nucleic acid accession number (GenBank)).

[0135] In this regard, the following HA protein sequences are particularly preferred: Influenza A / Vietnam / 1203 / 2004 (H5N1) HA protein (SEQ ID NOs: 13861-13871) - HA protein of influenza A / Vietnam / 1194 / 2004 (H5N1); (SEQ ID NOs: 13859-13860) - HA protein of influenza A / Hong Kong / 4801 / 2014 (H3N2) (sequence numbers 13853 to 13856) - HA protein of influenza A / Netherlands / 602 / 2009 (H1N1) (SEQ ID NOs: 13848-13850) - HA protein of influenza A / California / 07 / 2009 (H1N1) (SEQ ID NOs: 13836-13844) - HA protein of influenza A / Michigan / 45 / 2015 (H1N1) (SEQ ID NOs: 13845-13847)

[0136] In a specific embodiment, the antigenic peptide or protein is derived from the hemagglutinin (HA) protein of influenza B virus according to SEQ ID NOs: 26398-28576.

[0137] In this regard, it is further preferred that at least one coding sequence of the mRNA sequences of the invention encodes at least one antigenic peptide or protein derived from the influenza B virus hemagglutinin (HA) protein, or a fragment or variant thereof, wherein the influenza B virus hemagglutinin (HA) protein is selected from the hemagglutinin (HA) proteins listed in the Sequence Listing (see SEQ ID NOs: 1-32012 or SEQ ID NO: 224269 or SEQ ID NO: 224309 and the description in the section "Preferred Sequences of the Invention"), wherein each hemagglutinin (HA) is identified by the database accession number of the corresponding protein (Sequence Listing numeric headings indicating protein or nucleic acid accession numbers (GenBank) <223> (See ). For each protein or nucleic acid accession number (GenBank), search further into the sequence listing by numeric heading. <223> The following SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, <223> The following five SEQ ID NOs, which show the respective protein or nucleic acid accession numbers in: - HA protein of influenza B / Phuket / 3037 / 2013 (EPI540671; SEQ ID NOs: 28530-28532) - Influenza B / Brisbane / 60 / 2008 HA protein (SEQ ID NOs: 28524-28529)

[0138] In further specific embodiments, the antigenic peptide or protein is derived from the neuraminidase (NA) protein of influenza A virus according to SEQ ID NOs: 14032-26397, 224309, or 224310.

[0139] In this regard, it is further preferred that at least one coding sequence of the mRNA sequence of the present invention encodes at least one antigenic peptide or protein derived from the neuraminidase (NA) protein of influenza A virus, or a fragment or variant thereof, wherein the neuraminidase (NA) protein of influenza A virus is selected from the neuraminidase (NA) proteins listed in the Sequence Listing (see SEQ ID NOs: 1-32012 or SEQ ID NO: 224269 or SEQ ID NO: 224309 and the description in the section "Preferred Sequences of the Invention"), wherein each neuraminidase (NA) is identified by the database accession number of the corresponding protein (Sequence Listing numeric headings indicating protein or nucleic acid accession numbers (GenBank) <223> (See ). For each protein or nucleic acid accession number (GenBank), search further into the sequence listing by numeric heading. <223> The following SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, <223> The following five SEQ ID NOs, each with a respective protein or nucleic acid accession number, correspond to five modified / optimized nucleic acid sequences of mRNA as described herein that preferably encode proteins having the respective amino acid sequences set forth above (first entry with the respective protein or nucleic acid accession number (GenBank)).

[0140] In this regard, the following NA protein sequences are particularly preferred: - NA protein of influenza A / Hong Kong / 4801 / 2014 (H3N2): SEQ ID NOs: 26251 to 26254 - NA protein of influenza A / California / 7 / 2009(H1N1)pdm09: SEQ ID NOs: 26238 to 26243 - NA protein of influenza A / Vietnam / 1194 / 2004 (H5N1): SEQ ID NO: 224310 - NA protein of influenza A / Vietnam / 1203 / 2004 (H5N1): SEQ ID NOs: 26255-26257 - NA protein of influenza A / Netherlands / 602 / 2009 (H1N1): SEQ ID NOs: 26246 to 26250 - NA protein of influenza A / Michigan / 45 / 2015 (H1N1) (sequence numbers 26244-26245)

[0141] In a further specific embodiment, the antigenic peptide or protein is derived from the neuraminidase (NA) protein of influenza B virus according to SEQ ID NOs: 28577-30504.

[0142] In this regard, it is further preferred that at least one coding sequence of the mRNA sequence of the present invention encodes at least one antigenic peptide or protein derived from the neuraminidase (NA) protein of influenza B virus, or a fragment or variant thereof, wherein the neuraminidase (NA) protein of influenza B virus is selected from the neuraminidase (NA) proteins listed in the Sequence Listing (see SEQ ID NOs: 1-32012 or SEQ ID NO: 224269 or SEQ ID NO: 224309 and the description in the section "Preferred Sequences of the Invention"), wherein each neuraminidase (NA) is identified by the database accession number of the corresponding protein (Sequence Listing numeric headings indicating protein or nucleic acid accession numbers (GenBank) <223> (See ). For each protein or nucleic acid accession number (GenBank), search further into the sequence listing by numeric heading. <223> The following SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, <223> The following five SEQ ID NOs, each with a respective protein or nucleic acid accession number, correspond to five modified / optimized nucleic acid sequences of mRNA as described herein that preferably encode proteins having the respective amino acid sequences set forth above (first entry with the respective protein or nucleic acid accession number (GenBank)).

[0143] In this regard, the following NA protein sequences are particularly preferred: - NA protein of influenza B / Brisbane / 60 / 2008: SEQ ID NOs: 30455 to 30460 - NA protein of influenza B / Phuket / 3037 / 2013: SEQ ID NOs: 30461-30462

[0144] Furthermore, in this context, the coding region encoding at least one antigenic peptide or protein derived from influenza virus hemagglutinin (HA) and / or neuraminidase (NA), or a fragment, variant or derivative thereof, may be selected from any nucleic acid sequence comprising a coding region encoding hemagglutinin (HA) or neuraminidase (NA), or a fragment or variant thereof, from any influenza virus isolate.

[0145] In a preferred embodiment, the present invention thus provides an mRNA sequence comprising at least one coding region, wherein the coding region encoding influenza A virus hemagglutinin (HA) comprises or consists of any one of the nucleic acid sequences as disclosed in the Sequence Listing (i.e., SEQ ID NOs: 32013 to 46043; 64025 to 78055, 224085 to 224106, 96037 to 110067, 128049 to 142079, 160061 to 174091, 192073 to 206103; see the description above and in the section "Preferred sequences of the invention") or a fragment or variant of any one of these sequences.

[0146] In this regard, it is particularly preferred that the mRNA sequence according to the present invention comprises at least one coding region encoding influenza A virus hemagglutinin (HA) comprising an RNA sequence selected from the RNA sequences as disclosed in the Sequence Listing, see above and in the section "Preferred sequences of the present invention", (SEQ ID NOs: 32013-46043; 64025-78055, 224085-224106, 96037-110067, 128049-142079, 160061-174091, 192073-206103), or a fragment or variant thereof, that is identical or at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical.

[0147] In a particularly preferred embodiment, the mRNA sequence comprises at least one coding region encoding the hemagglutinin (HA) of an influenza A virus comprising an RNA sequence selected from the following RNA sequences: - mRNA encoding the HA protein of influenza A / Vietnam / 1203 / 2004 (H5N1), preferably mRNA sequences according to SEQ ID NOs: 45873 to 45883, 77885 to 77895, 109897 to 109907, 141909 to 141919, 173921 to 173931, 205933 to 205943 - mRNA encoding the HA protein of influenza A / Vietnam / 1194 / 2004 (H5N1), preferably mRNA sequences according to SEQ ID NOs: 45871, 45872, 77883, 77884, 109895, 109896, 141907, 141908, 173919, 173920, 205931, 205932 - mRNA encoding the HA protein of influenza A / Hong Kong / 4801 / 2014 (H3N2), preferably mRNA sequences according to SEQ ID NOs: 45865 to 45868, 77877 to 77877, 109889 to 109889, 141901 to 141901, 173913 to 173913, 205925 to 205925 - mRNA encoding the HA protein of influenza A / Netherlands / 602 / 2009 (H1N1), preferably mRNA sequences according to SEQ ID NOs: 45860 to 45862, 77872 to 77874, 109884 to 109886, 173908 to 173910, 205920 to 205922 - mRNA encoding the HA protein of influenza A / California / 07 / 2009 (H1N1), preferably mRNA sequences according to SEQ ID NOs: 45848 to 45856, 77860 to 77868, 109872 to 109880, 141884 to 141892, 173896 to 173904, 205908 to 205916 - mRNA encoding the HA protein of influenza A / Michigan / 45 / 2015 (H1N1), preferably mRNA sequences according to SEQ ID NOs: 45857 to 45859, 77869 to 77871, 109881 to 109883, 141893 to 141895, 173905 to 173907, 205917 to 205919.

[0148] In a preferred embodiment, the present invention further provides an mRNA sequence comprising at least one coding region, wherein the coding region encoding the hemagglutinin (HA) of influenza B virus is designated by a numerical index beginning with "derived and / or modified CDS sequence (wt)" or "derived and / or modified CDS sequence (opt1)", "derived and / or modified CDS sequence (opt2)", "derived and / or modified CDS sequence (opt3)", "derived and / or modified CDS sequence (opt4)", or "derived and / or modified CDS sequence (opt5)". <223> or as disclosed in the Sequence Listing having the sequence number "1" or "2", respectively, of Table 2 or Figure 21 of PCT / EP2016 / 075843 specification, or any one of SEQ ID NOs: 58410 to 60588, 90422 to 92600, 224107 to 224112, 122434 to 124612, 154446 to 156624, 186458 to 188636, 218470 to 220648, or a fragment or variant of any one of these sequences.

[0149] In this regard, the mRNA sequences of the present invention may be designated by a numerical heading beginning with "derived and / or modified CDS sequence (wt)" or "derived and / or modified CDS sequence (opt1)", "derived and / or modified CDS sequence (opt2)", "derived and / or modified CDS sequence (opt3)", "derived and / or modified CDS sequence (opt4)", or "derived and / or modified CDS sequence (opt5)". <223> or RNA sequences as disclosed in "Column B" or "Column C" of Table 2 or Figure 21 of PCT / EP2016 / 075843 specification, SEQ ID NOs: 58410 to 60588, 90422 to 92600, 224107 to 224112, 122434 to 124612, 154446 to 156624, 186458 to 188636, 218470 to 220648, It is particularly preferred that the nucleic acid sequence comprises at least one coding region encoding influenza B virus hemagglutinin (HA) comprising an RNA sequence selected from the group consisting of an RNA sequence that is 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the nucleic acid sequence of the present invention, or a fragment or variant of any one of these sequences.

[0150] In a particularly preferred embodiment, the mRNA sequence comprises at least one coding region encoding the hemagglutinin (HA) of influenza B virus comprising an RNA sequence selected from the following RNA sequences: - mRNA encoding the HA protein of influenza B / Phuket / 3037 / 2013, preferably mRNA sequences according to SEQ ID NOs: 60542 to 60544, 92554 to 92556, 124566 to 124568, 156578 to 156580, 188590 to 188592, 220602 to 220604 - mRNA encoding the HA protein of influenza B / Brisbane / 60 / 2008 (GI:223950973; FJ766840.1), preferably the mRNA sequences according to SEQ ID NOs: 60536 to 60541, 92548 to 92553, 124560 to 124565, 156572 to 156577, 188584 to 188589, 220596 to 220601.

[0151] In a preferred embodiment, the present invention further provides an mRNA sequence comprising at least one coding region, wherein the coding region encoding the neuraminidase (NA) of an influenza A virus is designated by a numerical index beginning with "derived and / or modified CDS sequence (wt)" or "derived and / or modified CDS sequence (opt1)", "derived and / or modified CDS sequence (opt2)", "derived and / or modified CDS sequence (opt3)", "derived and / or modified CDS sequence (opt4)", or "derived and / or modified CDS sequence (opt5)". <223> or as disclosed in the Sequence Listing having the sequence number "1" or "2", respectively, of Table 3 or Figure 22 of PCT / EP2016 / 075843 specification, or any one of SEQ ID NOs: 46044 to 58409, 224311, 224312, 78056 to 90421, 224113, 224313 to 224317, 110068 to 122433, 142080 to 154445, 174092 to 186457, 206104 to 218469, or a fragment or variant of any one of these sequences.

[0152] In this regard, the mRNA sequences of the present invention may be designated by a numerical heading beginning with "derived and / or modified CDS sequence (wt)" or "derived and / or modified CDS sequence (opt1)", "derived and / or modified CDS sequence (opt2)", "derived and / or modified CDS sequence (opt3)", "derived and / or modified CDS sequence (opt4)", or "derived and / or modified CDS sequence (opt5)". <223> or the RNA sequences as disclosed in "Column B" or "Column C" of Table 3 or Figure 22 of PCT / EP2016 / 075843 specification, respectively, SEQ ID NOs: 46044 to 58409, 224311, 224312, 78056 to 90421, 224113, 224313 to 224317, 110068 to 122433, 142080 to 154445, 174092 to 186457, 206104 to 218469 It is particularly preferred that the nucleic acid sequence comprises at least one coding region encoding influenza A virus neuraminidase (NA) comprising an RNA sequence selected from one or at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical RNA sequences, or a fragment or variant of any one of these sequences.

[0153] In a particularly preferred embodiment, the mRNA sequence comprises at least one coding region encoding the neuraminidase (NA) of an influenza A virus comprising an RNA sequence selected from the following RNA sequences: - mRNA encoding the NA protein of influenza A / Hong Kong / 4801 / 2014 (H3N2): SEQ ID NOs: 58263-58266, 90275-90278, 122287-122290, 154299-154302, 186311-186314, 218323-218326 - mRNA encoding the NA protein of influenza A / California / 7 / 2009(H1N1)pdm09: SEQ ID NOs: 58250-58255, 90262-90267, 122274-122279, 154286-154291, 186298-186303, 218310-218315 - mRNA encoding the NA protein of influenza A / Vietnam / 1194 / 2004 (H5N1): SEQ ID NO: 224312 - mRNA encoding the NA protein of influenza A / Vietnam / 1203 / 2004 (H5N1): SEQ ID NOs: 58267-58269, 90279-90281, 122291-122293, 154303-154305, 186315-186317, 218327-218329 - mRNA encoding the NA protein of influenza A / Michigan / 45 / 2015 (H1N1), preferably mRNA sequences according to SEQ ID NOs: 58256-58257, 90268-90269, 122280-122281, 154292-154293, 186304-186305, 218316-218317 - an mRNA encoding the NA protein of influenza A / Netherlands / 602 / 2009 (H1N1), preferably an mRNA sequence according to SEQ ID NOs: 58258 to 58262, 90270 to 90274, 122282 to 122286, 154294 to 154298, 186306 to 186310, 218318 to 218322.

[0154] In a preferred embodiment, the present invention further provides an mRNA sequence comprising at least one coding region, wherein the coding region encoding the neuraminidase (NA) of an influenza B virus is designated by a numerical index beginning with "derived and / or modified CDS sequence (wt)" or "derived and / or modified CDS sequence (opt1)", "derived and / or modified CDS sequence (opt2)", "derived and / or modified CDS sequence (opt3)", "derived and / or modified CDS sequence (opt4)", or "derived and / or modified CDS sequence (opt5)". <223> or the nucleic acid sequences as disclosed in the Sequence Listing having the sequence number "1" or "2", respectively, of Table 4 or Figure 23 of PCT / EP2016 / 075843 specification, any one of SEQ ID NOs: 60589 to 62516, 92601 to 94528, 124613 to 126540, 156625 to 158552, 188637 to 190564, 220649 to 222576, or a fragment or variant of any one of these sequences.

[0155] In this regard, the mRNA sequences of the present invention may be designated by a numerical heading beginning with "derived and / or modified CDS sequence (wt)" or "derived and / or modified CDS sequence (opt1)", "derived and / or modified CDS sequence (opt2)", "derived and / or modified CDS sequence (opt3)", "derived and / or modified CDS sequence (opt4)", or "derived and / or modified CDS sequence (opt5)". <223> or the RNA sequences as disclosed in "Column B" or "Column C" of Table 4 or Figure 23 of PCT / EP2016 / 075843 specification, SEQ ID NOs: 60589 to 62516, 92601 to 94528, 124613 to 126540, 156625 to 158552, 188637 to 190564, 220649 to 222576, or at least 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 390%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, 500%, 510%, 520%, 530%, 540%, 550%, 560%, 570%, 580%, 590%, 600%, 610%, 620%, 630%, 640%, 650%, 660%, 670%, 680%, 690%, 700%, 710%, 720%, 730%, 740%, 750%, 760%, 770%, 780%, 790%, 8 It is particularly preferred that the nucleic acid sequence comprises at least one coding region encoding influenza B virus neuraminidase (NA) comprising an RNA sequence selected from the group consisting of: 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical RNA sequences, or a fragment or variant of any one of these sequences.

[0156] In a particularly preferred embodiment, the mRNA sequence comprises at least one coding region encoding the neuraminidase (NA) of an influenza B virus comprising an RNA sequence selected from the following RNA sequences: - mRNA encoding the NA protein of influenza B / Brisbane / 60 / 2008 (GI:223950973; FJ766840.1): SEQ ID NOs: 62467-62472, 94479-94484, 126491-126496, 158503-158508, 190515-190520, 222527-222532 - mRNA encoding the NA protein of influenza B / Phuket / 3073 / 2013): SEQ ID NOs: 62473-62474, 94485-94486, 126497-126498, 158509-158510, 190521-190522, 222533-222534.

[0157] Rabies: In a particularly preferred embodiment of the first aspect of the invention, the mRNA compound comprising the mRNA sequence comprises a coding region encoding at least one antigenic peptide or protein derived from glycoprotein G of the rabies virus or a fragment or variant thereof.

[0158] In this regard, the amino acid sequence of the at least one antigenic peptide or protein may be selected from any peptide or protein or fragment or variant derived from the glycoprotein of the rabies virus or any synthetically engineered rabies virus peptide or protein.

[0159] In a preferred embodiment of the invention, the coding region encodes at least one antigenic peptide or protein derived from the glycoprotein of rabies virus or a fragment or variant thereof.

[0160] In this regard, it is particularly preferred that the at least one coding region encodes at least one full-length protein of a glycoprotein of the rabies virus or a variant thereof.

[0161] As used herein, the term "full-length protein" preferably relates to the full-length sequence of a protein as shown in the sequence listing of the present invention. More preferably, the term "full-length protein" preferably refers to the amino acid sequence as defined by any one of the SEQ ID NOs: 30505 to 32012 listed in the sequence listing or the amino acid sequence provided under the respective accession number in the database.

[0162] In this regard, it is further preferred that at least one coding sequence of the mRNA sequences of the present invention encodes at least one antigenic peptide or protein derived from a glycoprotein of the rabies virus, or a fragment or variant thereof, wherein the rabies virus glycoprotein is selected from the glycoproteins of the rabies virus proteins listed in the Sequence Listing (see SEQ ID NOs: 1-32012 or SEQ ID NO: 224269 or SEQ ID NO: 224309 and the description in the section "Preferred Sequences of the Invention"). Therein, each rabies virus glycoprotein is identified by the database accession number of the corresponding protein (see Sequence Listing numeric headings indicating protein or nucleic acid accession numbers (GenBank)). <223> (See ). For each protein or nucleic acid accession number (GenBank), search further into the sequence listing by numeric heading. <223> The following SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, <223> The following five SEQ ID NOs, each with a respective protein or nucleic acid accession number, correspond to five modified / optimized nucleic acid sequences of mRNA as described herein that preferably encode proteins having the respective amino acid sequences set forth above (first entry with the respective protein or nucleic acid accession number (GenBank)).

[0163] In this regard, the following glycoprotein sequences are particularly preferred: SEQ ID NOs: 31986, 31073, 31102.

[0164] Furthermore, in this context, the coding region encoding at least one antigenic peptide or protein derived from a glycoprotein of rabies virus, or a fragment, variant or derivative thereof, may be selected from any nucleic acid sequence comprising a coding region encoding a glycoprotein, or a fragment or variant thereof, from any rabies virus isolate.

[0165] In a preferred embodiment, the present invention further provides an mRNA sequence comprising at least one coding region, wherein the coding region encoding the glycoprotein of the rabies virus comprises or consists of any one of the nucleic acid sequences disclosed in the Sequence Listing (see above; preferably SEQ ID NOs: 62517 to 64024; 224270, 224274, 94529 to 96036, 224271 to 224273, 126541 to 128048, 158553 to 160060, 190565 to 192072, 222577 to 224084) or a fragment or variant of any one of these sequences.

[0166] In this regard, it is particularly preferred that the mRNA sequence according to the present invention comprises at least one coding region encoding a glycoprotein from any rabies virus comprising an RNA sequence selected from the RNA sequences identical or at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the RNA sequences as disclosed in the Sequence Listing (see explanation above; preferably SEQ ID NOs: 62517-64024; 224270, 224274, 94529-96036, 224271-224273, 126541-128048, 158553-160060, 190565-192072, 222577-224084), or a fragment or variant thereof.

[0167] In a particularly preferred embodiment, the mRNA sequence comprises at least one coding region encoding the glycoprotein of the rabies virus (RABV-G) comprising an RNA sequence selected from the following RNA sequences: mRNA encoding the glycoprotein of rabies virus (Pasteur strain), preferably mRNA sequences according to SEQ ID NOs: 63998, 96010, 128022, 160034, 192046, 224058.

[0168] Ebola: Ebolavirus: Ebolavirus and the genetically related Marburgvirus are human pathogens that cause severe disease. Ebolavirus and Marburgvirus are filoviruses, which are enveloped viruses characterized by negative-stranded RNA genomes. The Filoviridae family contains three genera: Ebolavirus, Marburgvirus, and Cuevavirus. The Cuevavirus and Marburgvirus genera contain only one species: Lloviu-cuevavirus (LLOV) and Marburg-marburgvirus (Marburg-marburgvirus), respectively (which are subdivided into Marburgvirus (MARV) and Ravnvirus (RAVV)). The genus Ebolavirus contains five known species: Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV) (= Côte d'Ivoire ebolavirus), and Zaire ebolavirus (EBOV). While Cueva virus was isolated from bats and its potential as a human pathogen is unknown, Ebola virus and Marburg virus are both human pathogens that cause Ebola virus disease (EVD) and Marburg disease, respectively, characterized by hemorrhagic fever and extremely high mortality rates. In the context of the present invention, any virus, viral member, viral strain, viral type, viral subtype, viral isolate, viral variant, or viral serotype or genetic reassortant of viruses belonging to, related to, or derived from the above-listed families and genera of viruses is considered an "Ebola virus."

[0169] In a particularly preferred embodiment of the first aspect of the invention, the mRNA compound comprising the mRNA sequence comprises a coding region encoding at least one antigenic peptide or protein derived from the glycoprotein (GP) and / or matrix protein 40 (VP40) and / or nucleoprotein (NP) of a virus of the genus Ebolavirus or Marburgvirus, or a fragment, variant or derivative thereof.

[0170] In this regard, the amino acid sequence of the at least one antigenic peptide or protein may be selected from any peptide or protein or fragment or variant derived from the glycoprotein (GP) and / or matrix protein 40 (VP40) and / or nucleoprotein (NP) glycoproteins of Ebola virus or any synthetically engineered Ebola virus peptide or protein.

[0171] In a preferred embodiment of the invention, the coding region encodes at least one antigenic peptide or protein derived from an Ebola virus glycoprotein or a fragment or variant thereof, and in this context it is particularly preferred that the at least one coding region encodes at least one full-length protein of an Ebola virus glycoprotein or a variant thereof.

[0172] In this regard, the following Ebola glycoprotein amino acid sequences are particularly preferred: SEQ ID NOs: 1-6 of WO2016097065, or fragments or variants of these sequences, and in this regard, SEQ ID NOs: 1-6 of WO2016097065 and the disclosure relating to SEQ ID NOs: 1-6 of WO2016097065 are incorporated herein by reference.

[0173] In this regard, the following Ebola VP40 amino acid sequences are particularly preferred: SEQ ID NOs: 7-12 of WO2016097065, or fragments or variants of these sequences, and in this regard, SEQ ID NOs: 7-12 of WO2016097065 and the disclosure relating to SEQ ID NOs: 7-12 of WO2016097065 are incorporated herein by reference.

[0174] In this regard, the following Ebola NP amino acid sequences are particularly preferred: SEQ ID NOs: 13-18 of WO2016097065, or fragments or variants of these sequences, and in this regard, SEQ ID NOs: 13-18 of WO2016097065 and the disclosure relating to SEQ ID NOs: 13-18 of WO2016097065 are incorporated herein by reference.

[0175] In a preferred embodiment, the present invention provides an mRNA sequence comprising at least one coding region, wherein the coding region encoding an antigenic peptide or protein as specified herein of an Ebola virus comprises or consists of a nucleic acid sequence according to SEQ ID NOs: 20-27 of WO2016097065, or any one of fragments or variants of these sequences. In this regard, SEQ ID NOs: 20-27 of WO2016097065 and the disclosure relating to SEQ ID NOs: 20-27 of WO2016097065 are incorporated herein by reference.

[0176] In a particularly preferred embodiment, the mRNA sequence comprises at least one coding region encoding an Ebola virus glycoprotein. In a particularly preferred embodiment, the mRNA sequence comprises at least one coding region encoding an Ebola virus VP40. In a particularly preferred embodiment, the mRNA sequence comprises at least one coding region encoding an Ebola virus NP.

[0177] In a particularly preferred embodiment, the mRNA sequence comprises at least one coding region encoding an antigenic peptide or protein of Ebola virus comprising an RNA sequence selected from the following RNA sequences: - mRNA encoding the GP protein of Ebola virus: SEQ ID NOs: 37-39 of WO2016097065, or fragments or variants of these sequences, in which context SEQ ID NOs: 37-39 of WO2016097065 and the disclosure relating to SEQ ID NOs: 37-39 of WO2016097065 are incorporated herein by reference. - mRNA encoding VP40 of Ebola virus: SEQ ID NOs: 40-42 of WO2016097065, or fragments or variants of these sequences, in which context SEQ ID NOs: 40-42 of WO2016097065 and the disclosure relating to SEQ ID NOs: 40-42 of WO2016097065 are incorporated herein by reference. - mRNA encoding Ebola virus NP: SEQ ID NOs: 43-44 of WO2016097065, or fragments or variants of these sequences, in which context SEQ ID NOs: 43-44 of WO2016097065 and the disclosure relating to SEQ ID NOs: 43-44 of WO2016097065 are incorporated herein by reference.

[0178] Particularly preferred is an mRNA sequence comprising a coding sequence encoding the GP according to SEQ ID NO: 224362.

[0179] Tumor antigens: Preferably, at least one coding sequence of the mRNA compound comprising the mRNA sequence according to the invention encodes a tumor antigen, preferably as defined herein, or a fragment or variant thereof, wherein the tumor antigen is preferably selected from the group consisting of 1A01_HLA-A / m; 1A02; 5T4; ACRBP; AFP; AKAP4; α-actinin-4 / m; α-methylacyl coenzyme A racemase; and R; ART-4; ARTC1 / m; AURKB; B2MG; B3GN5; B4GN1; B7H4; BAGE-1; BASI; BCL-2; bcr / abl; β-catenin ng / m;BING-4;BIRC7;BRCA1 / m;BY55;Calreticulin;CAMEL;CASP-8 / m;CASPA;Cathepsin_B;Cathepsin_L;CD1A;CD1B;CD1C;CD1D;CD1E;CD20;CD22;CD276;CD33;CD3E;CD3Z;CD44_isoform_1;CD44_isoform_6;CD4;CD52;CD55;CD56;CD80;CD86;CD8A;CDC27 / m;CDE30;CDK4 / m;CDKN2A / m;CEA;CEAM6;CH3L2;CLCA2;C ML28;CML66;COA-1 / m;coactosin-like_protein;collagen_XXIII;COX-2;CP1B1;CSAG2;CT45A1;CT55;CT-_9 / BRD6;CTAG2_isoform_LAGE-1A;CTAG2_isoform_LAGE-1B;CTCFL;Cten;cyclin_B1;cyclin_D1;cyp-B;DAM-10;DEP1A;E7;EF1A2;EFTUD2 / m;EGFR;EGLN3;ELF2 / m;EMMPRIN;EpCam;EphA2;EphA3;ErbB3;ERBB 4;ERG;ETV6;EWS;EZH2;FABP7;FCGR3A_version_1;FCGR3A_version_2;FGF5;FGFR2;fibronectin;FOS;FOXP3;FUT1;G250;GAGE-1;GAGE-2;GAGE-3;GAGE-4;GAGE-5;GAGE-6;GAGE7b;GAGE-8_(GAGE-2D);GASR;GnT-V;GPC3;GPNMB / m;GRM3;HAGE;HEPSIN;Her2 / neu;HLA-A2 / m;HOMEOBOX_NKX3.1;HOM-TES-85;HPG1;HS71A;HS71B;HST-2;hTERT;iCE;IF2B3;IL10;IL-13Ra2;IL2-RA;IL2-RB; IL2-RG;IL-5;IMP3;ITA5;ITB1;ITB6;THE-2;THE-4;KI20A;KIAA02 05;KIF2C;KK-LC-1;LDLR;LGMN;LIRB2;LY6K;MAGA5;MAGA8;MAGAB;MAGE-A10;MAGE-A12;MAGE-A1;MAGE-A2;MAGE-A3;MAGE-A4;MAGE-A6;MAGE-A9;MAG E-B10;MAGE-B16;MAGE-B17;MAGE-_B1;MAGE-B2;MAGE-B3;MAGE-B4;MAGE-B5;MAGE-B6;MAGE-C1;MAGE-C2;MAGE-C3;MAGE-D1;MAGE-D2;MAGE-D4;MAGE -_E1;MAGE-E1_(MAGE1);MAGE-E2;MAGE-F1;MAGE-H1;MAGEL2;MAGE_A; MART-1 / 。A;MART-2;MC1_R;M-CSF;ダダ;MITF;MMP1_1;MMP7;MUC-1;MUM -1 / m;MUM-2 / m;MYCN;MYO1A;MYO1B;MYO1C;MYO1D;MYO1E;MYO1F;MYO1G;MYO1H;NA17;NA88-A;Neo-PAP;NFYC / m;NGEP;NPM;NRCAM;NSE;NUF2;NY-ESO-1 ;OA1;OGT;OS-9;Chroscopy;p53;PAGE-4;PAI-1;PAI-2;PAP;PAT E;PAX3;PAX5;PD1L1;PDCD1;PDEF;PECA1;PGCB;PGFRB;Pim-1_-キ;Pin-1 ;PLAC1;PMEL;PML;POTEF;POTE;PRAME;PRDX5 / m;PRM2; ;PSA;PSB9;PSCA;PSGR;PSM;PTPRC;RAB8A;RAGE-1;RARE;RASH;RASK;RASN; RGS5;RHAMM / CD168;RHOC;RSSA;RU1;RU2;RUNX1;S-100;SAGE;SART-_1;SART-2;SART-3;SEPR;SERPINB5;SIA7F;SIA8A;SIAT9;SIRT2 / m;SOX10;SP17;Selected from the group consisting of SPNXA; SPXN3; SSX-1; SSX-2; SSX3; SSX-4; ST1A1; STAG2; STAMP-1; STEAP-1; survivin-2B; survivin; SYCP1; SYT-SSX-1; SYT-SSX-2; TARP; TCRg; TF2AA; TGFB1; TGFR2; TGM-4; TIE2; TKTL1; TPI / m; TRGV11; TRGV9; TRPC1; TRP-p8; TSG10; TSPY1; TVC_(TRGV3); TX101; tyrosinase; TYRP1; TYRP2; UPA; VEGFR1; WT1; and XAGE1.

[0180] Further antigens useful in the present invention are set forth herein below (gene name followed by the protein accession number in parentheses): 1A01_HLA-A / m (UniProtKB:P30443); 1A02 (UniProtKB:P01892); 5T4 (UniProtKB:Q13641); ACRBP (UniProtKB:Q8NEB7); AFP (UniProtKB:P02771); AKAP4 (UniProtKB:Q5JQC9); α-actinin-_4 / m (UniProtKB:B4DSX0); α-actinin-_4 / m (UniProtKB:B4E337); α-actinin-_4 / m (UniProtKB:O43707); α-methylacyl coenzyme _A_racemase (UniProtKB: A0A024RE16); α-methylacyl coenzyme _A_racemase (UniProtKB: A8KAC3); and R (UniProtKB: P10275); ART-4 (UniProtKB: Q9ULX3); ARTC1 / m (UniProtKB: P52961); AURKB (UniProtKB: Q96GD4); B2MG (UniProtKB: P61769); B3GN5 (UniProtKB: Q9BYG0); B4GN1 (UniProtKB: Q00973); B7H4 (UniProtKB :Q7Z7D3);BAGE-1(UniProtKB:Q13072);BASI(UniProtKB:P35613);BCL-2(UniProtKB:A9QXG9);bcr / abl(UniProtKB:A9UEZ4);bcr / abl(UniProtKB: A9UEZ7);bcr / abl(UniProtKB:A9UEZ8);bcr / abl(UniProtKB:A9UEZ9);bcr / abl(UniProtKB:A9UF00);bcr / abl(UniProtKB:A9UF01);bcr / abl(UniPr otKB:A9UF03);bcr / abl(UniProtKB:A9UF04);bcr / abl(UniProtKB:A9UF05);bcr / abl(UniProtKB:A9UF06);bcr / abl(UniProtKB:A9UF08);β-catenin / m (UniProtKB:P35222);β-catenin / m(UniProtKB:Q8WYA6);BING-4(UniProtKB:O15213);BIRC7(UniProtKB:Q96CA5);BRCA1 / m(UniProtKB:A0A024R1V0);BRCA1 / m(UniProtKB:A0A024R1V7);BRCA1 / m(UniProtKB:A0A024R1Z8);BRCA1 / m(UniProtKB:A0A068BFX7);BRCA1 / m(UniProtKB:C6YB45);BRCA1 / m(UniProtKB:C6YB47);BRCA1 / m(UniProtKB:G3XAC3);BY55(UniProtKB:O95971);カルレティキュリン(UniProtKB:B4DHR1);カルレティキュリン(UniProtKB:B4E2Y9);カルレティキュリン(UniProtKB:P27797);カルレティキュリン(UniProtKB:Q96L12);CAMEL(UniProtKB:O95987);CASP-8 / m(UniProtKB:Q14790);CASPA(UniProtKB:Q92851-4);カテプシン_B(UniProtKB:A0A024R374);カテプシン_B(UniProtKB:P07858);カテプシン_L(UniProtKB:A0A024R276);カテプシン_L(UniProtKB:P07711);カテプシン_L(UniProtKB:Q9HBQ7);CD1A(UniProtKB:P06126);CD1B(UniProtKB:P29016);CD1C(UniProtKB:P29017);CD1D(UniProtKB:P15813);CD1E(UniProtKB:P15812);CD20(UniProtKB:P11836);CD22(UniProtKB:O60926);CD22(UniProtKB:P20273);CD22(UniProtKB:Q0EAF5);CD276(UniProtKB:Q5ZPR3);CD33(UniProtKB:B4DF51);CD33(UniProtKB:P20138);CD33(UniProtKB:Q546G0);CD3E(UniProtKB:P07766);CD3Z(UniProtKB:P20963);CD44_アイソフォーム_1(UniProtKB:P16070);CD44_アイソフォーム_6(UniProtKB:P16070-6);CD4(UniProtKB:P01730);CD52(UniProtKB:P31358);CD52(UniProtKB:Q6IBD0);CD52(UniProtKB:V9HWN9);CD55(UniProtKB:B1AP15);CD55(UniProtKB:D3DT85);CD55(UniProtKB:D3DT86);CD55(UniProtKB:P08174);CD56(Un iProtKB:P13591);CD80(UniProtKB:A0N0P2);CD80(UniProtKB:P33681);CD86(UniProtKB:P42081);CD8A(UniProtKB:P01732);CDC27 / m(UniProt KB:G5EA36);CDC27 / m(UniProtKB:P30260);CDE30(UniProtKB:P28908);CDK4 / m(UniProtKB:A0A024RBB6);CDK4 / m(UniProtKB:P11802);CDK4 / m( UniProtKB:Q6LC83);CDK4 / m(UniProtKB:Q96BE9);CDKN2A / m(UniProtKB:D1LYX3);CDKN2A / m(UniProtKB:G3XAG3);CDKN2A / m(UniProtKB:K7PML8) CDKN2A / m (UniProtKB: L8E941); CDKN2A / m (UniProtKB: Q8N726); CEA (RefSeq: NP_004354); CEAM6 (UniProtKB: P40199); CH3L2 (UniProtKB: Q15782); CLCA2 (UniProtKB: Q9UQC9); CML28 (UniProtKB: Q9NQT4); CML66 (UniProtKB: Q96RS6); COA-1 / m (UniProtKB: Q5T124); coactosin-like protein (UniProtKB B:Q14019);Collagen_XXIII(UniProtKB:L8EAS4);Collagen_XXIII(UniProtKB:Q86Y22);COX-2(UniProtKB:Q6ZYK7);CP1B1(UniProtKB:Q16678);CSAG2(UniProtKB:Q9Y5P2-2);CSAG2(UniProtKB:Q9Y5P2);CT45A1(UniProtKB:Q5HYN5);CT55(UniProtKB:Q8WUE5);CT-_9 / BRD6(UniProtKB:Q58F21);CTAG2_アイソフォーム_LAGE-1A(UniProtKB:O75638-2);CTAG2_アイソフォーム_LAGE-1B(UniProtKB:O75638);CTCFL(UniProtKB:Q8NI51);Cten(UniProtKB:Q8IZW8);サイクリン_B1(UniProtKB:P14635);サイクリン_D1(UniProtKB:P24385);cyp-B(UniProtKB:P23284);DAM-10(UniProtKB:P43366);DEP1A(UniProtKB:Q5TB30);E7(UniProtKB:P03129);E7(UniProtKB:P06788);E7(UniProtKB:P17387);E7(UniProtKB:P06429);E7(UniProtKB:P27230);E7(UniProtKB:P24837);E7(UniProtKB:P21736);E7(UniProtKB:P26558);E7(UniProtKB:P36831);E7(UniProtKB:P36833);E7(UniProtKB:Q9QCZ1);E7(UniProtKB:Q81965);E7(UniProtKB:Q80956);EF1A2(UniProtKB:Q05639);EFTUD2 / m(UniProtKB:Q15029);EGFR(UniProtKB:A0A0B4J1Y5);EGFR(UniProtKB:E7BSV0);EGFR(UniProtKB:L0R6G1);EGFR(UniProtKB:P00533-2);EGFR(UniProtKB:P00533);EGFR(UniProtKB:Q147T7);EGFR(UniProtKB:Q504U8);EGFR(UniProtKB:Q8NDU8);EGLN3(UniProtKB:Q9H6Z9);ELF2 / m(UniProtKB:B7Z720);EMMPRIN(UniProtKB:Q54A51);EpCam(UniProtKB:P16422);EphA2(UniProtKB:P29317);EphA3(UniProtKB:P29320);EphA3(UniProtKB:Q6P4R6);ErbB3(UniProtKB:B3KWG5);ErbB3(UniProtKB:B4DGQ7);ERBB4(UniProtKB:Q15303);ERG(UniProtKB:P11308);ETV6(UniProtKB:P41212);EWS(UniProtKB:Q01844);EZH2(UniProtKB:F2YMM1);EZH2(UniP rotKB:G3XAL2);EZH2(UniProtKB:L0R855);EZH2(UniProtKB:Q15910);EZH2(UniProtKB:S4S3R8);FABP7(UniProtKB:O15540);FCGR3A_version_1(U UniProtKB:P08637;FCGR3A_version_2(CCDS:CCDS1232.1);FGF5(UniProtKB:P12034);FGF5(UniProtKB:Q60518);FGFR2(UniProtKB:P21802);fibronectin(UniProtKB:A0A024R5I6);fibronectin(UniProtKB:A0A024RB01);fibronectin(UniProtKB:A0A024RDT9);fibronectin(UniProtKB:A0A024RDV5);fibronectin Ionectin (UniProtKB:A6NH44); Fibronectin (UniProtKB:A8K6A5); Fibronectin (UniProtKB:B2R627); Fibronectin (UniProtKB:B3KXM5); Fibronectin (UniProtKB:B4DIC5); Fibronectin (UniProtKB:B4DN21); Fibronectin (UniProtKB:B4DS98); Fibronectin (UniProtKB:B4DTH2); Fibronectin (UniProtKB:B4DTK1); Fibronectin tin (UniProtKB:B4DU16); fibronectin (UniProtKB:B7Z3W5); fibronectin (UniProtKB:B7Z939); fibronectin (UniProtKB:G5E9X3); fibronectin (UniProtKB:Q9H382); FOS (UniProtKB:P01100); FOXP3 (UniProtKB:Q9BZS1); FUT1 (UniProtKB:P19526); G250 (UniProtKB:Q16790); GAGE-1 (Genbank:AAA82744);GAGE-2(UniProtKB:Q6NT46);GAGE-3(UniProtKB:Q13067);GAGE-4(UniProtKB:Q13068);GAGE-5(UniProtKB:Q13069);GAGE-6(UniProtKB:Q13070);GAGE7b(UniProtKB:O76087);GAGE-8_(GAGE-2D)(U; niProtKB:Q9UEU5);GASR(UniProtKB:P32239);GnT-V(UniProtKB:Q09328);GPC3(UniProtKB:I6QTG3);GPC3(UniProtKB:P51654);GPC3(UniProtKB:Q8IYG2);GPNMB / m(UniProtKB:A0A024RA55);GPNMB / m(UniProtKB:Q14956);GPNMB / m(UniProtKB:Q8IXJ5);GPNMB / m(UniProtKB:Q96F58);GRM3(UniProtKB:Q14832);HAGE(UniProtKB:Q9NXZ2);ヘプシン(UniProtKB:B2ZDQ2);ヘプシン(UniProtKB:P05981);Her2 / neu(UniProtKB:B4DTR1);Her2 / neu(UniProtKB:L8E8G2);Her2 / neu(UniProtKB:P04626);Her2 / neu(UniProtKB:Q9UK79);HLA-A2 / m(UniProtKB:Q95387);HLA-A2 / m(UniProtKB:Q9MYF8);ホメオボックス_NKX3.1(UniProtKB:Q99801);HOM-TES-85(UniProtKB:B2RBQ6);HOM-TES-85(UniProtKB:Q9P127);HPG1(Pubmed:12543784);HS71A(UniProtKB:P0DMV8);HS71B(UniProtKB:P0DMV9);HST-2(UniProtKB:P10767);hTERT(UniProtKB:O94807);iCE(UniProtKB:O00748);IF2B3(UniProtKB:O00425);IL10(UniProtKB:P22301);IL-13Ra2(UniProtKB:Q14627);IL2-RA(UniProtKB:P01589);IL2-RB(UniProtKB:P14784);IL2-RG(UniProtKB:P31785);IL-5(UniProtKB:P05113);IMP3(UniProtKB:Q9NV31);ITA5(UniProtKB:P08648);ITB1(UniProtKB:P05556);ITB6(UniProtKB:P18564);Kallikrein-2 (UniProtKB: A0A024R4J4); kallikrein-2 (UniProtKB: A0A024R4N3); kallikrein-2 (UniProtKB: B0AZU9); kallikrein-2 (UniProtKB: B4DU77); kallikrein-2 (UniProtKB: P20151); kallikrein-2 (UniProtKB: Q6T774); kallikrein-2 (UniProtKB: Q6T775); kallikrein-4 (UniProtKB: A0A0C4DFQ5); kallikrein-4 (UniProtKB KB:Q5BQA0);Kallikrein-4(UniProtKB:Q96PT0);Kallikrein-4(UniProtKB:Q96PT1);Kallikrein-4(UniProtKB:Q9Y5K2);KI20A(UniProtKB:O95235);KIAA02 05(UniProtKB:Q92604);KIF2C(UniProtKB:Q99661);KK-LC-1(UniProtKB:Q5H943);LDLR(UniProtKB:P01130);LGMN(UniProtKB:Q99538);LIRB2( UniProtKB:Q8N423);LY6K(UniProtKB:Q17RY6);MAGA5(UniProtKB:P43359);MAGA8(UniProtKB:P43361);MAGAB(UniProtKB:P43364);MAGE-A10( UniProtKB:A0A024RC14);MAGE-A12(UniProtKB:P43365);MAGE-A1(UniProtKB:P43355);MAGE-A2(UniProtKB:P43356);MAGE-A3(UniProtKB:P43 357);MAGE-A4(UniProtKB:A0A024RC12);MAGE-A4(UniProtKB:P43358);MAGE-A4(UniProtKB:Q1RN33);MAGE-A6(UniProtKB:A8K072);MAGE-A6(U niProtKB:P43360);MAGE-A6(UniProtKB:Q6FHI5);MAGE-A9(UniProtKB:P43362);MAGE-B10(UniProtKB:Q96LZ2);MAGE-B16(UniProtKB:A2A368);MAGE-B17(UniProtKB:A8MXT2);MAGE-_B1(UniProtKB:Q96TG1);MAGE-B2(UniProtKB:O15479);MAGE-B3(UniProtKB:O15480);MAGE-B4(UniProtKB:O15481);MAGE-B5(UniProtKB:Q9BZ81);MAGE-B6(UniProtKB:Q8N7X4);MAGE-C1(UniProtKB:O60732);MAGE-C2(UniProtKB:Q9UBF1);MAGE-C3(UniProtKB:Q8TD91);MAGE-D1(UniProtKB:Q9Y5V3);MAGE-D2(UniProtKB:Q9UNF1);MAGE-D4(UniProtKB:Q96JG8);MAGE-_E1(UniProtKB:Q6IAI7);MAGE-E1_(MAGE1)(UniProtKB:Q9HCI5);MAGE-E2(UniProtKB:Q8TD90);MAGE-F1(UniProtKB:Q9HAY2);MAGE-H1(UniProtKB:Q9H213);MAGEL2(UniProtKB:Q9UJ55);マンマグロビン_A(UniProtKB:Q13296);マンマグロビン_A(UniProtKB:Q6NX70);MART-1 / メランA(UniProtKB:Q16655);MART-2(UniProtKB:Q5VTY9);MC1_R(UniProtKB:Q01726);MC1_R(UniProtKB:Q1JUL4);MC1_R(UniProtKB:Q1JUL6);MC1_R(UniProtKB:Q1JUL8);MC1_R(UniProtKB:Q1JUL9);MC1_R(UniProtKB:Q1JUM0);MC1_R(UniProtKB:Q1JUM2);MC1_R(UniProtKB:Q1JUM3);MC1_R(UniProtKB:Q1JUM4);MC1_R(UniProtKB:Q1JUM5);MC1_R(UniProtKB:Q6UR92);MC1_R(UniProtKB:Q6UR94);MC1_R(UniProtKB:Q6UR95);MC1_R(UniProtKB:Q6UR96);MC1_R(UniProtKB:Q6UR97);MC1_R(UniProtKB:Q6UR98);MC1_R(UniProtKB:Q6UR99);MC1_R(UniProtKB:Q6URA0);MC1_R(UniProtKB:Q86YW1);MC1_R(UniProtKB:V9Q5S2);MC1_R(UniProtKB:V9Q671);MC1_R(UniProtKB:V9Q783);MC1_R(UniProtKB:V9Q7F1);MC1_R(UniProtKB:V9Q8N1);MC1_R(UniProtKB:V9Q977);MC1_R(UniProtKB:V9Q9P5);MC1_R(UniProtKB:V9Q9R8);MC1_R(UniProtKB:V9QAE0);MC1_R(UniProtKB:V9QAR2);MC1_R(UniProtKB:V9QAW3);MC1_R(UniProtKB:V9QB02);MC1_R(UniProtKB:V9QB58);MC1_R(UniProtKB:V9QBY6);MC1_R(UniProtKB:V9QC17);MC1_R(UniProtKB:V9QC66);MC1_R(UniProtKB:V9QCQ4);MC1_R(UniProtKB:V9QDF4);MC1_R(UniProtKB:V9QDN7);MC1_R(UniProtKB:V9QDQ6);M-CSF(UniProtKB:P09603);メソテリン(UniProtKB:Q13421);MITF(UniProtKB:O75030-8);MITF(UniProtKB:O75030-9);MITF(UniProtKB:O75030);MMP1_1(UniProtKB:B3KQS8);MMP7(UniProtKB:P09237);MUC-1(Genbank:AAA60019);MUM-1 / m(RefSeq:NP_116242);MUM-2 / m(UniProtKB:Q9Y5R8);MYCN(UniProtKB:P04198);MYO1A(UniProtKB:Q9UBC5);MYO1B(UniProtKB:O43795);MYO1C(UniProtKB:O00159);MYO1D(UniProtKB:O94832);MYO1E(UniProtKB:Q12965);MYO1F(UniProtKB:O00160);MYO1G(UniProtKB:B0I1T2);MYO1H(RefSeq:NP_001094891);NA17(UniProtKB:Q3V5L5);NA88-A(Pubmed:10790436);Neo-PAP(UniProtKB:Q9BWT3);NFYC / m(UniProtKB:Q13952 );NGEP(UniProtKB:Q6IWH7);NPM(UniProtKB:P06748);NRCAM(UniProtKB:Q92823);NSE(UniProtKB:P09104);NUF2(UniProtKB:Q9BZD4);NY-ESO- 1 (UniProtKB:P78358); OA1 (UniProtKB:P51810); OGT (UniProtKB:O15294); OS-9 (UniProtKB:B4DH11); OS-9 (UniProtKB:B4E321); OS-9 (UniProtKB:B7Z8E7); OS-9 (UniProtKB:Q13438); osteocalcin (UniProtKB:P02818); osteopontin (UniProtKB:A0A024RDE2); osteopontin (UniProtKB:A0A024RDE6); Theopontin (UniProtKB:A0A024RDJ0); osteopontin (UniProtKB:B7Z351); osteopontin (UniProtKB:F2YQ21); osteopontin (UniProtKB:P10451); p53 (UniProtKB:P04637); PAGE-4 (UniProtKB:O60829); PAI-1 (UniProtKB:P05121); PAI-2 (UniProtKB:P05120); PAP (UniProtKB:Q06141); PAP (UniProtKB:Q53S56 );PATE(UniProtKB:Q8WXA2);PAX3(UniProtKB:P23760);PAX5(UniProtKB:Q02548);PD1L1(UniProtKB:Q9NZQ7);PDCD1(UniProtKB:Q15116);PDEF (UniProtKB:O95238);PECA1(UniProtKB:P16284);PGCB(UniProtKB:Q96GW7);PGFRB(UniProtKB:P09619);Pim-1_-kinase(UniProtKB:A0A024RD25);Pin-1(UniProtKB:O15428);Pin-1(UniProtKB:Q13526);Pin-1(UniProtKB:Q49AR7);PLAC1(UniProtKB:Q9HBJ0);PMEL(UniProtKB:P40967);PML(UniProtKB:P29590);POTEF(UniProtKB:A5A3E0);POTE(UniProtKB; :Q86YR6);PRAME(UniProtKB:A0A024R1E6);PRAME(UniProtKB:P78395);PRDX5 / m(UniProtKB:P30044);PRM2(UniProtKB:P04554);プロステイン(UniProtKB:Q96JT2);プロテイナーゼ-3(UniProtKB:D6CHE9);プロテイナーゼ-3(UniProtKB:P24158);PSA(UniProtKB:P55786);PSB9(UniProtKB:P28065);PSCA(UniProtKB:D3DWI6);PSCA(UniProtKB:O43653);PSGR(UniProtKB:Q9H255);PSM(UniProtKB:Q04609);PTPRC(RefSeq:NP_002829);RAB8A(UniProtKB:P61006);RAGE-1(UniProtKB:Q9UQ07);RARA(UniProtKB:P10276);RASH(UniProtKB:P01112);RASK(UniProtKB:P01116);RASN(UniProtKB:P01111);RGS5(UniProtKB:O15539);RHAMM / CD168(UniProtKB:O75330);RHOC(UniProtKB:P08134);RSSA(UniProtKB:P08865);RU1(UniProtKB:Q9UHJ3);RU2(UniProtKB:Q9UHG0);RUNX1(UniProtKB:Q01196);S-100(UniProtKB:V9HW39);SAGE(UniProtKB:Q9NXZ1);SART-_1(UniProtKB:O43290);SART-2(UniProtKB:Q9UL01);SART-3(UniProtKB:Q15020);SEPR(UniProtKB:Q12884);SERPINB5(UniProtKB:P36952);SIA7F(UniProtKB:Q969X2);SIA8A(UniProtKB:Q92185);SIAT9(UniProtKB:Q9UNP4);SIRT2 / m(UniProtKB:A0A024R0G8);SIRT2 / m(UniProtKB:Q8IXJ6);SOX10(UniProtKB:P56693);SP17(UniProtKB:Q15506);SPNXA(UniProtKB:Q9NS26);SPXN3(UniProtKB:Q5MJ09);SSX-1(UniProtKB:Q16384);SSX-2(UniProtKB:Q16385);SSX3(UniProtKB:Q99909);SSX-4(UniProtKB:O60224);ST1A1(UniProtKB:P50225);STAG2(UniProtKB:Q8N3U4-2);STAMP-1(UniProtKB:Q8NFT2);STEAP-1(UniProtKB:A0A024RA63);STEAP-1(UniProtKB:Q9UHE8);サバイビン-2B(UniProtKB:O15392-2);サバイビン(UniProtKB:O15392);SYCP1(UniProtKB:A0A024R0I2);SYCP1(UniProtKB:B7ZLS9);SYCP1(UniProtKB:Q15431);SYCP1(UniProtKB:Q3MHC4);SYT-SSX-1(UniProtKB:A4PIV7);SYT-SSX-1(UniProtKB:A4PIV8);SYT-SSX-2(UniProtKB:A4PIV9);SYT-SSX-2(UniProtKB:A4PIW0);TARP(UniProtKB:Q0VGM3);TCRg(UniProtKB:A2JGV3);TF2AA(UniProtKB:P52655);TGFB1(UniProtKB:P01137);TGFR2(UniProtKB:P37173);TGM-4(UniProtKB:B2R7D1);TIE2(UniProtKB:Q02763);TKTL1(UniProtKB:P51854);TPI / m(UniProtKB:P60174);TRGV11(UniProtKB:Q99601);TRGV9(UniProtKB:A4D1X2);TRGV9(UniProtKB:Q99603);TRGV9(UniProtKB:Q99604);TRPC1(UniProtKB:P48995);TRP-p8(UniProtKB:Q7Z2W7);TSG10(UniProtKB:Q9BZW7);TSPY1(UniProtKB:Q01534);TVC_(TRGV3)(Genbank:M13231.1);TX101 (UniProtKB: Q9BY14-2); tyrosinase (UniProtKB: A0A024DBG7); tyrosinase (UniProtKB: L8B082); tyrosinase (UniProtKB: L8B086); tyrosinase (UniProtKB: L8B0B9); tyrosinase (UniProtKB: O75767); tyrosinase (UniProtKB: P14679); tyrosinase (UniProtKB: U3M8N0); tyrosinase (UniProtKB: U3M9D5; tyrosinase (UniProtKB: U3M9J2); TYRP1 (UniProtKB: P17643); TYRP2 (UniProtKB: P40126); UPA (UniProtKB: Q96NZ9); VEGFR1 (UniProtKB: B5A924); WT1 (UniProtKB: A0A0H5AUY0); WT1 (UniProtKB: P19544); WT1 (UniProtKB: Q06250); XAGE1 (UniProtKB: Q9HD64);

[0181] Checkpoint inhibitors Negative regulatory T cell surface molecules have been discovered that are upregulated on activated T cells, thereby attenuating their activity and, therefore, reducing the effectiveness of activated T cells in killing tumor cells. These inhibitory molecules were called negative costimulatory molecules because of their similarity to the T cell costimulatory molecule CD28. These proteins, also known as immune checkpoint proteins, function in multiple pathways, including attenuation of initial activation signals, competition for positive costimulation, and direct inhibition of antigen-presenting cells (Bour-Jordan et al., 2011. Immunol Rev. 241(1):180-205).

[0182] In the context of the present invention, a checkpoint modulator is typically a molecule such as a protein (e.g., an antibody), dominant-negative receptor, decoy receptor, or ligand or fragment or variant thereof that modulates the function of an immune checkpoint protein, e.g., it inhibits or reduces the activity of a checkpoint inhibitor (or inhibitory checkpoint molecule), or it stimulates or enhances the activity of a checkpoint stimulator (or stimulatory checkpoint molecule). Thus, a checkpoint modulator as defined herein affects the activity of a checkpoint molecule.

[0183] In this context, inhibitory checkpoint molecules are defined as, and can be used synonymously with, checkpoint inhibitors, and stimulatory checkpoint molecules are defined as, and can be used synonymously with, checkpoint stimulators.

[0184] Preferably, the checkpoint modulator is selected from an agonist antibody, an antagonist antibody, a ligand, a dominant negative receptor, and a decoy receptor, or a combination thereof.

[0185] Methods for making and using antibodies encoded by mRNA are known in the art (e.g., WO 2008 / 083949 or PCT / EP2017 / 060226).

[0186] Preferred inhibitory checkpoint molecules that may be inhibited by checkpoint modulators in the context of the present invention are PD-1, PD-L1, CTLA-4, PD-L2, LAG3, TIM3 / HAVCR2, 2B4, A2aR, B7H3, B7H4, BTLA, CD30, CD160, CD155, GAL9, HVEM, IDO1, IDO2, KIR, LAIR1, and VISTA.

[0187] Preferred stimulatory checkpoint molecules that may be stimulated by checkpoint modulators in the context of the present invention are CD2, CD27, CD28, CD40, CD137, CD226, CD276, GITR, ICOS, OX40 and CD70.

[0188] According to a preferred embodiment, the pharmaceutical composition or vaccine comprising the RNA of the invention is for the use as described herein, which use comprises - as an additional pharmaceutically active ingredient - a checkpoint modulator selected from the group consisting of checkpoint modulators selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, TIGIT-inhibitors, OX40 stimulants, 4-1BB stimulants, CD40L stimulants, CD28 stimulants and GITR stimulants.

[0189] According to a preferred embodiment, a checkpoint modulator as used herein targets a member of the PD-1 pathway. Members of the PD-1 pathway are typically proteins involved in PD-1 signaling. On the one hand, this group includes proteins PD-L1 and PD-L2, which are upstream of PD-1 and induce PD-1 signaling, e.g., as ligands of PD-1, and the signaling receptor PD-1. On the other hand, this group includes signaling proteins downstream of the PD-1 receptor. Particularly preferred members of the PD-1 pathway in the context of the present invention are PD-1, PD-L1, and PD-L2.

[0190] In the context of the present invention, a PD-1 pathway antagonist (or PD-1 inhibitor) is preferably defined herein as a compound that has the ability to impair PD-1 pathway signaling, preferably signaling mediated by the PD-1 receptor. Thus, a PD-1 pathway antagonist can be any antagonist of any member of the PD-1 pathway that has the ability to antagonize PD-1 pathway signaling.

[0191] In preferred embodiments, a checkpoint modulator as used herein is a PD-1 inhibitor or a PD-L1 inhibitor, where the PD-1 inhibitor is preferably an antagonistic antibody against PD-1, and the PD-L1 inhibitor is preferably an antagonistic antibody against PD-L1.

[0192] In this regard, the antagonist may be an antagonist antibody, as defined herein, that targets any member of the PD-1 pathway, preferably an antagonist antibody against the PD-1 receptor PD-L1 or PD-L2. Such an antagonist antibody may also be encoded by a nucleic acid. The PD-1 pathway antagonist may also be a fragment of the PD-1 receptor that blocks the activity of the PD-1 ligand. B7-1 or a fragment thereof may also act as a PD-1 antagonist ligand. In addition, the PD-1 pathway antagonist may be a protein (or a nucleic acid encoding the same) that contains an amino acid sequence that binds to PD-1 but has the ability to disrupt PD-1 signaling, for example, by inhibiting the interaction of PD-1 with B7-H1 or B7-DL (WO 2014 / 127917; WO 2012062218).

[0193] In particular, the anti-PD1 antibodies nivolumab (MDX-1106 / BMS-936558 / ONO-4538), (Brahmer et al., 2010. J Clin Oncol. 28(19):3167-75; PMID:20516446); pidilizumab (CT-011), (Berger et al., 2008. Clin Cancer Res. 14(10):3044-51; PMID:18483370); pembrolizumab (MK-3475, SCH 900475); AMP-224, and MEDI0680 (AMP-514) are preferred.

[0194] Also particularly preferred are the anti-PD-L1 antibodies MDX-1105 / BMS-936559 (Brahmer et al. 2012. N Engl J Med. 366(26):2455-65; PMID:22658128); atezolizumab (MPDL3280A / RG7446); durvalumab (MEDI4736); and avelumab (MSB0010718).

[0195] According to another embodiment, the checkpoint modulator used herein is an OX40 stimulator. OX40 is a member of the TNFR receptor superfamily and is expressed on the surface of antigen-activated mammalian CD4+ and CD8+ T lymphocytes. OX40 ligand (OX40L, also known as gp34, ACT-4-L, and CD252) is a protein that specifically interacts with the OX40 receptor. The term OX40L includes whole OX40 ligand, soluble OX40 ligand, and fusion proteins containing a functionally active portion of OX40 ligand covalently linked to a second portion, e.g., a protein domain. Also included within the definition of OX40L are variants that differ in amino acid sequence from naturally occurring OX40L but retain the ability to specifically bind to the OX40 receptor. Additionally, within the definition of OX40L are variants thereof that enhance the biological activity of OX40. An OX40 agonist is a molecule that induces or enhances the biological activity of OX40, e.g., OX40-mediated signal transduction. An OX40 agonist is preferably defined herein as a binding molecule capable of specifically binding to OX40. Thus, an OX40 agonist can be any agonist that binds to OX40 and has the ability to stimulate OX40 signaling. In this context, an OX40 agonist can be an agonist antibody that binds to OX40.

[0196] OX40 agonists and anti-OX40 monoclonal antibodies are described in WO 1995 / 021251, WO 1995 / 012673, and WO 1995 / 21915. In particular, the anti-OX40 antibody 9B12, a murine anti-OX40 monoclonal antibody directed against the extracellular domain of human OX40, is preferred (Weinberg et al., 2006. J. Immunother. 29(6):575-585).

[0197] In another embodiment, a checkpoint modulator as used herein is an antagonist antibody selected from the group consisting of anti-CTLA4, anti-PD1, anti-PD-L1, anti-Vista, anti-Tim-3, anti-TIGIT, anti-LAG-3, and anti-BTLA.

[0198] Preferably, anti-CTLA4 antibodies that can be used as checkpoint modulators are directed against cytotoxic T lymphocyte antigen-4 (CTLA-4). CTLA-4 is primarily expressed in the intracellular compartment of T cells. After strong or persistent stimulation of naive T cells via the T cell receptor (TCR), CTLA-4 is transported to the cell surface and concentrated at the immunological synapse. CTLA-4 then competes with CD28 for CD80 / CD86 and downregulates TCR signaling through its effect on Akt signaling. Thus, CTLA-4 functions physiologically as a signal suppressor (Weber, J. 2010. Semin. Oncol. 37(5):430-9).

[0199] In a preferred embodiment, the pharmaceutical composition or vaccine comprising the RNA of the present invention is for use as described herein, and the use comprises—as an additional pharmaceutically active ingredient—a CTLA4 antagonist, preferably an antagonist antibody against CTLA4 (anti-CTLA4 antibody). The term "CTLA4 antagonist," as used herein, includes any compound, such as an antibody, that antagonizes the physiological function of CTLA4. In the context of the present invention, the term "anti-CTLA4 antibody" may refer to an antagonist antibody against CTLA4 (or a functional fragment or variant of said antibody) or a nucleic acid, preferably RNA, encoding said antagonist antibody (or a functional fragment thereof). A functional fragment or variant of an anti-CTLA4 antibody preferably acts as a CTLA4 antagonist. More preferably, the term "anti-CTLA4 antibody" refers to a monoclonal antibody against CTLA4 (or a functional fragment or variant of such an antibody) or a nucleic acid encoding a monoclonal antibody against CTLA4 (or a functional fragment or variant of such an antibody). The term "anti-CTLA4 antibody," as used herein, may refer to a heavy or light antibody chain, respectively, or may also refer to both antibody chains (heavy and light), or to a fragment or variant of any one of these chains. Preferably, a fragment or variant of an anti-CTLA4 antibody as used herein is preferably a functional fragment or variant as described herein.

[0200] Particularly preferred are the anti-CTLA-4 antibodies ipilimumab (Yervoy®), tremelimumab, and AGEN-1884. Further preferred anti-CTLA4 antibodies as used herein include BMS 734016; BMS-734016; BMS734016; MDX 010; MDX 101; MDX-010; MDX-101; MDX-CTLA-4; MDX-CTLA4; MDX010; Winglore; and Yervoy, or a functional fragment or variant of any one of these antibodies.

[0201] According to a further embodiment, a checkpoint modulator as used herein is at least one antibody listed in Table 1, or a fragment or variant thereof.

[0202] [Table 1]

[0203] [Table 2]

[0204] Standard therapy More preferably, the subject to be administered the pharmaceutical composition or vaccine comprising an RNA of the present invention, a combination thereof, or a pharmaceutical composition or vaccine comprising one or more of said RNAs is a patient suffering from a tumor or cancer disease as described herein who has been or will be administered chemotherapy (e.g., first-line or second-line chemotherapy), radiation therapy, chemoradiotherapy (combined chemotherapy and radiation therapy), kinase inhibitors, antibody therapy and / or checkpoint modulators (e.g., CTLA4 inhibitors, PD1 pathway inhibitors), or who has achieved a partial response or stable disease after receiving one or more of the above-specified treatments. More preferably, the subject is a patient suffering from a tumor or cancer disease as described herein who has been or will be administered a compound conventionally used in any of these diseases as described herein, more preferably a patient who will be or will be administered a checkpoint modulator.

[0205] The following compounds are preferred compounds that are preferably used in standard therapy and that can be applied in combination with a pharmaceutical composition or vaccine comprising the RNA of the present invention: cetuximab (Erbitux), albumin-bound paclitaxel (Abraxane), (gimeracil + oteracil + tegafur) (TS-1), docetaxel (docetaxel, doxel, Taxotere, docetaxel An, Docel, Nanoxel M).M), Tautax, Docetaxel-AS, Docetaxel-M, Qvidadotax, Relidoce, Taxelo, Oncodocel, Doxotel, Pacancer, Docetrust, Dodetax, Dodabur, Soulaxcin, Taxedol, Docefim ), Docetaxel, Ribodoc, Critidoc, Asodoc, Chemodoc, Docelibbs, Docenat, Dincilezan, Dostradixinol, Docefrez, Camitotic, Oncotaxel, Somatixel, Berotaxel Taxel, Qvidadotax, Taxceus, Cetadocure, Docetaxel CT, Tevaxter, Docirena, Eurotere, Axtere, Celotax, Taxanit, Drobanos, Cetado, Doxocad, Taxceus, Egido x), Tedocad, Docecad, Docecad, Docelex, Docetax, Docetaxel, Docetere, Dotax, Taxuba, Monotaxel, Taceedo, Detaxl, Docet, Docetaxel, Ferdotax, Wintaxel), (Tegafur + uracil) (Uft, UftE, Tefudex, Unitoral, Luporal, Tagracil, Fluorouracil (5-FU), (Gimeracil + Oteracil + Tegafur) ODT (TS-1 combination OD), Bleomycin sulfate (Tecnomicina, Cinaleo), Bleomycin, Bloicin-S, Bonar, Bleocin n), Bleomycin sulfate, Bleo, Bleocel, Bleotex, Oncobleo, Bleonco, Bleosol, Lyoble, Bleomycin sulfate, Blenamax, Bleomycin, Blenoxane, Bleomycinina, Bleomycin Veron Bellon, Bleoprim), carboplatin (Carboplatin, Platamine CS, Carbaccord, Carboplatina, Carboplatino, Paraplatin, Carbosin, Tecnocarb, Carbomerck, Paract, Carboplatin CTRS, Carboplatin Anselquimo Chimos, carboplatin, Carbokem, Carbotinol, Fauldcarbo, Evocarb, Citoplatina, Platin, ciprofloxacin (Hypoflox, Ufexil), ciprofloxacin hydrochloride (Ciprofloxacin Pharma)Pharma, Prodin, Ciproxin, Cisplatin, Stritin, Ifapla, Accocit, Unistin, Cancertin, Cisplan, Citoplax, Nuoxin, Placis, Cisplatino, Displanor, Randa, Cispla, Fauldcispla, Briplatin, Platinex, Platinol, Platinex, Riboplatin, Cisplatin, Platistine CS CS), Platosin, Accocit, Cisplatino), Cyclophosphamide (Endoxan, Cyclophosphamide), Doxifluridine (Doxifluridine, May Vladimir), Doxorubicin (Doxorubicin Hydrochloride, Adriamycin RDF, Doxorubicin, Doxorubicin PFS), Epirubicin Hydrochloride (Brecila, Cloridrato De Epirubicin) Epirrubicina, Epirubicin, Farmorubicina, Nuovodox, Adnexa, 4-Eppedo, Favicin, Fluorouracil (Agicil, Fluorouracil, Fauldfluor, Oncourcil, Flocil, 5FlucellFlucel), folic acid plus methotrexate (Truxofol), human adenovirus type 5 (recombinant) (Oncorine), hydroxyurea (Oxyrea, Durea, Myelostat, Riborea, Unidrea, Ondrea, Hydran, Leukocel, hydroxyurea, Hydrea), ifosfamide (Holoxan, Ifosfamide EG), levamisole (Zirsol), methotrexate Methotrexate (Tratoben, Methotrexate, Fresexate, Neometho, Fauldmetro, Methotrexate sodium, Methocel, Hytas, Methaccord, Methofill, Metotrexato, Traxacord, Plastomet, Tevatrex, Metrex, Caditrex, Carditrex, Vibzi) , Imutrex, Biotrexate, Methorex, Mexate, Neotrexate, Oncotrex, Remtrex, Trixilem, Hi-Trex, Metorex, Trex, Unitrexate, Ebetrexac, Fauldexato, Lantarel, Maxtrex, Miantrex CS, Rheumatrex, Folex, Folex PFSPFS, Abitrexate, Tevametho, Trexall, Emthexate, Abitrexate, Meadow, Mitomycin (Mitomycin C, Mitomycin, Mitonco, Lyomit), Nedaplatin (Jiebaishu, Aoxianda, Aqupla), Nimesulide (Nimulid), Nimotuzumab (Biomab EGFR) EGFR, Laedemab), Nitrofurantoin (Furatsilin), Ofloxacin (Entof), Paclitaxel (Paclitaxel, Taxol), Peplomycin sulfate (Pepleo), Picibanil (Picibanil), Pirarubicin (Pirarubicin hydrochloride, Rarubicin, Pinorubin), Sodium Glycidazole (Sodium glycididazole (CMNa), tegafur (Utefos, Icarus, Futraful, tegafur-gimeracil-oteracil potassium), temoporfin (Foscan), topotecan hydrochloride (topotecan), ubenimex (Ubenimex), vinblastine sulfate (Vblastin), vincristine sulfate (vincristine, vincristine sulfate, vincristine, stibine), vindesine sulfate (Eldisine), carboplatin (Carboplatin Qualimed)Qualimed, Carboplatin, Carboplatino, Carboplatin, Cisplatin, Docetaxel, Kamdocon, Naltoxater, Docetaxel, Fluorouracil, Methotrexate, Methotrexate Sodium, Mexate, Mexate Aq Aq), Biometrox, Medsatrexate, Otaxem, Vincristine sulfate (Oncovin), Fluorouracil, Sunitinib malate, Acitretin, Fibrin sealant, Cetuximab, Erlotinib, Cisplatin; Docetaxel; Fluorouracil, Undisclosed anticancer drugs , gefitinib, pravastatin sodium, sirolimus, undisclosed chemotherapy, cisplatin; docetaxel; fluorouracil, sirolimus, fluorouracil; undisclosed taxane, methyl aminolevulinate hydrochloride, cisplatin; docetaxel; fluorouracil, erlotinib hydrochloride, cetuximab, imiquimod, undisclosed herbal medicine, aspirin; enalapril maleate, undisclosed chemotherapy, cetuximab, (gi gimeracil + oteracil + tegafur); carboplatin; cisplatin, cisplatin; fluorouracil; nimotuzumab, carboplatin; albumin-bound paclitaxel, cisplatin; nedaplatin, bleomycin, nedaplatin, cisplatin; paclitaxel, albumin-bound paclitaxel, (gimeracil + oteracil + tegafur), bleomycin; undisclosed chemotherapy, apatinib; docetaxel, undisclosed Published immunomodulatory supplements, BCM-95, aminolevulinic acid hydrochloride, nedaplatin, cisplatin; palifermin, cetuximab, gefitinib, bevacizumab, beragen pmatucel-L, cisplatin; tirapazamine, cisplatin; tirapazamine, cisplatin; gemcitabine; paclitaxel; topotecan; vinorelbine, cisplatin; fluorouracil, panitumumab, carboplatin; docetaxel ; gemcitabine hydrochloride; vinorelbine tartrate, amifostine; fluorouracil, cisplatin; fluorouracil, carboplatin; paclitaxel, tirapazamine, cisplatin; epoetin alfa, figitumumab, melphalan; tumor necrosis factor alf, cisplatin; fluorouracil, cisplatin; undisclosed chemotherapy, docetaxel, contusugene ladenovec ladenovec), cisplatin; fluorouracil; paclitaxel, docetaxel, human papillomavirus [serotypes 16 and 18] (bivalent) vaccine, isotretinoin, cisplatin; fluorouracil, misonidazole, paclitaxel, palifermin, endostatin, pilocarpine, cisplatin; docetaxel; filgrastim; fluorouracil; paclitaxel, cisplatin; docetaxel; filgrastim; fluorouracil; paclitaxel, cisplatin; irinotecan hydrochloride, cisplatin;Gemcitabine, cisplatin; epirubicin; fluorouracil; undisclosed chemotherapy, methyl aminolevulinate hydrochloride, carboplatin; paclitaxel, carbogen; carbon dioxide; niacinamide, cisplatin; fluorouracil, talimogene laherparepvec, epoetin alfa, cisplatin; fluorouracil; panitumumab, cisplatin; fluorouracil, cisplatin; fluorouracil, aldesleukin, cisplatin; fluorouracil cisplatin; paclitaxel, cisplatin; fluorouracil, fluorouracil; leucovorin; lobaplatin, cisplatin, cisplatin; ethyl mercaptan; ifosfamide; mesna; mitolactol, doxorubicin; levamisole, (tegafur + uracil), cisplatin; fluorouracil, cisplatin; vinorelbine, carboplatin; cisplatin; gemcitabine hydrochloride, Corynebacterium parvum (Corynebacterium parvum); doxorubicin, capecitabine; cisplatin; fluorouracil; paclitaxel, fluorouracil; leucovorin; methotrexate, rAd-p53, cetuximab; cisplatin; docetaxel, PV-10, methyl aminolevulinate hydrochloride, cisplatin; fluorouracil, paclitaxel; topotecan hydrochloride, carboplatin; cisplatin; paclitaxel, cisplatin; topotecan hydrochloride, cisplatin; etoposide, docetaxel; fluorouracil, aspirin, cisplatin; gemcitabine, Lactobacillus brevis (Lactobacillus brevis) CD2, cisplatin; docetaxel, fosbretabulin tromethamine, panitumumab, fluorouracil, paclitaxel, carboplatin; cisplatin; docetaxel; fluorouracil, fluorouracil, erlotinib hydrochloride, cisplatin; undisclosed chemotherapy; vinorelbine, (gimeracil + oteracil + tegafur); carboplatin, cetuximab, contusugene ladenovec, cetuximab, methyl aminolevulinate hydrochloride, cyclophosphamide, (gimeracil + oteracil + tegafur); cisplatin, albumin-bound paclitaxel, carboplatin; paclitaxel, cisplatin;Gemcitabine, capecitabine; cisplatin, docetaxel, Z-100, cisplatin; ifosfamide; paclitaxel, nimotuzumab, irinotecan hydrochloride, celecoxib; methotrexate, Nutrison, carboplatin; cisplatin; fluorouracil; paclitaxel, cisplatin; paclitaxel, cisplatin; docetaxel; vinorelbine, paclitaxel, (gimeracil + oteracil + tegafur); cisplatin, carboplatin; paclitaxel, aminolevulinic acid methyl hydrochloride, Aibin, cisplatin; fluorouracil, porfimer sodium, carboplatin; cisplatin; tocotrienol; vinorelbine, (gimeracil + oteracil + tegafur); cisplatin; paclitaxel, docetaxel, i Pilimumab, cisplatin, VB-4847, celecoxib; thalidomide, cisplatin; epirubicin; fluorouracil, cisplatin; fluorouracil, fluorouracil, carboplatin; paclitaxel, cetuximab; cisplatin; docetaxel, autologous cytokine-induced killer cells, cisplatin; docetaxel; fluorouracil, cisplatin; epirubicin; fluorouracil, tergenpumatucel-L, cetuximab; cisplatin; docetaxel, Elental, cisplatin; nimotuzumab; paclitaxel, eicosapentaenoic acid; undisclosed nutritional supplement, palbociclib, pembrolizumab (Keytruda), nimotuzumab, apatursen, and dacomitinib.

[0206] Oncology indications As used herein, the terms "tumor," "cancer," or "cancer disease" include, but are not limited to, adenoid cystic carcinoma, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma / malignant fibrous histiocytoma, brain stem glioma, brain tumor, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma / carcinoid, Burkitt's lymphoma, pediatric cancer, luteinoid tumors, gastrointestinal carcinoid tumors, cancer of unknown primary origin, primary central nervous system lymphoma, childhood cerebellar astrocytoma, childhood cerebral astrocytoma / malignant glioma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, colon cancer, cutaneous T-cell lymphoma including mycosis fungoides and Sézary syndrome, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma of the Ewing's tumor family, pediatric extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct carcinoma, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancercancer), gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), extracranial, extragonadal, or ovarian germ cell tumor, gestational trophoblastic tumor, brain stem glioma, childhood cerebral astrocytoma, childhood visual pathway and hypothalamic glioma, gastric carcinoid, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma (liver cancer), Hodgkin's lymphoma, human papillomavirus (HPV)-associated cancer, hypopharyngeal cancer, childhood hypothalamic and visual pathway glioma, intraocular melanoma, pancreatic islet cell carcinoma (endocrine pancreas), Kaposi's sarcoma, kidney cancer (renal cell carcinoma), laryngeal cancer, lip and oral cavity cancer, liposarcoma , liver cancer, non-small cell lung cancer, small cell lung cancer, lymphoma, AIDS-related lymphoma, Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, malignant fibrous histiocytoma / osteosarcoma of bone, childhood medulloblastoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, adult malignant mesothelioma, childhood mesothelioma, head and neck cancer, oral cancer, childhood multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, multiple myeloma (bone marrow cancer), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer (Table stratified epithelial and stromal tumors), ovarian germ cell tumors, ovarian tumors of low malignant potential, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germ cell tumor, childhood pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary adenoma, plasma cell neoplasm / plasmacytoma / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma (kidney cancer), renal pelvis and ureter cancer, retinoblastoma, childhood rhabdomyosarcoma, salivary gland cancer, Ewing's sarcoma family tumors, Kaposi's sarcoma, soft tissue sarcoma, uterine sarcoma, skin It refers to a malignant disease preferably selected from the group consisting of skin cancer (non-melanoma), skin cancer (melanoma), Merkel cell skin cancer, small intestine cancer, squamous cell carcinoma, metastatic squamous cell carcinoma of the cervix of unknown primary site, soft tissue sarcoma (STS), pediatric supratentorial primitive neuroectodermal tumor, testicular cancer (seminoma and non-seminoma), throat cancer, pediatric thymoma, thymoma and thymic carcinoma, thyroid cancer, pediatric thyroid cancer, renal pelvis and ureteral transitional cell carcinoma, gestational trophoblastic tumor, urethral cancer, endometrial cancer, uterine sarcoma, vaginal cancer, pediatric visual pathway and hypothalamic glioma, vulvar cancer, and pediatric Wilms' tumor (kidney cancer).

[0207] Allergenic antigens: Antigens associated with allergies or allergic diseases (allergens or allergenic antigens) are preferably derived from a source selected from the list consisting of: Acarus spp. (Aca s 1, Aca s 10, Aca s 10.0101, Aca s 13, Aca s 13.0101, Aca s 2, Aca s 3, Aca s 7, Aca s 8), Acanthocybium spp. (Aca so 1), Acanthocheilonema spp. (Aca v 3, Aca v 3.0101), Acetes spp. (Ace ja 1), Actinidia spp. (Act a 1, Act c 1, Act c 10, Act c 10.0101, Act c 2, Act c 4, Act c 5, Act c 5.0101, Act c 8, Act c 8.0101, Act c chitinase, Act d 1, Act d 1.0101, Act d 10, Act d 10.0101, Act d 10.0201, Act d 11, Act d 11.0101, Act d 2, Act d 2.0101, Act d 3, Act d 3.0101, Act d 3.02, Act d 4, Act d 4.0101, Act d 5, Act d 5.0101, Act d 6, Act d 6.0101, Act d 7, Act d 7.0101, Act d 8, Act d 8.0101, Act d 9, Act d 9.0101, Act d chitinase, Act e 1, Act e 5), Acyrthosiphon spp. (Acy pi 7, Acy pi 7.0101, Acy pi 7.0102), Adenia spp. (Ade v RIP), Aedes spp. (Aed a 1, Aed a 1.0101, Aed a 2, Aed a 2.0101, Aed a 3, Aed a 3.0101, Aed a 4, Aed a 7, Aed a 7.0101, Aed a 7.0102, Aed a 7.0103, Aed a 7.0104, Aed a 7.0105, Aed a 7.0106, Aed a 7.0107, Aed a 7.0108, Aed a 7.0109, Aed a 7.0110, Aed a 7.0111, Aed al 1, Aed al 3, Aed al 37kD, Aed v 37kD, Aed v 63kD), Aegilops spp (Aeg ta 28, Aeg ta α_gliadin, Aeg um 28, Aeg un 28), Aethaloperca spp (Aet ro 1), Agropyron spp (Agr c 7), Agrostis spp (Agr ca 1, Agr ca 5, Agr g 1, Agr g 4, Agr s 5), Agrobacterium spp (Agr sp CP4) EPSPS), giant panda species (Ailuropoda spp) (Ail me Phosvitin, Ail me TCTP), Aix spp. (Aix ga 1, Aix sp 1), Aleuroglyphus spp. (Ale o 1, Ale o 10, Ale o 10.0101, Ale o 10.0102, Ale o 13, Ale o 14, Ale o 2, Ale o 20, Ale o 3, Ale o 5, Ale o 7, Ale o 8, Ale o 9), Allium spp. (All a 3, All a alliin lyase, All c 3, All c 30kD, All c 4, All c alliin lyase, All p alliin lyase, All s Alliin lyase), Alnus spp. (Aln g 1, Aln g 1.0101, Aln g 1 / Bet v 1 / Cor a 1 TPC7, Aln g 1 / Bet v 1 / Cor a 1 TPC9, Aln g 2, Aln g 4, Aln g 4.0101), Alopochen spp. (Alo ae 1), Alopecurus spp. (Alo p 1, Alo p 5), Alternaria spp. (Alt a 1, Alt a 1.0101, Alt a 1.0102, Alt a 10, Alt a 10.0101, Alt a 12, Alt a 12.0101, Alt a 13, Alt a 13.0101、High to 2、High to 3、High to 3.0101、High to 4、High to 4.0101、High to 5、High to 5.0101、High to 6、High to 6.0101、High to 7、High to 7.0101、High to 70kD、High to 8、High to 8、High to 9、High to MnSOD、Alt a NTF2、Alt a TCTP、Alt ar 1、Alt arg 1、Alt b 1、Alt bl 1、Alt br 1、Alt c 1、Alt ca 1、Alt ce 1、Alt ch 1、Alt ci 1、Alt co 1、Alt cr 1、Alt ct 1、Alt cu 1、Alt cy 1、Alt d 1、Alt du 1、Alt e 1、Alt et 1、Alt eu 1、Alt ga 1、High gr 1、High j 1, Alt l 1, Alt lo 1, Alt m 1, Alt me ​​1, Alt mi 1, Alt mo 1, Alt o 1, Alt p 1, Alt ph 1, Alt po 1, Alt ps 1, Alt r 1, Alt s 1, Alt se 1, Alt sm 1, Alt so 1, Alt su 1, Alt t 1, Alt te 1, Alt to 1), Amaranthus spp. (Amaranthus spp.) (Amaranthus 2, Amaranthus 2.0101, Ama v 2, Ama v 2.0101, Ama v 2.0201), Ambrosia spp. (Amb a 1, Amb a 1.0101, Amb a 1.0201, Amb a 1.0202, Amb a 1.0301, Amb a 1.0302, Amb a 1.0303, Amb a 1.0304, Amb at 1.0305、With at 1.0401、With at 1.0402、With at 1.0501、With at 1.0502、With at 10、With at 10.0101、With at 3、With at 3.0101、With at 4、With at 4.0101、With at 5、With at 5.0101、With at 6、With at 6.0101、With at 7、With at 7.0101、With at 8、With at 8.0101、With at 8.0102, Amb a 9, Amb a 9.0101, Amb a 9.0102, Amb a CPI, Amb p 1, Amb p 5, Amb p 5.0101, Amb p 5.0201, Amb t 5, Amb t 5.0101, Amb t 8), Ammothea spp) (Amm h 7, Amm h 7.0101), Anadara spp (Ana br 1), Ananas spp (Ana c 1, Ana c 1.0101, Ana c 2, Ana c 2.0101、Ana c 2.0101 (MUXF3)), Anas spp (Ana ca 1), Anarhichas spp (Ana l 1), Anacardium spp) (Ana o 1, Ana o 1.0101, Ana o 1.0102, Ana o 2, Ana o 2.0101, Ana o 3, Ana o 3.0101), Anas spp (Ana p 1, Ana p 2, Ana p 3), Anguilla spp (Ang a 1, Ang j 1), Anisakis spp (Ani s 1, Ani s 1.0101, Ani s 10, Ani s 10.0101, Ani s 11, Ani s 11.0101, Ani s 12, Ani s 12.0101, Ani s 2.Ani s 2.0101,Ani s 24kD,Ani s 3,Ani s 3.0101,Ani s 4,Ani s 4.0101,Ani s 5,Ani s 5.0101,Ani s 6,Ani s 6.0101,Ani s 7,Ani s 7.0101、Ani s 8、Ani s 8.0101、Ani s 9、Ani s 9.0101、Ani s CCOS3、Ani s シトクロムB、Ani s FBPP、Ani s NADHDS4L、Ani s NARaS、Ani s PEPB、Ani sトロポニン), Anopheles spp (Ano da 17, Ano da 17.0101, Year 27, Year 27.0101, Year 7, Year 7.0101, Year g 7, Year g 7.0101), Anser spp (Ans a 1, Ans a 2, Ans a 3, Ans in 1), Anthoxanthum spp (Ant o 1, Ant o 1.0101, Ant o 12, Ant o 13, Ant o 2, Ant o 4, Ant o 5, Ant o 6, Ant o 7), Apis spp (Api c 1, Api c 1.0101, Api c 10, Api c 2, Api c 4, Api d 1, Api d 1.0101, Api d 4, Api fl 4), Apium spp (Api g 1, Api g 1.0101, Api g 1.0201, Api g 2, Api g 2.0101, Api g 3, Api g 3.0101, Api g 4, Api g 4.0101, Api g 5, Api g 5.0101, Api g 6, Api g 6.0101), Apis spp (Api m 1, Api m 1.0101, Api m 10, Api m 10.0101, Api m 11, Api m 11.0101, Api m 11.0201, Api m 13kD, Api m 2, Api m 2.0101, Api m 3, Api m 3.0101, Api m 4, Api m 4.0101, Api m 5, Api m 5.0101, Api m 6, Api m 6.0101, Api m 7, Api m 7.0101, Api m 8, Api m 8.0101, Api m 9, Api m 9.0101, Api m A1 - A2, Api m A1 - A2 - A3, Api m apalbumin 1, Api m apalbumin 2, Api me 1, Api me 4), Arachis spp (Ara d 2, Ara d 6, Ara f 3, Ara f 4, Ara h 1, Ara h 1.0101, Ara h 10, Ara h 10.0101, Ara h 10.0102, Ara h 11, Ara h 11.0101, Ara h 2, Ara h 2.0101、Ara h 2.0102、Ara h 2.0201、Ara h 2.0202、Ara h 3、Ara h 3.0101、Ara h 4、Ara h 4.0101、Ara h 5、Ara h 5.0101、Ara h 6、Ara h 6.0101、Ara h 7、Ara h 7.0101、Ara h 7.0201、Ara h 7.0202、Ara h 8、Ara h 8. 0101, Ara h 8.0201, Ara h 9, Ara h 9.0101, Ara h 9.0201, Ara h agglutinin, Ara h oleosin 18kD, Ara i 2, Ara i 6), Arabidopsis spp. (Ara t 3, Ara t 8, Ara t GLP), Archosargus spp. (Arc pr 1), Archaeopotamobius spp. (Arc s 8, Arc s 8.0101), Aequipecten spp. (Arg i 1), Argas spp. (Arg r 1, Arg r 1.0101), Ariopsis spp. (Ari fe 1), Armoracia spp. (Arm r HRP), Arrhenatherum spp. (Arr e 1, Arr e 5), Artemisia spp. (Art a 1, Art ap 1), Artemia spp. (Art fr 1, Art fr 1.0101, Art fr 5, Art fr 5.0101), Arthrobacter spp. (Art gl CO), Achorion spp. (Art gy 7), Artocarpus spp. (Art h 17kD, Art h 4), Arthrospira spp (Art pl β_phycocyanin), Artemisia spp (Art v 1, Art v 1.0101, Art v 1.0102, Art v 1.0103, Art v 1.0104, Art v 1.0105, Art v 1.0106, Art v 1.0107, Art v 2, Art v 2.0101, Art v 3, Art v 3.0101, Art v 3.0201, Art v 3.0202, Art v 3.0301, Art v 4, Art v 4.0101, Art v 4.0201, Art v 47kD, Art v 5, Art v 5.0101, Art v 6, Art v 6.0101, Art v 60kD), Arthroderma spp. (Art va 4), Ascaris spp. (Asc l 3, Asc l 3.0101, Asc l 3.0102, Asc l 34kD, Asc s 1, Asc s 1.0101, Asc s 3, Asc s 3.0101, Asc s GST), Aspergillus spp. (Asp aw glucoamylase, Asp c 22, Asp f 1, Asp f 1.0101, Asp f 10, Asp f 10.0101, Asp f 11, Asp f 11.0101, Asp f 12, Asp f 12.0101, Asp f 13, Asp f 13.0101, Asp f 15, Asp f 15.0101, Asp f 16, Asp f 16.0101, Asp f 17, Asp f 17.0101, Asp f 18, Asp f 18.0101, Asp f 2, Asp f 2.0101, Asp f 22, Asp f 22.0101, Asp f 23, Asp f 23.0101, Asp f 27, Asp f 27.0101, Asp f 28, Asp f 28.0101, Asp f 29, Asp f 29.0101, Asp f 3, Asp f 3.0101, Asp f 34, Asp f 34.0101, Asp f 4, Asp f 4.0101, Asp f 5, Asp f 5.0101, Asp f 56kD, Asp f 6, Asp f 6.0101, Asp f 7, Asp f 7.0101, Asp f 8, Asp f 8.0101, Asp f 9, Asp f 9.0101, Asp f AfCalAp, Asp f AT_V, Asp f catalase, Asp f chitosanase, Asp f CP, Asp f DPPV, Asp f FDH, Asp f γ_actin, Asp f glucosidase, Asp f GPI, Asp f GST, Asp f GT, Asp f IAO, Asp f IPMI, Asp f LPL1, Asp f LPL3, Asp f mannosidase, Asp f MDH, Asp f PL, Asp f PUP, Asp f RPS3, Asp f SXR, Asp fl 13, Asp fl 13.0101, Asp fl 18, Asp fl 2, Asp fl 21, Asp fl 3, Asp fl 4, Asp fl 7, Asp fl 8, Asp fl 9, Asp me seaprose, Asp n 14, Asp n 14.0101, Asp n 18, Asp n 18.0101, Asp n 25, Asp n 25.0101, Asp n 30, Asp n glucoamylase, Asp n hemicellulase, Asp n pectinase, Asp o 13, Asp o 13.0101, Asp o 21, Asp o 21.0101, Asp o 3, Asp o 4, Asp o 7, Asp o 8, Asp o lactase, Asp o lipase, Asp oc 13, Asp r 1, Asp sa AP, Asp sp glucoamylase, Asp sp glucose oxidase, Asp sp PL, Asp sp PME, Asp sy 13, Asp v 13, Asp v 13.0101, Asp v catalase A, Asp v enolase, Asp v GAPDH, Asp v MDH, Asp v SXR), Asparagus spp. (Aspa o 1, Aspa o 1.01, Aspa o 1.02, Aspa o 17kD, Aspa o 4), Aspergillus spp. (Aspe ni 2, Aspe ni 3, Aspe ni 4, Aspe ni 7, Aspe ni 8, Aspe ni 9), Avena spp. (Ave s 1, Ave s 12, Ave s 13, Ave s 2, Ave s 4, Ave s 5, Ave s 7), Babylonia spp. (Bab ja 1), Bacillus spp. (Bac al subtilisin, Bac cl subtilisin, Bac l subtilisin, Bac li aA, Bac li subtilisin), Bactrocera spp. spp) (Bac ol 27, Bac ol 27.0101), Bacillus spp) (Bac sp aA1, Bac sp aA3, Bac sp decarboxylase, Bac st amyM, Bac su subtilisin, Bac t Cry1Ab, Bac t Cry1Fa, Bac t Cry3Bb1, Bac t Cry9c), Bagre spp) (Bag ma 1), Balistes spp) (Bal ca 1), Balanus spp) (Bal r 1, Bal r 1.0101), Beauveria spp) (Bea b Ald, Bea b Enol, Bea b f2, Bea b Hex), Brazil nut species (Bertholletia spp) (Ber e 1, Ber e 1.0101, Ber e 2, Ber e 2.0101), species of the genus Beryx (Beryx spp) (Ber sp 1), species of the genus Betula (Betula spp) (Bet ab 1, Bet al 1, Bet ch 1, Bet co 1, Bet da 1, Bet gr 1, Bet hu 1, Bet le 1, Bet me 1, Bet n 1, Bet p 1, Bet pa 1, Bet po 1, Bet pu 1, Bet pu 2, Bet pu 4, Bet pu 6, Bet pu 7, Bet sc 1, Bet ut 1, Bet v 1, Bet v 1 B1 - B1 - B1, Bet v 1 fv Mal 4x, Bet v 1.0101, Bet v 1.0102, Bet v 1.0103, Bet v 1.0201, Bet v 1.0301, Bet v 1.0401, Bet v 1.0402, Bet v 1.0501, Bet v 1.0601, Bet v 1.0602, Bet v 1.0701, Bet v 1.0801, Bet v 1.0901, Bet v 1.1001, Bet v 1.1101, Bet v 1.1201, Bet v 1.1301, Bet v 1.1401, Bet v 1.1402, Bet v 1.1501, Bet v 1.1502, Bet v 1.1601, Bet v 1.1701, Bet v 1.1801, Bet v 1.1901, Bet v 1.2001, Bet v 1.2101, Bet v 1.2201, Bet v 1.2301, Bet v 1.2401, Bet v 1.2501, Bet v 1.2601, Bet v 1.2701, Bet v 1.2801, Bet v 1.2901, Bet v 1.3001, Bet v 1.3101, Bet v 2, Bet v 2.0101, Bet v 3, Bet v 3.0101, Bet v 4, Bet v 4.0101, Bet v 6, Bet v 6.0101, Bet v 6.0102, Bet v 7, Bet v 7.0101, Bet v 8, Bet v glucanase), species of the genus Beta (Beta spp) (Beta v 1, Beta v 1.0101, Beta v 2, Beta v 2.0101), Blattella spp (Bla g 1, Bla g 1.0101, Bla g 1.0102, Bla g 1.0103, Bla g 1.0201, Bla g 1.0202, Bla g 2, Bla g 2.0101, Bla g 2.0201, Bla g 36kD, Bla g 4, Bla g 4.0101, Bla g 4.0201, Bla g 5, Bla g 5.0101, Bla g 5.0201, Bla g 6, Bla g 6.0101, Bla g 6.0201, Bla g 6.0301, Bla g 7, Bla g 7.0101, Bla g 8, Bla g Bla t 8.0101, Bla g 9, Bla g enolase, Bla g GSTD1, Bla g RACK1, Bla g TPI, Bla g trypsin, Bla g vitellogenin), Blatta spp. (Bla o 1, Bla o 7), Blomia spp. (Blo t 1, Blo t 1.0101, Blo t 1.0201, Blo t 10, Blo t 10.0101, Blo t 10.0102, Blo t 11, Blo t 11.0101, Blo t 12, Blo t 12.0101, Blo t 12.0102, Blo t 13, Blo t 13.0101, Blo t 14, Blo t 15, Blo t 18, Blo t 19, Blo t 19.0101, Blo t 2, Blo t 2.0101, Blo t 2.0102, Blo t 2.0103, Blo t 20, Blo t 21, Blo t 21.0101, Blo t 3, Blo t 3.0101, Blo t 4, Blo t 4.0101, Blo t 5, Blo t 5.0101, Blo t 6, Blo t 6.0101, Blo t 7, Blo t 8, Blo t 9, Blo t HSP70), Bombus sp. spp)(Bom ar 4, Bom hy 4, Bom p 1,. Bom p 1.0101, Bom p 2, Bom p 3, Bom p 4, Bom p 4.0101, Bom t 1, Bom t 1.0101, Bom t 4, Bom t 4.0101), Bombyx spp. (Bomb m 1, Bomb m 1.0101, Bomb m 7, Bomb m 7.0101, Bomb m 7.0102, Bomb m 7.0103, Bomb m 7.0104, Bomb m 7.0105, Bomb m 7.0106), Boophilus spp. (Boo m 1, Boo m 7, Boo m 7.0101), Bos spp. (Bos d 2, Bos d 2.0101, Bos d 2.0102, Bos d 2.0103, Bos d 3, Bos d 3.0101, Bos d 4, Bos d 4.0101, Bos d 5, Bos d 5.0101, Bos d 5.0102, Bos d 6, Bos d 6(MDA), Bos d 6.0101, Bos d 7, Bos d 7.0101, Bos d 8, Bos d 8 αS1, Bos d 8 αS2, Bos d 8 β, Bos d 8 kappa, Bos d α2I, Bos d α2I.0101, Bos d chymosin, Bos d Fibrin, Bos d Gelatin, Bos d HG, Bos d insulin, Bos d lactoferrin, Bos d lactoperoxidase, Bos d myoglobin, Bos d OBP, Bos d OSCP, Bos d phosvitin, Bos d PLA2, Bos d PRVB, Bos d thrombin, Bos d TI, Bos gr ALA, Bos gr myoglobin), Bothrops spp (Bot as 1, Bot at 1), Bouteloua spp (Bou g 1), Biting spp (Bov ov 1), Brama spp (Bra du 1), Brassica spp (Bra j 1, Bra j 1.0101, Bra n 1, Bra n 1.0101, Bra n 4, Bra n 7, Bra n 8, Bra n PG, Bra ni 8, Bra o 3, Bra o 3.0101, Bra r 1, Bra r 1.0101, Bra r 2, Bra r 2.0101, Bra r 3, Bra r 4, Bra r 7), Bromus spp. (Bro a 1, Bro a 4), Brosme spp. (Bro br 1), Bromus spp. (Bro i 1, Bro i 5, Bro i 7), Brugia spp. (Bru m 3, Bru m 3.0101, Bru m Bm33), Asian buffalo species (Bubalus spp) (Bub b ALA, Bub b BLG, Bub b casein, Bub b casein αS1, Bub b casein αS2, Bub b casein β, Bub b casein κ), Caenorhabditis spp (Cae b 3, Cae b 3.0101, Cae br 3, Cae br 3.0101, Cae e 3, Cae e 3.0101, Cae e 3.0102, Cae re 13, Cae re 13.0101), Pigeonpea species (Cajanus spp) (Caj c 1), Caligus spp (Cal cl 1, Cal cl 1.0101, Cal cl 1.0102), Calamus spp. (Cal le 1), Callinectes spp. (Cal s 2), Camelus spp. (Cam d ALA, Cam d casein, Cam d casein αS1, Cam d casein αS2, Cam d casein β, Cam d casein κ), Camponotus spp. (Cam fl 7, Cam fl 7.0101), Canis spp. (Can f 1, Can f 1.0101, Can f 2, Can f 2.0101, Can f 3, Can f 3.0101, Can f 4, Can f 4.0101, Can f 5, Can f 5.0101,Can f 6,Can f 6.0101, Can f Feld1-like, Can f Homs2-like, Can f phosvitin, Can f TCTP), Canthidermis spp. (Can ma 1), Cancer spp. (Can mg 2, Can p 1), Cannabis spp. (Can s 3), Candida spp. (Cand a 1, Cand a 1.0101, Cand a 3, Cand a 3.0101, Cand a CAAP, Cand a CyP, Cand a enolase, Cand a FPA, Cand a MnSOD, Cand a PGK, Cand b 2, Cand b 2.0101, Cand b FDH, Cand r lipase), Capsicum spp. (Cap a 1, Cap a 1.0101, Cap a 17kD, Cap a 2, Cap a 2.0101, Cap a 30kD, Cap a glucanase, Cap ch 17kD), Caprella spp. (Cap e 1), Capra spp. (Cap h ALA, Cap h BLG, Cap h casein, Cap h casein αS1, Cap h casein αS2, Cap h casein β, Cap h casein κ, Cap h GSA), Capitulum spp. (Cap m 1), Carassius spp. (Car au 1), Carpinus spp. (Car b 1, Car b 1.0101, Car b 1.0102, Car b 1.0103, Car b 1.0104, Car b 1.0105, Car b 1.0106, Car b 1.0107, Car b 1.0108, Car b 1.0109, Car b 1.0110, Car b 1.0111, Car b 1.0112, Car b 1.0113, Car b 1.0201, Car b 1.0301, Car b 1.0302, Car b 2, Car b 4), Caranx spp (Car cr 1), Carya spp (Car i 1, Car i 1.0101, Car i 2, Car i 4, Car i 4.0101), Carcinus spp. (Car ma 2), Caryota spp. (Car mi 2), Carica spp. (Car p 1, Car p chitinase, Car p chymopapain, Car p endoprotease), Castanea spp. (Cas c 24kD, Cas s 1, Cas s 1.0101, Cas s 1.0102, Cas s 1.0103, Cas s 2, Cas s 5, Cas s 5.0101, Cas s 8, Cas s 8.0101, Cas s 9, Cas s 9.0101), Catharanthus spp. (Cat r 1, Cat r 1.0101, Cat r 17kD, Cat r 2), Caulolatilus spp. (Cau ch 1), Cavia spp. (Cav p 1, Cav p 1.0101, Cav p 2, Cav p 2.0101, Cav p 3, Cav p 3.0101, Cav p gelatin, Cav p GSA), Centropristis spp. (Cen s 1), Cephalopholis spp. (Cep so 1), Charybdis spp. (Cha f 1, Cha f 1.0101), Chaetodipterus spp (Cha fa 1), Chamaecyparis spp (Cha o 1, Cha o 1.0101, Cha o 2, Cha o 2.0101), Chenopodium spp (Che a 1, Che a 1.0101, Che a 2, Che a 2.0101, Che a 3, Che a 3.0101), Chironomus spp (Chi k 1, Chi k 10, Chi k 10.0101), Chinchilla spp (Chi l 21kD_a, Chi l 21kD_b), Chironocetes spp. spp)(Chi o 1, Chi o 1.0101, Chi o 2, Chi o 4, Chi o 6, Chi o α_アクチン, Chi o SERCA), Chironomus spp (Chi t 1, Chi t 1.0101, Chi t 1.0201, Chi t 2, Chi t 2.0101, Chi t 2.0102, Chit 3, Chit 3.0101, Chit 4, Chit 4.0101, Chit 5, Chit 5.0101, Chit 6, Chit 6.0101, Chit 6.0201, Chit 7, Chit 7.0101, Chit 8, Chit 8.0101、Chi t 9、Chi t 9.0101), Chlamys spp (Chl n 1), Chloephaga spp (Chl pi 1), Chortoglyphus spp (Cho a 10), Chrysomela spp (Chr tr 7, Chr tr 7.0101), Cicer spp (Cic a 2S アルブミン, Cic aアルブミン), Cichorium spp (Cic i 1), Cimex spp (Cim l ニトロフォリン), Citrus spp (Cit l 1, Cit l 3, Cit l 3.0101), Citrullus spp (Cit la 2, Cit la MDH, Cit la TPI), Citrus spp (Cit r 3, Cit r 3.0101, Cit s 1, Cit s 1.0101, Cit s 2, Cit s 2.0101、Cit s 3、Cit s 3.0101、Cit s 3.0102、Cit s IFR)、Cladosporium spp) (Cla c 14, Cla c 14.0101, Cla c 9, Cla c 9.0101, Cla h 1, Cla h 10, Cla h 10.0101, Cla h 12, Cla h 12.0101, Cla h 2, Cla h 2.0101, Cla h 42kD, Cla h 5. Cla h 5.0101, Cla h 6, Cla h 6.0101, Cla h 7, Cla h 7.0101, Cla h 8, Cla h 8 CSP, Cla h 8.0101, Cla h 9, Cla h 9.0101, Cla h abH, Cla h GST, Cla h HCh1, Cla h HSP70, Cla h NTF2, Cla h TCTP), Clostridium spp. (Clo hi collagenase, Clo t toxoid), Clupea spp. (Clu h 1, Clu h 1.0101, Cl. uh 1.0201, Clu h 1.0301), Cocos spp (Coc n 2, Coc n 4, Coc n 5), Coccidioides spp (Coc po 8), Coffea spp (Cof a 1, Cof a 1.0101), Columba spp (Col l PSA), Coprinus spp (Cop c 1, Cop c 1.0101, Cop c 2, Cop c 2.0101, Cop c 3, Cop c 3.0101, Cop c 4, Cop c 5, Cop c 5.0101, Cop c 6, Cop c 7, Cop c Corylus spp 1.0403,Cor a 1.0404,Cor a 10,Cor a 10.0101,Cor a 11,Cor a 11.0101,Cor a 12,Cor a 12.0101,Cor a 13,Cor a 13.0101,Cor a 14,Cor a 14.0101,Cor a 2,Cor a 2.0101, Cor a 2.0102, Cor a 8, Cor a 8.0101, Cor a 9, Cor a 9.0101), Corynebacterium spp (Cor d toxoid), Corylus spp (Cor he 1), Coryphaena spp (Cor hi 1), Coriandrum spp (Cor s 1, Cor s 11kD, Cor s 2), Cotoneaster spp (Cot l 3), Crangon spp (Cra c 1, Cra c 1.0101, Cra c 2, Cra c 2.0101, Cra c 4, Cra c 4.0101, Cra c 5, Cra c 5.0101, Cra c 6, Cra c 6.0101, Cra c 8, Cra c 8.0101), Crassostrea spp. (Cra g 1), Cricetus spp. (Cri c HSA), Crivellia spp. (Cri pa 1), Crocus spp. (Cro s 1, Cro s 1.0101, Cro s 2, Cro s 2.0101, Cro s 3, Cro s 3.01, Cro s 3.02), Cryptomeria spp. (Cry j 1, Cry j 1.0101, Cry j 1.0102, Cry j 1.0103, Cry j 2, Cry j 2.0101, Cry j 2.0102, Cry j 3, Cry j 3.1, Cry j 3.2, Cry j 3.3, Cry j 3.4, Cry j 3.5, Cry j 3.6, Cry j 3.7, Cry j 3.8, Cry j 4, Cry j AP, Cry j chitinase, Cry j CPA9, Cry j IFR, Cry j LTP, Cry j P1-P2), Cryphonectria spp. (Cry p AP), Ctenocephalides spp. (Cte f 1, Cte f 1.0101, Cte f 2, Cte f 2.0101, Cte f 3, Cte f 3.0101), Ctenopharyngodon spp. (Cte id 1), Cucumis spp (Cuc m 1, Cuc m 1.0101, Cuc m 2, Cuc m 2.0101, Cuc m 3, Cuc m 3.0101, Cuc m Lec17, Cuc m MDH), Cucurbita spp (Cuc ma 18kD, Cuc ma 2, Cuc p 2, Cuc p AscO), Cucumis spp (Cuc s 2), Culicoides spp (Cul n 1, Cul n 10, Cul n 11, Cul n 2, Cul n 3, Cul n 4, Cul n 5, Cul n 6, Cul n 7, Cul n 8, Cul n 9, Cul n HSP70), Culex spp (Cul q 28kD, Cul q 35kD, Cul q 7, Cul q 7.0101, Cul q 7.0102), Culicoides spp (Cul so 1), Cuminum spp (Cum c 1, Cum c 2), Cupressus spp (Cup a 1, Cup a 1.0101, Cup a 1.02, Cup a 2, Cup a 3, Cup a 4, Cup a 4.0101, Cup s 1, Cup s 1.0101, Cup s 1.0102, Cup s 1.0103, Cup s 1.0104, Cup s 1.0105, Cup s 3, Cup s 3.0101, Cup s 3.0102, Cup s 3.0103, Cup s 8), Cochliobolus spp (Cur l 1, Cur l 1.0101, Cur l 2, Cur l 2.0101, Cur l 3, Cur l 3.0101, Cur l 4, Cur l 4.0101, Cur l ADH, Cur l GST, Cur l MnSOD, Cur l origin, Cur l Trx, Cur l ZPS1), Cyanochen spp (Cya cy 1), Cynoscion spp (Cyn ar 1), Cynosurus spp (Cyn cr 1, Cyn cr 5), Cynodon spp (Cyn d 1, Cyn d 1.0101, Cyn d 1.0102, Cyn d 1.0103, Cyn d 1.0104, Cyn d 1.0105, Cyn d 1.0106, Cyn d 1.0107, Cyn d 1.0201, Cyn d 1.0202, Cyn d 1.0203, Cyn d 1.0204, Cyn d 10, Cyn d 11, Cyn d 12, Cyn d 12.0101, Cyn d 13, Cyn d 15, Cyn d 15.0101, Cyn d 2, Cyn d 22, Cyn d 22.0101, Cyn d 23, Cyn d 23.0101, Cyn d 24, Cyn d 24.0101, Cyn d 4, Cyn d 5, Cyn d 6, Cyn d 7, Cyn d 7.0101), Cynoscion spp (Cyn ne 1), Cynomys spp (Cyn sp Lipocalin), Cyprinus spp (Cyp c 1, Cyp c 1.01, Cyp c 1.02), Daboia spp (Dab ru 1), Dactylis spp (Dac g 1, Dac g 1.01, Dac g 1.0101, Dac g 1.02, Dac g 12, Dac g 13, Dac g 2, Dac g 2.0101, Dac g 3, Dac g 3.0101, Dac g 4, Dac g 4.0101, Dac g 5, Dac g 5.0101, Dac g 7), Dama spp (Dam d CSA), Danio spp (Dan re 1, Dan re 2, Dan re α2I, Dan re CK), Dasyatis spp (Das ak 1, Das am 1, Das sa 1), Daucus spp (Dau c 1, Dau c 1.0101, Dau c 1.0102, Dau c 1.0103, Dau c 1.0104, Dau c 1.0105, Dau c 1.0201, Dau c 1.0301, Dau c 3, Dau c 4, Dau c 4.0101, Dau c CyP), Decapterus spp (Dec ru 1), Dendronephthya spp (Den n 1, Den n 1.0101), Dermatophagoides spp (Der f 1, Der f 1.0101, Der f 1.0102, Der f 1.0103, Der f 1.0104, Der f 1.0105, Der f 1.0106, Der f 1.0107, Der f 1.0108, Der f 1.0109, Der f 1.0110, Der f 10, Der f 10.0101, Der f 10.0102, Der f 11, Der f 11.0101, Der f 13, Der f 13.0101, Der f 14, Der f 14.0101, Der f 15, Der f 15.0101, Der f 16, Der f 16.0101, Der f 17, Der f 17.0101, Der f 18, Der f 18.0101, Der f 2, Der f 2.0101, Der f 2.0102, Der f 2.0103, Der f 2.0104, Der f 2.0105, Der f 2.0106, Der f 2.0107, Der f 2.0108, Der f 2.0109, Der f 2.0110, Der f 2.0111, Der f 2.0112, Der f 2.0113, Der f 2.0114, Der f 2.0115, Der f 2.0116, Der f 2.0117, Der f 20, Der f 21, Der f 22, Der f 22.0101, Der f 3, Der f 3.0101, Der f 4, Der f 5, Der f 6, Der f 6.0101, Der f 7, Der f 7.0101, Der f 8, Der f 9, Der f HSP70), Dermanyssus spp (Der g 10, Der g 10.0101), Dermatophagoides spp (Der m 1, Der m 1.0101, Der p 1, Der p 1.0101, Der p 1.0102, Der p 1.0103, Der p 1.0104, Der p 1.0105, Der p 1.0106, Der p 1.0107, Der p 1.0108, Der p 1.0109, Der p 1.0110, Der p 1.0111, Der p 1.0112, Der p 1.0113, Der p 1.0114, Der p 1.0115, Der p 1.0116, Der p 1.0117, Der p 1.0118, Der p 1.0119, Der p 1.0120, Der p 1.0121, Der p 1.0122, Der p 1.0123, Der p 1.0124, Der p 10, Der p 10.0101, Der p 10.0102, Der p 10.0103, Der p 11, Der p 11.0101, Der p 13, Der p 14, The p 14.0101, The p 15, The p 18, The p 2, The p 2.0101, The p 2.0102, The p 2.0103, The p 2.0104, The p 2.0105, The p 2.0106, The p 2.0107, The p 2.0108, The p 2.0109, The p. 2.0110, Der p 2.0111, Der p 2.0112, Der p 2.0113, Der p 2.0114, Der p 2.0115, Der p 20, Der p 20.0101, Der p 21, Der p 21.0101, Der p 23, Der p 23.0101, Der p 3, Der p 3.0101, Der p 4, Der p 4.0101, Der p 5, Der p 5.0101, Der p 5.0102, Der p 6, Der p 6.0101, Der p 7, Der p 7.0101, Der p 8, Der p 8.0101, Der p 9, Der p 9.0101, Der p 9.0102, Der p P1-P2, Der p P2-P1, Der s 1, Der s 2, Der s 3), Dianthus spp. (Dia c RIP), Dicranopteris spp. (Dic l 2S albumin), Diospyros spp. (Dio k 17kD, Dio k 4, Dio k IFR), Dioscorea spp. (Dio p TSP), Diplodus spp. (Dip ho 1), Distichlis spp. (Dis s 1, Dis s 7), Ditrema spp. (Dit te 1), Dolichovespula spp. (Dol a 1, Dol a 2, Dol a 5, Dol a 5.0101), Dolichos spp. (Dol b agglutinin), Vespula spp. (Dol m 1, Dol m 1.0101, Dol m 1.02, Dol m 2, Dol m 2.0101, Dol m 5, Dol m 5.0101, Dol m 5.02), Drosophila spp. (Dro an 7, Dro an 7.0101, Dro er 7, Dro er 7.0101, Dro er 7.0102, Dro gr 7, Dro gr 7.0101, Dro gr 7.0102, Dro m 7, Dro m 7.0101, Dro m 7.0102, Dro m 7.0103, Dro m 7.0104, Dro m 7.0105, Dro m 7.0106, Dro m 7.0107, Dro m 7.0108, Dro m 7.0109, Dro m 7.0110, Dro m 7.0111, Dro m 7.0112, Dro m 7.0113, Dro m 9, Dro m MnSOD, Dro mo 7, Dro mo 7.0101, Dro pp 7, Dro pp 7.0101, Dro se 7, Dro se 7.0101, Dro si 7, Dro si 7.0101, Dro si 7.0102, Dro vi 7, Dro vi 7.0101, Dro wi 7, Dro wi 7.0101, Dro y 7, Dro y 7.0101, Dro y 7.0102, Dro y 7.0103), Echium spp (Ech p Cytochrome C), Elaeis spp (Ela g 2, Ela g Bd31kD), Elops spp (Elo sa 1), Embellisia spp (Emb a 1, Emb i 1, Emb nz 1, Emb t 1), Engraulis spp (Eng e 1), Enteroctopus spp (Ent d 1), Epinephelus spp (Epi bl 1, Epi co 1, Epi fl 1, Epi mc 1, Epi mo 1), Epicoccum spp (Epi p 1, Epi p 1.0101, Epi p 12kD, Epi p GST), Epinephelus spp (Epi po 1, Epi un 1), Equisetum spp (Equ a 17kD), Equus spp (Equ as 4, Equ as DSA, Equ bu 4, Equ c 1, Equ c 1.0101, Equ c 2, Equ c 2.0101, Equ c 2.0102, Equ c 3, Equ c 3.0101, Equ c 4, Equ c 4.0101, Equ c 5, Equ c 5.0101, Equ c ALA, Equ c BLG, Equ c Casein, Equ c Casein β, Equ c Casein κ, Equ c PRVB, Equ he 4, Equ z ZSA), species of the genus Cancer (Erimacrus spp) (Eri i 1, Eri i 1.0101, Eri i 1.0102), species of the genus Eriocheir (Eriocheir spp) (Eri s 1, Eri s 1.0101, Eri s 2), species of the genus Erwinia (Erwinia spp) (Erw ch Asparaginase), species of the genus Escherichia (Escherichia spp) (Esc c Asparaginase, Esc c β GAL), species of the genus Esox (Esox spp) (Eso l 1), species of the genus Euphausia (Euphausia spp) (Eup p 1, Eup p 1.0101), species of the genus Euphasia (Euphasia spp) (Eup s 1, Eup s 1.0101), species of the genus Euroglyphus (Euroglyphus spp) (Eur m 1, Eur m 1.0101, Eur m 1.0102, Eur m 1.0103, Eur m 10, Eur m 14, Eur m 14.0101, Eur m 2, Eur m 2.0101, Eur m 2.0102, Eur m 3, Eur m 3.0101, Eur m 4, Eur m 4.0101), species of the genus Evynnis (Evynnis spp) (Evy j 1), species of the genus Fagopyrum (Fagopyrum spp) (Fag e 1, Fag e 1.0101, Fag e 10kD, Fag e 19kD, Fag e 2, Fag e 2.0101, Fag e TI), species of the genus Fagus (Fagus spp) (Fag s 1, Fag s 1.0101, Fag s 2, Fag s 4), species of the genus Fagopyrum (Fagopyrum spp) (Fag t 1, Fag t 10kD, Fag t 2, Fag t 2.0101), species of the genus Felis (Felis spp) (Fel d 1, Fel d 1.0101, Fel d 2, Fel d 2.0101, Fel d 3, Fel d 3.0101, Fel d 4, Fel d 4.0101, Fel d 5, Fel d 5.0101, Fel d 6, Fel d 6.0101, Fel d 7, Fel d 7.0101, Fel d 8, Fel d 8.0101, Fel d IgG), Fenneropenaeus spp. (Fen c 1, Fen c 2, Fen me 1, Fen me 1.0101), Festuca spp. (Fes e 1, Fes e 13, Fes e 4, Fes e 5, Fes e 7, Fes p 1, Fes p 13, Fes p 4, Fes p 4.0101, Fes p 5, Fes r 1, Fes r 5), Ficus spp. (Fic c 17kD, Fic c 4, Fic c ficin), Fenniculum spp. (Foe v 1, Foe v 2), Forsythia spp. (For s 1), Forcipomyia spp. (For t 1, For t 1.0101, For t 2, For t 2.0101, For t 7, For t FPA, For t myosin, For t TPI), Fragaria spp. (Fra a 1, Fra a 1.0101, Fra a 3, Fra a 3.0101, Fra a 3.0102, Fra a 3.0201, Fra a 3.0202, Fra a 3.0203, Fra a 3.0204, Fra a 3.0301, Fra a 4, Fra a 4.0101, Fra c 1), Fraxinus spp. (Fra e 1, Fra e 1.0101, Fra e 1.0102, Fra e 1.0201, Fra e 12, Fra e 2, Fra e 3, Fra e 9), Fragaria spp. (Fra v 1), Fusarium spp. (Fus c 1, Fus c 1.0101, Fus c 2, Fus c 2.0101, Fus c 3, Fus s 1, Fus s 45kD, Fus sp lipase), Gadus spp. (Gad c 1, Gad c 1.0101, Gad c APDH, Gad m 1, Gad m 1.0101, Gad m 1.0102, Gad m 1.0201, Gad m 1.0202, Gad m 45kD, Gad m gelatin, Gad ma 1), Gallus spp (Gal d 1, Gal d 1.0101, Gal d 2, Gal d 2.0101, Gal d 3, Gal d 3.0101, Gal d 4, Gal d 4.0101, Gal d 5, Gal d 5.0101, Gal d 6, Gal d 6.0101, Gal d Apo I, Gal d Apo VI, Gal d GPI, Gal d HG, Gal d IgY, Gal d L-PGDS, Gal d Ovomucin, Gal d Phosvitin, Gal d PRVB, Gal la 4), Galleria spp. (Gal m 18kD, Gal m 24kD), Gallus spp. (Gal so 4), Gammarus spp. (Gam s TM), Gelonium spp. (Gel m RIP), Geothelphusa spp. (Geo de 1), Glossina spp. (Glo m 5, Glo m 5.0101, Glo m 7, Glo m 7.0101, Glo m 7.0102, Glo m 7.0103), Glycine spp. (Gly a Bd30K, Gly ar Bd30K, Gly ca Bd30K, Gly cl Gly d 10, Gly d 10.0101, Gly d 13, Gly d 2, Gly d 2.0101, Gly d 2.0201, Gly d 2.03, Gly d 2 / Lep d 2 L1, Gly d 2 / Lep d 2 L2, Gly d 2 / Lep d 2 L3, Gly d 2 / Lep d 2 L4, Gly d 2 / Lep d 2 R1, Gly d 2 / Lep d 2 R2, Gly d 2 / Lep d 2 R3, Gly d 2 / Lep d 2 R4, Gly d 2 / Lep d 2 R5, Gly d 20, Gly d 3, Gly d 5, Gly d 5.01, Gly d 5.02, Gly d 7, Gly d 8), Glycine spp. (Gly f Bd30K, Gly l Bd30K, Gly m 1, Gly m 1.0101, Gly m 1.0102, Gly m 2, Gly m 2.0101, Gly m 2S albumin, Gly m 3, Gly m 3.0101, Gly m 3.0102, Gly m 39kD, Gly m 4, Gly m 4.0101, Gly m. 5, Gly m 5.0101, Gly m 5.0201, Gly m 5.0301, Gly m 5.0302, Gly m 50kD, Gly m 6, Gly m 6.0101, Gly m 6.0201, Gly m 6.0301, Gly m 6.0401, Gly m 6.0501, Gly m 68kD, Gly m agglutinin, Gly m Bd28K, Gly m Bd30K, Gly m Bd60K, Gly m CPI, Gly m EAP, Gly m TI, Gly mi Bd30K, Gly s Bd30K, Gly t Bd30K, Gly to Bd30K), Gossypium sp. spp)(Gos h vicilin), Haemophilus spp. (Hae in P6), Haemaphysalis spp. (Hae l 7, Hae l 7.0101, Hae q 7, Hae q 7.0101), Haliotis spp. (Hal a 1, Hal d 1, Hal di 1, Hal di PM, Hal m 1, Hal m 1.0101, Hal r 1, Hal r 49kD, Hal ru 1), Harmonia spp. (Har a 1, Har a 1.0101, Har a 2, Har a 2.0101), Harpegnathos spp. (Har sa 7, Har sa 7.0101, Har sa 7.0102), Helianthus spp. (Hel a 1, Hel a 1.0101, Hel a 2, Hel a 2.0101, Hel a 2S albumin, Hel a 3, Hel a 3.0101, Hel a 4), Helix spp. (Hel ap 1, Hel as 1, Hel as 1.0101), Heligmosomoides spp. (Hel p 3, Help p 3.0101), Helianthus spp (Hel tu 1), Hemanthias spp (Hem le 1), Hemifusus spp (Hem t 1), Heterodera spp (Het g 3, Het g 3.0101), Hevea spp (Hev b 1, Hevea b 1.0101, Hevea b 10, Hevea b 10.0101, Hevea b 10.0102, Hevea b 10.0103, Hevea b 11, Hevea b 11.0101, Hevea b 11.0102, Hevea b 12, Hevea b 12.0101, Hevea b 13, Hevea b 13.0101, Hevea b 14, Hevea b 14.0101, Hevea b 2, Hevea b 2.0101, Hevea b 3, Hevea b 3.0101, Hevea b 4, Hevea b 4.0101, Hevea b 5, Hevea b 5.0101, Hevea b 6, Hevea b 6.01, Hevea b 6.02, Hevea b 6.0202, Hevea b 6.03, Hevea b 7, Hevea b 7.01, Hevea b 7.02, Hevea b 7.D2, Hevea b 7.S2, Hevea b 8, Hevea b 8.0101, Hevea b 8.0102, Hevea b 8.0201, Hevea b 8.00102, Hol l 2, Hol l 4, Hol l 5, Hol l 5.0101, Hol l 5.0201), Holocnemus spp. (Hol pl 9, Hol pl hemocyanin), Lobster spp. (Homarus spp.) (Hom a 1, Hom a 1.0101, Hom a 1.0102, Hom a 1.0103, Hom a 3, Hom a 3.0101, Hom a 4, Hom a 6, Hom a 6.0101, Hom g 1, Hom g 2), Homo spp. (Hom s 1, Hom s 1.0101, Hom s 2, Hom s 2.0101, Hom s 3, Hom s 3.0101, Hom s 4, Hom s 4.0101, Hom s 5, Hom s 5.0101, Hom's AAT, Hom's ACTH, Hom's Adalimumab, Hom's ALA, Hom's α_actin, Hom's α-galactosidase, Hom's APDH, Hom's arylsulfatase B, Hom's casein, Hom's CyP A, Hom's CyP B, Hom's CyP C, Hom's DSF70, Hom's DSG3, Hom's eIF6, Hom's etanercept, Hom's factor IX, Hom's factor VII, Hom's factor VIII, Hom's G-CSF, Hom's glucocerebrosidase, Hom's glucosidase, Hom's HLA-DR-α, Hom's HSA, Hom's iduronidase, Hom's Idursulfase, Hom's IgA, Hom's insulin, Hom's lactoferrin, Hom's laminin γ_2, Hom's MnSOD, Hom's oxytocin, Hom's P2, Hom's phosvitin, Hom's profilin, Hom's PSA, Hom's RP1, Hom's TCTP, Hom's TL, Hom's TPA, Hom's TPO, Hom's transaldolase, Hom's Trx, Hom's tubulin-α, Hom's / Mus m basiliximab, Hom's / Mus m cetuximab, Hom's / Mus m cetuximab (Gal-Gal), Hom's / Mus m infliximab, Hom's / Mus m natalizumab, Hom's / Mus m Omalizumab, Hom s / Mus m palivizumab, Hom s / Mus m rituximab, Hom s / Mus m tocilizumab, Hom s / Mus m trastuzumab), Hoplostethus spp (Hop a 1), Hordeum spp (Hor v 1, Hor v 12, Hor v 12.0101, Hor v 13, Hor v 14, Hor v 15, Hor v 15.0101, Hor v 16, Hor v 16.0101, Hor v 17, Hor v 17.0101, Hor v 18kD, Hor v 2, Hor v 21, Hor v 21.0101, Hor v 28, Hor v 33, Hor v 4, Hor v 5, Hor v 5.0101, Hor v BDAI, Hor v BTI), Humicola spp. (Hum in cellulase), Humulus spp. (Hum j 1, Hum j 1.0101, Hum j 10kD, Hum j 2), Huso spp. (Hus h 1), Hylocereus spp. (Hyl un LTP), Hymenocephalus spp. (Hym st 1), Hyperoglyphe spp. (Hyp by 1), Silver carp species (Hypophthalmichthys spp) (Hyp mo 1), Hypophthalmichthy spp) (Hyp no 1), Channel catfish species (Ictalurus spp) (Ict fu 1, Ict p 1), Imperata spp) (Imp c 4, Imp c 5, Imp c VIIIe1), Ixodes spp) (Ixo r 2, Ixo sc 7, Ixo sc 7.0101), Jasus spp) (Jas la 1, Jas la 1.0101, Jas la 1.0102), Juglans spp) (Jug ca 1, Jug ca 2, Jug ci 1, Jug ci 2, Jug n 1, Jug n 1.0101, Jug n 2, Jug n 2.0101, Jug r 1, Jug r 1.0101, Jug r 2, Jug r 2.0101, Jug r 3, Jug r 3.0101, Jug r 4, Jug r 4.0101, Jug r 5) Juniperus spp 3, Jun r 3.1, Jun r 3.2, Jun v 1, Jun v 1.0101, Jun v 1.0102, Jun v 3, Jun v 3.0101, Jun v 3.0102, Jun v 4), Katsuwonus spp. (Kat p 1), Kyphosus spp. (Kyp se 1), Lachnolaimus spp. (Lac ma 1), Lachesis spp. (Lac mu 1), Lactuca spp. (Lac s 1, Lac s 1.0101), Lagocephalus spp. (Lag la 1), Larus spp. (Lar a 1, Lar a 2, Lar a 3), Larimichthys spp. spp) (Lar po 1), Lates spp) (Lat c 1), Lateolabrax spp) (Lat ja 1), Lathyrus spp) (Lat oc agglutinin), Leiostomus spp) (Lei xa 1), Lens spp) (Len c 1, Len c 1.0101, Len c 1.0102, Len c 1.0103, Len c 2, Len c 2.0101, Len c 3, Len c 3.0101, Len c agglutinin), Leopardus spp) (Leo p 1), Lepidoglyphus spp) (Lep d 10, Lep d 10.0101, Lep d 12, Lep d 13, Lep d 13.0101, Lep d 2, Lep d 2.0101, Lep d 2.0102, Lep d 2.0201, Lep d 2.0202, Lep d 3, Lep d 39kD, Lep d 5, Lep d 5.0101, Lep d 5.0102, Lep d 5.0103, Lep d 7, Lep d 7.0101, Lep d 8, Lep d α tubulin), Bluegill species (Lepomis spp) (Lep gi 1), Leptomelanosoma spp (Lep i 1), bluegill species (Lepomis spp. ) (Lep ma 1), Lepisma spp. (Lep s 1, Lep s 1.0101, Lep s 1.0102), Lepeophtheirus spp. (Lep sa 1, Lep sa 1.0101, Lep sa 1.0102, Lep sa 1.0103), Leptailurus spp. (Lep se 1), Lepidorhombus spp. (Lep w 1, Lep w 1.0101), Lethocerus spp. (Let in 7, Let in 7.0101, Let in 7.0102), Leuciscus spp. (Leu ce 1), Lewia spp. (Lew in 1), Ligustrum spp. (Lig v 1, Lig v 1.0101, Lig v 1.0102, Lig v 2), Lilium spp. (Lil l 2, Lil l PG), Limanda spp. (Lim fe 1), Limnonectes spp. (Lim m 1), Limulus spp. (Lim p 1, Lim p 1.0101, Lim p 2, Lim p LPA), Liposcelis spp. (Lip b 1, Lip b 1.0101), Litchi spp. (Lit c 1, Lit c 1.0101, Lit c IFR, Lit c TPI), Lithobates spp (Lit ca 1), Litopenaeus spp (Lit se 1, Lit v 1, Lit v 1.0101, Lit v 2, Lit v 2.0101, Lit v 3, Lit v 3.0101, Lit v 4, Lit v 4.0101), Filiaria spp (Loa lo 3, Loa lo 3.0101), Lobotes spp (Lob su 1), Locusta spp (Loc m 7, Loc m 7.0101), species of the genus Loligo (Lol b 1, Lol e 1), species of the genus Lolium (Lol m 2, Lol m 5, Lol p 1, Lol p 1.0101, Lol p 1.0102, Lol p 1.0103, Lol p 10, Lol p 11, Lol p 11.0101, Lol p 12, Lol p 13, Lol p 2, Lol p 2.0101, Lol p 3, Lol p 3.0101, Lol p 4, Lol p 4.0101, Lol p 5, Lol p 5.0101, Lol p 5.0102, Lol p 7, Lol p CyP, Lol p FT, Lol p legumin), species of the genus Lonomia (Lon o 7, Lon o 7.0101), species of the genus Lophodytes (Lop cu 1), species of the genus Lophonetta (Lop sp 1), species of the genus Lupinus (Lup a 1, Lup a α - congulin, Lup a δ - congulin, Lup a γ - congulin, Lup an 1, Lup an 1.0101, Lup an α - congulin, Lup an δ - congulin, Lup an γ - congulin, Lup l 17kD), species of the genus Lutjanus (Lut a 1, Lut c 1, Lut cy 1, Lut gr 1, Lut gu 1, Lut jo 1), species of the genus Lutraria (Lut p 1), species of the genus Lutjanus (Lut pu 1, Lut sy 1), species of the genus Lycopersicon (Lyc e 1, Lyc e 1.0101, Lyc e 11S globulin, Lyc e 2, Lyc e 2.0101, Lyc e 2.0102, Lyc e 3, Lyc e 3.0101, Lyc e 4, Lyc e 4.0101, Lyc e ARP60S, Lyc e chitinase, Lyc e glucanase, Lyc e peroxidase, Lyc e PG, Lyc e PME, Lyc e PR23, Lyc e vicilin), Maconellicoccus spp. (Mac h 7, Mac h 7.0101), Macruronus spp. (Mac ma 1, Mac n 1), Maclura spp. (Mac po 17kD), Macrobrachium spp. (Mac ro 1, Mac ro 1.0101, Macro ro hemocyanin), Macropus spp. (Macr s gelatin), Malus spp. (Mal d 1, Mal d 1.0101, Mal d 1.0102, Mal d 1.0103, Mal d 1.0104, Mal d 1.0105, Mal d 1.0106, Mal d 1.0107, Mal d 1.0108, Mal d 1.0109, Mal d 1.0201, Mal d 1.0202, Mal d 1.0203, Mal d 1.0204, Mal d 1.0205, Mal d 1.0206, Mal d 1.0207, Mal d 1.0208, Mal d 1.0301, Mal d 1.0302, Mal d 1.0303, Mal d 1.0304, Mal d 1.0401, Mal d 1.0402, Mal d 1.0403, Mal d 2, Mal d 2.0101, Mal d 3, Mal d 3.0101, Mal d 3.0102, Mal d 3.0201, Mal d 3.0202, Mal d 3.0203, Mal d 4, Mal d 4.0101, Mal d 4.0102, Mal d 4.0201, Mal d 4.0202, Mal d 4.0301, Mal d 4.0302), Malpighia spp (Mal g 4, Mal g hevein), Malus spp. (Mal p 1), Malassezia spp. (Mala f 2, Mala f 2.0101, Mala f 3, Mala f 3.0101, Mala f 4, Mala f 4.0101, Mala g 10, Mala s 1, Mala s 1.0101, Mala s 10, Mala s 10.0101, Mala s 11, Mala s 11.0101, Mala s 12, Mala s 12.0101, Mala s 13, Mala s 13.0101, Mala s 5, Mala s 5.0101, Mala s 6, Mala s 6.0101, Mala s 7, Mala s 7.0101, Mala s 8, Mala s 8.0101, Mala s 9, Mala s 9.0101), Manihot spp. 5, Man e 5.0101, Man e FPA, Man e GAPDH), Mangifera spp. (Man i 1, Man i 14kD, Man i 2, Man i 3, Man i 3.01, Man i 3.02, Man i chitinase), Marsupenaeus spp. (Mar j 1, Mar j 1.0101, Mar j 2, Mar j 4), Matricaria spp. (Mat c 17kD), Mecopoda spp. (Mec e 7), Megalobrama spp. (Meg am 2, Meg am CK), Megathura spp. (Meg c hemocyanin), Megalops spp. spp) (Meg sp 1), Melanogrammus spp) (Mel a 1), Meleagris spp) (Mel g 1, Mel g 2, Mel g 3, Mel g PRVB, Mel g TSA), Melicertus spp) (Mel l 1), Menticirrhus spp) (Men am 1), Mercurialis spp) (Mer a 1, Mer a 1.0101), Merluccius spp (Mer ap 1, Mer au 1, Mer bi 1, Mer ca 1, Mer ga 1, Mer hu 1), Merlangius spp (Mer me 1), Merluccius spp (Mer mr 1, Mer pa 1, Mer po 1, Mer pr 1, Mer se 1), Meriones spp (Mer un 23kD), Metalhizium spp (Met a 30), Metapenaeopsis spp (Met ba 1) Species of the genus *Metapenaeus* spp (Met e 1, Met e 1.0101, Met e 2), Species of the genus *Metasequoia* spp (Met gl 2), Species of the genus *Metapenaeus* spp (Met j 1, Met j 2), Species of the genus *Metanephrops* spp (Met ja 1), Species of the genus *Metapenaeopsis* spp (Met la 1), Species of the genus *Metanephrops* spp (Met t 2), Species of the genus *Micromesistius* spp (Mic po 1) Species of the genera *Micropogonias* (Mic un 1), *Mimachlamys* (Mim n 1), *Momordica* (Mom c RIP), *Morus* (Mor a 17kD, Mor a 4), *Morone* (Mor am 1), *Morus* (Mor n 3, Mor n 3.0101), *Morone* (Mor sa 1, Mor sc 1), *Mugil* (Mug c 1), *Muraenolepis* spp) (Mur mi 1), Musa spp (Mus a 1, Mus a 1.0101, Mus a 2, Mus a 2.0101, Mus a 3, Mus a 3.0101, Mus a 4, Mus a 4.0101, Mus a 5, Mus a 5.Mus spp. (Mus m 1, Mus m 1.0101, Mus m 1.0102, Mus m 2, Mus m gelatin, Mus m IgG, Mus m MSA, Mus m muromonab, Mus m phosvitin), Mustela spp. (Mus p 17kD), Musa spp. (Mus xp 1, Mus xp 2, Mus xp 5), Mycteroperca spp. (Myc bo 1, Myc mi 1, Myc ph 1), Myceliophthora spp. (Myc sp laccase), Myrmecia spp. spp) (Myr p 1, Myr p 1.0101, Myr p 2, Myr p 2.0101, Myr p 2.0102, Myr p 3, Myr p 3.0101), Mytilu. s spp) (Myt e 1, Myt g 1, Myt g PM), Myzus spp) (Myz p 7, Myz p 7.0101), Nemorhedus spp) (Nae go Hya), Necator spp) (Nec a calreticulin), Nemipterus spp) (Nem vi 1), Neosartorya spp) (Neo fi 1, Neo fi 22), Neochen spp) (Neo ju 1), Neoscona spp) (Neo n 7, Neo n 7.0101), Nephelium spp) (Nep l GAPDH), Nephrops spp. (Nep n 1, Nep n DF9), Neptunea spp. (Nep po 1, Nep po 1.0101), Nicotiana spp. (Nic t 8, Nic t osmotin, Nic t bilin), Nimbya spp. (Nim c 1, Nim s 1), Nippostrongylus spp. (Nip b Ag1), Nycticebus spp. (Nyc c 1), Octopus spp. (Oct f 1, Oct l 1, Oct v 1, Oct v 1.0101, Oct v PM), Ocyurus spp (Ocy ch 1), Olea spp (Ole e 1, Ole e 1.0101, Ole e 1.0102, Ole e 1.0103, Ole e 1.0104, Ole e 1.0105, Ole e 1.0106, Ole e 1.0107, Ole e 10, Ole e 10.0101, Ole e 11, Ole e 11.0101, Ole e 11.0102, Ole e 12, Ole e 13, Ole e 2, Ole e 2.0101, Ole e 3, Ole e 3.0101, Ole e 36kD, Ole e 4, Ole e 4.0101, Ole e 5, Ole e 5.0101, Ole e 6, Ole e 6.0101, Ole e 7, Ole e 7.0101, Ole e 8, Ole e 8.0101, Ole e 9, Ole e 9.0101), Ommastrephes spp. (Omm b 1, Omm b 1.0101), Oncorhynchus spp. (Onc ke 1, Onc ke 18 kD, Onc ke α2I, Onc ke vitellogenin, Onc m 1, Onc m 1.0101, Onc m 1.0201, Onc m α2I, Onc m protamine, Onc m vitellogenin, Onc ma 1, Onc ma FPA, Onc ma FSA, Onc ma TPI, Onc n 1), Onchocerca spp. spp) (Onc o 3, Onc o 3.0101), Pacific salmon (Oncorhynchus spp) (Onc ts 1), Onchocerca spp) (Onc v 3, Onc v 3.0101), Oratosquilla spp) (Ora o 1, Ora o 1.0101), Oreochromis spp) (Ore a 1, Ore mo 1, Ore mo 2, Ore mo FPA, Ore mo SCAF7145, Ore ni 1, Ore ni 18kD, Ore ni 45kD), house dust mite (Ornithonyssus spp) (Orn sy 10, Orn sy 10.0101, Orn sy 10.0102), Oryctolagus spp. (Ory c 1, Ory c 1.0101, Ory c 2, Ory c casein, Ory c phosvitin, Ory c RSA), Oryza spp. (Ory s 1, Ory s 1.0101, Ory s 11, Ory s 12, Ory s 12.0101, Ory s 13, Ory s 14, Ory s 17kD, Ory s 19kD, Ory s 2, Ory s 23, Ory s 3, Ory s 7, Ory s aA_TI, Ory s GLP52, Ory s GLP63, Ory s glyoxalase I, Ory s NRA), Ostrya spp. (Ost c 1, Ost c 1.0101), Ovis spp. (Ovi a ALA, Ovi a BLG, Ovi a casein, Ovi a casein αS1, Ovi a casein αS2, Ovi a casein β, Ovi a casein κ, Ovi a phosvitin, Ovi a SSA), Pachycondyla spp. (Pac c 3), Pagrus spp. (Pag m 1, Pag pa 1), Pampus spp. (Pam ar 1, Pam c 1), Pandalus spp. (Pan b 1, Pan b 1.0101), Pangasius spp. (Pan bo 1), Pandalus spp. spp) (Pan e 1, Pan e 1.0101, Pan e 4), Panulirus spp) (Pan h 1, Pan hy 1), Pangasius spp) (Pan hy 18kD, Pan hy 45kD), Panulirus spp) (Pan j 1), Panthera spp) (Pan l 1, Pan o 1, Pan p 1), Panulirus spp) (Pan s 1, Pan s 1.0101), Panthera spp) (Pan t 1), Pan spp) (Pan tr TCTP), Papaver spp spp) (Pap s 17kD, Pap s 2, Pap s 34kD), swallowtail butterfly species (Papilio spp) (Pap xu 7, Pap xu 7.0101, Pap xu 7.0102), flounder species (Paralichthys spp) (Par a 1), Asian catfish species (Parasilurus spp) (Par as 1, Par c 1), red king crab species (Paralithodes spp) (Par c 1.0101, Par c 1.0102, Par f 1), Parthenium spp) (Par h 1), housefish species (Parietaria spp) (Par j 1, Par j 1.0101, Par j 1.0102, Par j 1.0103, Par j 1.0201, Par j 2, Par j 2.0101, Par j 2.0102, Par j 3, Par j 3.0101, Par j 3.0102, Par j 4, Par j 4.0101, Par j J1-J2), Paralichthys spp (Par le 1), Parietaria spp (Par m 1, Par o 1, Par o 1.0101), Paralichthys spp (Par ol 1, Par ol α2I), Parahucho spp (Par pe Vitellogenin), Passiflora spp (Pas e Chitinase, Pas e Hevein), Paspalum spp (Pas n 1, Pas n 1.0101, Pas n 13), Patinopecten spp (Pat y 1), Pediculus spp (Ped h 7, Ped h 7.0101), Penaeus spp (Pen a 1, Pen a 1.0101, Pen a 1.0102, Pen a 1.0102(103-117), Pen a 1.0102(109-123), Pen a 1.0102(1-15), Pen a 1.0102(115-129), Pen a 1.0102(121-135), Pen a 1.0102(127-141), Pen a 1.0102(13-27), Pen a 1.0102(133-147), Pen a 1.0102(139-153), Pen a 1.0102(145-159)), Farfantepenaeus spp (Pen a 1.0102(151-165)), Penaeus spp (Pen a 1.0102(157-171), Pen a 1.0102(163-177), Pen a 1.010(169-183), Pen a 1.0102(175-189), Pen a 1.0102(181-195), Pen a 1.0102(187-201), Pen a 1.0102(193-207), Pen a 1.0102(19-33), Pen a 1.Pen a 1.0102(199-213), Pen a 1.0102(205-219), Pen a 1.0102(211-225), Pen a 1.0102(217-231), Pen a 1.0102(223-237), Pen a 1.0102(229-243)), Farfantepenaeus spp. (Pen a 1.0102(235-249)), Penaeus spp. (Pen a 1.0102(241-255), Pen a 1.0102(247-261), Pen a 1.0102(253-267), Pen a 1.0102(25-39), Pen a 1.0102(259-273), Pen a 1.0102(265-279), Pen a 1.0102(270-284), Pen a 1.0102(31-45), Pen a 1.0102(37-51), Pen a 1.0102(43-57), Pen a 1.0102(49-63)), Farfantepenaeus spp. (Pen a 1.0102(55-69)), Penaeus spp. (Pen a 1.0102(61-75), Pen a 1.0102(67-81), Pen a 1.0102(7-21), Pen a 1.0102(73-87), Pen a 1.0102(79-93), Pen a 1.0102(85-99), Pen a 1.0102(91-105), Pen a 1.0102(97-111), Pen a 1.0103), Penicillium spp (Pen b 13, Pen b 13.0101, Pen b 26, Pen b 26.0101, Pen c 1, Pen c 13, Pen c 13.0101, Pen c 18, Pen c 19, Pen c 19.0101, Pen c 2, Pen c 22, Pen c 22.0101, Pen c 24, Pen c 24.0101, Pen c 3, Pen c 3.0101, Pen c 30, Pen c 30.0101, Pen c 32, Pen c 32.0101, Pen c MnSOD, Pen ch 13, Pen ch 13.0101, Pen ch 18, Pen ch 18.0101, Pen ch 20, Pen ch 20.0101, Pen ch 31, Pen ch 31.0101, Pen ch 33, Pen ch 33.0101, Pen ch 35, Pen ch 35.0101, Pen ch MnSOD), Penaeus. species of Penicillium spp (Pen i 1, Pen i 1.0101, Pen m 1, Pen m 1.0101, Pen m 1.0102, Pen m 2, Pen m 2.0101, Pen m 3, Pen m 3.0101, Pen m 4, Pen m 4.0101, Pen m 6, Pen m 6.0101), species of Penicillium spp (Pen o 18, Pen o 18.0101), species of Penaeus spp (Pena o 1, Pena o 1.0101), species of Periplaneta spp (Per a 1, Per a 1.0101, Per a 1.0102, Per a 1.0103, Per a 1.0104, Per a 1.0105, Per a 1.0201, Per a 10, Per a 10.0101, Per a 2, Per a 3, Per a 3.0101, Per a 3.0201, Per a 3.0202, Per a 3.0203, Per a 4, Per a 5, Per a 6, Per a 6.0101, Per a 7, Per a 7.0101, Per a 7.0102, Per a 7.0103, Per a 9, Per a 9.0101, Per a cathepsin, Per a FABP, Per a trypsin, Per f 1, Per f 7, Per f 7.0101), species of Perna spp (Per v 1), species of Persea spp (Pers a 1, Pers a 1.0101, Pers a 4), species of Petroselinum spp (Pet c 1, Pet c 2, Pet c 3), species of Phalaris spp (Pha a 1, Pha a 1.0101, Pha a 5, Pha a 5.0101, Pha a 5.02, Pha a 5.03, Pha a 5.04), species of Phaseolus spp (Pha v 3, Pha v 3.0101, Pha v 3.0201, Pha v aAI, Pha v aAI.0101, Pha v chitinase, Pha v PHA, Pha v phaeolin), species of Phleum spp (Phl p 1, Phl p 1.0101, Phl p 1.0102, Phl p 11, Phl p 11.0101, Phl p 12, Phl p 12.0101, Phl p 12.0102, Phl p 12.0103, Phl p 13, Phl p 13.0101, Phl p 2, Phl p 2.0101, Phl p 3, Phl p 3.0101, Phl p 3.0102, Phl p 4, Phl p 4.0101, Phl p 4.0102, Phl p 4.0201, Phl p 4.0202, Phl p 4.0203, Phl p 4.0204, Phl p 5, Phl p 5.0101, Phl p 5.0102,Phl p 5.0103, Phl p 5.0104, Phl p 5.0105, Phl p 5.0106, Phl p 5.0107, Phl p 5.0108, Phl p 5.0109, Phl p 5.0201, Phl p 5.0202, Phl p 5.0203, Phl p 5.0204, Phl p 5.0205, Phl p 5.0206, Phl p 5.0207, Phl p 6, Phl p 6.0101, Phl p 6.0102, Phl p 7, Phl p 7.0101, Phl p P1-P2-P5-P6, Phl p P2-P6, Phl p P5-P1,Phl p P6-P2), *Phoenix* spp. (Pho d 2, Pho d 2.0101, Pho d 40kD, Pho d 90kD), *Phodopus* spp. (Pho s 21kD), *Phoma* spp. (Pho t 1), *Phragmites* spp. (Phr a 1, Phr a 12, Phr a 13, Phr a 4, Phr a 5), ​​*Phytolacca* spp. (Phy a RIP), *Pimpinella* spp. (Pim a 1, Pim a 5) 2), Pinna spp (Pin a 1), Piper spp (Pip n 14kD, Pip n 28kD), Pisum spp (Pis s 1, Pis s 1.0101, Pis s 1.0102, Pis s 2, Pis s 2.0101, Pis s 5, Pis s agglutinin, Pis s albumin), Pistacia spp. (Pis v 1, Pis v 1.0101, Pis v 2, Pis v 2.0101, Pis v 2.0201, Pis v 3, Pis v 3.0101, Pis v 4, Pis v 4.0101, Pis v 5, Pis v 5.0101), Platanus spp. (Pla a 1, Pla a 1.0101, Pla a 2, Pla a 2.0101, Pla a 3, Pla a 3.0101, Pla a 8), Platichthys spp. (Pla f 1), Plantago spp. (Pla l 1, Pla l 1.0101, Pla l 1.0102, Pla l 1.0103, Pla l cytochrome C), Platanus spp. (Pla oc 1, Pla or 1, Pla or 1.0101, Pla or 2, Pla or 2.0101, Pla or 3, Pla or 3.0101, Pla or 4, Pla or CyP, Pla r 1), Plectropomus spp. (Ple ar 1), Pleospora spp. (Ple h 1), Plectropomus spp. (Ple le 1), Plodia spp. Poa p 1, Poa p 1.0101, Poa p 10, Poa p 12, Poa p 13, Poa p 2, Poa p 4, Poa p 5, Poa p 5.0101, Poa p 6, Poa p 7), Polistes spp (Pol a 1, Pol a 1.0101, Pol a 2, Pol a 2.0101, Pol a 5, Pol a 5.0101, Pol d 1, Pol d 1.0101, Pol d 1.0102, Pol d 1.0103, Pol d 1.0104, Pol d 4, Pol d 4.0101, Pol d 5, Pol d 5.0101, Pole 1, Pole 1.0101, Pole 2, Pole 4, Pole 4.0101, Pole 5, Pole 5.0101, Pol f 5, Pol f 5.0101, Pol g 1, Pol g 1.0101, Pol g 2, Pol g 4, Pol g 5, Pol g 5.0101, Pol he MLT, Pol m 5, Pol m 5.0101), Chironomus species (Polypedilum spp) (Pol n 1), Goose Barnacle species (Pollicipes spp) (Pol po 1), Pollock species (Pollachius spp) (Pol vi 1), Polybia species (Polybia spp) (Poly p 1, Poly p 1.0101, Poly p 2, Poly p 5, Poly s 5, Poly s 5.0101), Jack Mackerel species (Pomatomus spp) (Pom sa 1), Orangutan species (Pongo spp) (Pon ab HSA), Pontastacus species (Pontastacus spp) (Pon l 4, Pon l 4.0101, Pon l 7, Pon l 7.0101), Swimming Crab species (Portunus spp) (Por s 1, Por s 1.0101, Por s 1.0102, Por tr 1, Por tr 1.0101), Protortonia species (Protortonia spp) (Pro ca 38kD), Red Swamp Crayfish species (Procumbarus spp) (Pro cl 1, Pro cl 1.0101, Pro cl 21kD), Prosopis species (Prosopis spp) (Pro j 20kD), Cherry species (Prunus spp) (Pru ar 1, Pru ar 1.0101, Pru ar 3, Pru ar 3.0101, Pru av 1, Pru av 1.0101, Pru av 1.0201, Pru av 1.0202, Pru av 1.0203, Pru av 2, Pru av 2.0101, Pru av 3, Pru av 3.0101, Pru av 4, Pru av 4.0101, Pru c 1, Pru d 1, Pru d 2, Pru d 3, Pru d 3.0101, Pru du 4, Pru du 1, Pru du 2, Pru du 2S Albumin, Pru du 3, Pru du 3.0101, Pru du 4, Pru du 4.0101, Pru du 4.0102, Pru du 5, Pru du 5.0101, Pru du 6, Pru du 6.0101, Pru du 6.0201, Pru du Conglutin, Pru p 1, Pru p 1.0101, Pru p 2, Pru p 2.0101, Pru p 2.0201, Pru p 2.0301, Pru p 3, Pru p 3.0101, Pru p 3.0102, Pru p 4, Pru p 4.0101, Pru p 4.0201, Pru sa 3), Psilocybe spp. (Psi c 1, Psi c 1.0101, Psi c 2, Psi c 2.0101), Psoroptes spp. (Pso o 1, Pso o 10, Pso o 10.0101, Pso o 11, Pso o 13, Pso o 14, Pso o 2, Pso o 21, Pso o 3, Pso o 5, Pso o 7), Puma spp. (Pum c 1), Punica spp. (Pun g 3), Pyrus spp. (Pyr c 1, Pyr c 1.0101, Pyr c 3, Pyr c 3.0101, Pyr c 4, Pyr c 4.0101, Pyr c 5, Pyr c 5.0101, Pyr py 2), Quercus spp. (Que a 1, Que a 1.0101, Que a 1.0201, Que a 1.0301, Que a 1.0401, Que a 2, Que a 4), Rachycentron spp. (Rac ca 1), Rana spp. (Ran e 1, Ran e 1.0101, Ran e 2, Ran e 2.0101), Ranina spp. (Ran ra 1), Rangifer spp. (Ran t BLG), Rattus spp. (Rat n 1, Rat n 1.0101, Rat n casein, Rat n gelatin, Rat n IgG, Rat n phosvitin, Rat n RSA, Rat n transferrin), Rhizomucor spp (Rhi m AP), Rhizopus spp (Rhi nv lipase, Rhi o lipase), Rhomboplites spp (Rho au 1), Rhodotorula spp (R. ho m 1, Rho m 1.0101, Rho m 2, Rho m 2.0101), Ricinus spp. (Ric c 1, Ric c 1.0101, Ric c 2, Ric c 3, Ric c 8, Ric c RIP), Rivulus spp. (Riv ma 1), Robinia spp. (Rob p 2, Rob p 4, Rob p glucanase), Rosa spp. (Ros r 3), Roystonea spp. (Roy e 2), Rubus spp. (Rub i 1, Rub i 1.0101, Rub i 3, Rub i 3.0101, Rub i Chitinase, Rub i CyP), Saccharomyces spp. (Sac c carboxypeptidase Y, Sac c CyP, Sac c enolase, Sac c glucosidase, Sac c invertase, Sac c MnSOD, Sac c P2, Sac c profilin), Salvelinus spp. (Sal f 1), Salsola spp. (Sal k 1, Sal k 1.0101, Sal k 1.0201, Sal k 1.0301, Sal k 1.0302, Sal k 2, Sal k 2.0101, Sal k 3, Sal k 3.0101, Sal k 4, Sal k 4.0101, Sal k 4.0201, Sal k 5, Sal k 5.0101), Salvelinus spp. (Sal le vitellogenin), Atlantic salmon spp. (Salmo spp.) (Sal s 1, Sal s 1.0101, Sal s 1.0201, Sal s 2, Sal s 2.0101, Sal s gelatin), Sambucus spp. (Sam n 1), Sander spp. (San lu 1), Saponaria spp. (Sap o RIP), Sardinops spp. (Sar m 1), Sarkidiornis spp. (Sar ml 1), Sardina spp. (Sar p 1), Sarcoptes spp. (Sar s 1, Sar s 14, Sar s 3, Sar s GST, Sar s PM), Sardinops spp. (Sar sa 1, Sar sa 1.0101), Schistosoma spp. (Sch j GST, Sch j PM, Sch j Sj22, Sch j Sj67, Sch ma Sm20, Sch ma Sm21, Sch ma Sm22, Sch ma Sm31), Sciaenops spp. (Sci oc 1), Scomber spp. (Sco a 1), Scombermorus spp. (Sco ca 1), Scomberomorus spp. (Sco g 1), Scomber spp. (Sco j 1, Sco ma 1, Sco s 1), Scolopendra spp. (Sco y 7, Sco y 7.0101), Scylla spp (Scy o 1, Scy o 1.0101, Scy o 2, Scy pa 1, Scy pa 2, Scy s 1, Scy s 1.0101, Scy s 2), Sebastes spp (Seb fa 1, Seb in 1, Seb m Sec c 1, Sec c 12, Sec c 13, Sec c 2, Sec c 20, Sec c 20.0101, Sec c 20.0201, Sec c 28, Sec c 3, Sec c 4, Sec c 4.0101, Sec c 4.0201, Sec c 5, Sec c 5.0101, Sec c aA_TI, Sec c aA_TI.0101), Senecio spp. (Sen j MDH, Sen j PL), Sepia spp. (Sep e 1, Sep e 1.0101), Sepioteuthis spp. (Sep l 1, Sep l 1.0101), Sepia spp. (Sep m 1), Seriola spp. (Ser d 1, Ser la 1), Sergestes spp. (Ser lu 1), Seriola spp. (Ser q 1, Ser ri 1), Sesamum spp. (Ses i 1, Ses i 1.0101, Ses i 2, Ses i 2.0101, Ses i 3, Ses i 3.0101, Ses i 4, Ses i 4.0101, Ses i 5, Ses i 5.0101, Ses i 6, Ses i 6.0101, Ses i 7, Ses i 7.0101, Ses i 8), Shigella spp. (Shi bo GST, Shi dy GST), Simulia spp. (Sim vi 1, Sim vi 2, Sim vi 3, Sim vi 4, Sim vi 70kD), Sinapis spp. (Sin a 1, Sin a 1.0101, Sin a 1.0104, Sin a Sinonovacula spp. 1, Sin c 1.0101), Solenopsis spp (Sol g 2, Sol g 2.0101, Sol g 3, Sol g 3.0101, Sol g 4, Sol g 4.0101, Sol g 4.0201, Sol i 1, Sol i 1.0101, Sol i 2, Sol i 2.0101, Sol i 3, Sol i 3.0101, Sol i 4, Sol i 4.0101), Solenocera spp (Sol me 1), Solenopsis spp (Sol r 1, Sol r 2, Sol r 2.0101, Sol r 3, Sol r 3.0101, Sol s 2, Sol s 2.0101, Sol s 3, Sol s 3.0101, Sol s 4), Solea spp (Sol so 1, Sol so TPI), Solanum spp (Sola t 1, Sola t 1.0101, Sola t 2, Sola t 2.0101, Sola t 3, Sola t 3.0101, Sola t 3.0102, Sola t 4, Sola t 4.0101, Sola t 8, Sola t glucanase), Sorghum spp. (Sor b 1, Sor h 1, Sor h 1.0101, Sor h 12, Sor h 7), Sparus spp. (Spa a 1), Sphyrna spp. (Sph ti 1), Spirulina spp. (Spi mx β_phycocyanin), Spinacia spp. (Spi o 2, Spi o rubisco), Squilla spp. (Squ ac 1, Squ ac 1.0101, Squ o 1, Squ o 1.0101), Staphylococcus spp. (Sta a FBP, Sta a SEA, Sta a SEB, Sta a SEC, Sta a SED, Sta a SEE, Sta a TSST), Stachybotrys spp. (Sta c 3, Sta c 3.0101, Sta c cellulase, Sta c hemolysin, Sta c SchS34, Sta c stachyrase A), Stemphylium spp. (Ste b 1, Ste c 1, Ste v 1), Stolephorus spp. (Sto i 1), Struthio spp. (Str c 1, Str c 2, Str c 3), Streptococcus spp. (Str dy streptokinase), Streptomyces spp. (Str g pronase), Streptococcus spp. (Str pn PspC), Strongylocentrotus spp. (Str pu 18kD, Str pu vitellogenin), Streptococcus spp. (Str py SPEA, Str py SPEC, Str py streptokinase), Strongyloides spp. (Str st 45kD), Streptomyces spp. (Str v PAT), Styela spp. (Sty p 1), Suidasia spp. (Sui m 1, Sui m 13, Sui m 2, Sui m 3, Sui m 5, Sui m 5.01, Sui m 5.02, Sui m 5.03, Sui m 6, Sui m 7, Sui m 8, Sui m 9), Sus spp. (Sus s ACTH, Sus s ALA, Sus s amylase, Sus s BLG, Sus s casein, Sus s casein αS1, Sus s casein αS2, Sus s casein β, Sus s casein κ, Sus s gelatin, Sus s HG, Sus s insulin, Sus s lipase, Sus s pepsin, Sus s phosvitin, Sus s PRVB, Sus s PSA, Sus s TCTP), Syntelopodeuma spp. (Syntelopodeuma spp.) ...0101), Syringa spp. (Syr v 1, Syr v 1.0101, Syr v 1.0102, Syr v 1.0103, Syr v 2, Syr v 3, Syr v 3.0101), Tabanus spp. (Tab y 1, Tab y 1.0101, Tab y 2, Tab y 2.0101, Tab y 5, Tab y 5.0101), Tadorna spp. (Tad ra 1), Talaromyces spp. (Tal st 22, Tal st 3, Tal st 8), Taraxacum spp. (Tar o 18kD), Taxodium spp. (Tax d 2), Tegenaria spp. (Teg d hemocyanin), Teladorsagia spp. (Tel ci 3), Thaumetopoea spp. (Tha p 1, Tha p 1.0101, Tha p 2, Tha p 2.0101), Theragra spp. (The c 1), Thermomyces spp. (The l lipase, The sp lipase, The sp xylanase), Thunnus spp. (Thu a 1, Thu a. 1.0101, Thu a collagen, Thu al 1, Thu at 1, Thu o 1, Thu o collagen), Thuja spp. (Thu oc 3, Thu p 1), Thunnus spp. (Thu t 1, Thu to 1), Thyrsites spp. (Thy at 1), Thyrophygus spp. (Thy y 7, Thy y 7.0101), Todarodes spp. (Tod p 1, Tod p 1.0101, Tod p 1.0102), Toxoptera spp. (Tox c 7, Tox c 7.0101), Toxocara spp. (Tox ca TES120, Tox ca TES26, Tox ca TES30), Toxoplasma spp. (Tox g HSP70), Trachypenaeus spp. (Tra c 1), Trachinotus spp. (Tra ca 1), Trachurus spp. (Tra j 1, Tra j gelatin, Tra tr gelatin), Triticum spp. (Tri a 1, Tri a 10kD, Tri a 12, Tri a 12.0101, Tri a 12.0102, Tri a 12.0103, Tri a 12.0104, Tri a 13, Tri a 14, Tri a 14.0101, Tri a 14.0201, Tri a 15, Tri a 15.0101, Tri a 18, Tri a 18.0101, Tri a 19, Tri a 19.0101, Tri a 2, Tri a 21, Tri a 21.0101, Tri a 23kd, Tri a 25, Tri a 25.0101, Tri a 26, Tri a 26.0101, Tri a 27, Tri a 27.0101, Tri a 28, Tri a 28.0101, Tri a 29, Tri a 29.0101, Tri a 29.0201, Tri a 3, Tri a 30, Tri a 30.0101, Tri a 31, Tri a 31.0101, Tri a 32, Tri a 32.0101, Tri a 33, Tri a 33.0101, Tri a 34, Tri a 34.0101, Tri a 35, Tri a 35.0101, Tri a 36, ​​Tri a 36.0101, Tri a 37, Tri a 37.0101, Tri a 4, Tri a 4.0101, Tri a 4.0201, Tri a 5, Tri a 7, Tri a aA_SI, Tri a α_gliadin, Tri a bA, Tri a Bd36K, Tri a β_gliadin, Tri a chitinase, Tri a CM16, Tri a DH, Tri a endochitinase, Tri a γ_gliadin, Tri a germin, Tri a gliadin, Tri a GST, Tri a LMW Glu, Tri a LMW-GS B16, Tri a LMW-GS P42, Tri a LMW-GS P73, Tri a LTP2, Tri a ω2_gliadin, Tri a peroxidase, Tri a peroxidase 1, Tri a SPI, Tri a TLP, Tri a tritin, Tri a XI), Tritirachium spp (Tri al proteinase K), Tribolium spp (Tri ca 17, Tri ca 17.0101, Tri ca 7, Tri ca 7.0101), Trichostrongylus spp (Tri co 3, Tri co 3.0101), Trichophyton spp (Tri eq 4), Trigonella spp (Tri fg 1, Tri fg 2, Tri fg 3, Tri fg 4), Trichosanthes spp (Tri k RIP), Trichiurus spp (Tri le 1), Triticum spp (Tri m ペルオキシダーゼ), Trichophyton spp (Tri me 2, Tri me 4), Trisetum spp (Tri p 1, Tri p 5), Trichinella spp (Tri ps) 3. Trips 3.0101), Trichophyton spp (Tri r 2, Tri r 2.0101, Tri r 4, Tri r 4.0101), Trichoderma spp (Tri rs セルラーゼ), Triticum spp (Tri s 14), Trichophyton spp (Tri sc 2, Tri sc 4, Tri so 2), Trichinella spp (Tri sp 3, Tri sp 3.0101, Tri sp 3.0102, Tri sp 3.0103, Tri sp 3.0104, Tri sp 3.0105, Tri sp 3.0106), Trichophyton spp (Tri t 1, Tri t 1.0101, Tri t 4, Tri t 4.0101), Triticum spp (Tri td 14, Tri td aA_TI), Trichoderma spp (Tri v selra ze), Trichophyton spp (Tri ve 4), Triatoma spp (Tria p 1, Tria p 1).0101), Triplochiton spp. (Trip s 1), Turbo spp. (Tur c 1, Tur c PM), Tyrophagus spp. (Tyr p 1, Tyr p 10, Tyr p 10.0101, Tyr p 10.0102, Tyr p 13, Tyr p 13.0101, Tyr p 2, Tyr p 2.0101, Tyr p 24, Tyr p 24.0101, Tyr p 3, Tyr p 3.0101, Tyr p 4, Tyr p 5, Tyr p 5.01, Tyr p 5.02, Tyr p 5.03, Tyr p 7, Tyr p α-tubulin), Ulocladium spp. (Ulo a 1, Ulo at 1, Ulo b 1, Ulo c 1, Ulo co 1, Ulo cu 1, Ulo mu 1, Ulo ob 1, Ulo se 1, Ulo su 1, Ulo tu 1), Uncia spp. (Unc u 1), Urophycis spp. (Uro te 1), Vaccinium spp. (Vac m 3), Varroa spp. (Var j 13kD), Venerupis spp. (Ven ph 1, Ven ph 1.0101), Vespula spp. (Ves f 1, Ves f 2, Ves f 5, Ves f 5.0101, Ves g 1, Ves g 2, Ves g 5, Ves g 5.0101, Ves m 1, Ves m 1.0101, Ves m 2, Ves m 2.0101, Ves m 5, Ves m 5.0101, Ves m MLT, Ves p 1, Ves p 2, Ves p 5, Ves p 5.0101, Ves s 1, Ves s 1.0101, Ves s 2, Ves s 5, Ves s 5.0101, Ves v 1, Ves v 1.0101, Ves v 2, Ves v 2.0101, Ves v 2.0201, Ves v 3, Ves v 3.0101, Ves v 5, Ves v 5.0101, Ves v 5-Pol a 5, Ves vi 5, Ves vi 5.0101)、Vespa spp(Vesp c 1、Vesp c 1.0101、Vesp c 2、Vesp c 5、Vesp c 5.0101、Vesp c 5.0102、Vesp m 1、Vesp m 1.0101、Vesp m 5. Vesp m 5.0101. Vesp ma 1. Vesp ma 2. Vesp ma 5. Vesp ma MLT. Vesp v MLT 17kD, Vig r 5, Vig r 8S, Vig r, Vig r, Vig r β-chain (Vitis spp) (Vit v 1 , Vit v 1.0101 , Vit v 4 , Vit v 5 , Vit v rhinoceros , Vit v TLP ) , thyme ( Xiphias spp ) ( Xip g 1 , Xip g 1.0101, Xip g 25kD), Zea m 1.0101, Zea m 11, Zea m 12, Zea m 12.0101, Zea m 12.0102、Zea m 12.0103、Zea m 12.0104、Zea m 12.0105、Zea m 13、Zea m 14、Zea m 14.0101、Zea m 14.0102、Zea m 2、Zea m 20S, Zea m 22, Zea m 25, Zea m 25.0101, Zea m 27kD, Zea m 3, Zea m 4, Zea m 5, Zea m 50kD, Zea m 7. Zea m rhinoceros, Zea m G1, Zea m G2, Zea m PAO, Zea m Zm13) and zebra mussels (Zeus spp) (Zeu fa 1) rhinoceros (Ziziphus spp) (Ziz m 1, Ziz m 1.0101), rhinoceros (Zoarces spp) (Zoa a ISP III) Sweet potato (Zygophyllum spp) (Zyg f 2).

[0208] This is a great deal of snowflakes The kingdom of the kingdom is called the Calais (Campaign).

[0209] Most preferably, the allergenic antigen is preferably grass pollen (e.g., rye pollen), tree pollen (e.g., hazel, birch, alder, ash pollen), flower pollen, herb pollen (e.g., bromelain pollen), house dust mite (e.g., Der f 1, Der p 1, Eur m 1, Der m 1 Der f 2, Der p 2, Eur m 2, Tyr p 2, Lep d 2), mold (e.g., Acremonium, Aspergillus, Cladosporium, Fusarium, Mucor, Penicillium, Rhizopus, Stachybotrys, Trichoderma, or Alternaria allergens), animal (e.g., feline Fel d1, Fel d 2, Fel d3, or Fel d4), food (e.g. allergens from fish (e.g. bass, cod, flounder), seafood (e.g. crab, lobster, shrimp), egg, wheat, nuts (e.g. peanuts, almonds, cashews, walnuts), soy, milk, etc.) or insect venom (e.g. allergens from wasp, bee, hornet, ant, mosquito, or mite venom).

[0210] Autoimmune autoantigens: Autoimmune autoantigens, i.e., antigens or autoantigens associated with autoimmune diseases, are associated with autoimmune diseases affecting one or more of the following organ systems: circulatory system, digestive system, endocrine system, excretory system, immune system, integumentary system, muscular system, nervous system, reproductive system, respiratory system, and skeletal system, and preferably may be associated with the cardiovascular system, neuroendocrine system, musculoskeletal system, or gastrointestinal system. The circulatory system is the organ system responsible for the pumping and flow of blood to and from the body and lungs via the heart, blood vessels, and blood vessels. The digestive system is responsible for the digestion and processing of food via the salivary glands, esophagus, stomach, liver, gallbladder, pancreas, intestine, colon, rectum, and anus. The endocrine system is responsible for communication within the body using hormones produced by endocrine glands such as the hypothalamus, pituitary gland or gland, pineal gland or gland, thyroid gland, parathyroid gland, and adrenal glands. The excretory system includes the kidneys, ureters, bladder, and urethra and is involved in fluid balance, electrolyte balance, and urine excretion. The immune system includes structures involved in the movement of lymph between tissues and the bloodstream, lymph, lymph nodes, and blood vessels, which may be involved in transporting cellular and humoral components of the immune system. The immune system is involved in defense against disease-causing agents and also includes white blood cells, tonsils, adenoids, the thymus, and the spleen. The integumentary system includes skin, hair, and nails. The muscular system, together with the skeletal system, including bones, cartilage, ligaments, and tendons, enables muscle movement and provides structural support. The nervous system, involved in the collection, transmission, and processing of information, includes the brain, spinal cord, and nerves. The reproductive system includes the genitals, such as the ovaries, fallopian tubes, uterus, vagina, mammary glands, testes, vas deferens, seminal vesicles, prostate, and penis. The respiratory system includes the organs used for breathing, including the pharynx, larynx, trachea, bronchi, lungs, and diaphragm, and works together with the circulatory system.

[0211] Autoimmune autoantigens (antigens or autoantigens associated with autoimmune diseases) include Addison's disease (autoimmune adrenalitis, Addison's disease (Morbus Addison)), alopecia areata, Addison's anemia (Morbus Biermer's disease), autoimmune hemolytic anemia (AIHA), cold autoimmune hemagglutinin disease (CHD) and cold hemagglutinin disease (CHD). disease), cold autoimmune hemolytic anemia (AIHA) (cold agglutinin disease (CHAD)), warm autoimmune hemolytic anemia (AIHA) (warm AIHA, warm autoimmune hemolytic anemia (AIHA)), autoimmune Donath-Landsteiner hemolytic anemia (paroxysmal cold hemoglobinuria), antiphospholipid syndrome (APS), atherosclerosis, autoimmune arthritis, temporal arteritis, Takayasu's arteritis (Takayasu's disease, aortic arch disease), temporal arteritis / giant cell arteritis, autoimmune chronic gastritis, autoimmune infertility, autoimmune inner ear disease (AIED), Graves' disease (Graves' disease (Morbus Basedow)), Bechterew's disease (Morbus Bechterew), ankylosing spondylitis, ankylosing spondylitis ankylosans), Behcet's syndrome (Behcet's disease (Morbus Behcet)), enteropathy including autoimmune inflammatory bowel disease (ulcerative colitis (including Crohn's disease (Morbus Crohn), Crohn's disease), cardiomyopathy, especially autoimmune cardiomyopathy, idiopathic dilated cardiomyopathy (DCM), celiac sprue dermatitis (gluten-induced enteropathia), chronic fatigue immune deficiency syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CIDP), chronic polyarthritis, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan's syndrome, CREST syndrome (a syndrome associated with calcinosis cutis, Raynaud's phenomenon, esophageal motility disorders, sklerodaktylia and telangiectasia), Crohn's disease (Morbus Crohn, ulcerative colitis), Dühring's dermatitis herpetiformisduring), autoimmune skin diseases, dermatomyositis, diabetes, type 1 diabetes mellitus (type I diabetes, insulin-dependent diabetes mellitus), type 2 diabetes mellitus (type II diabetes), essential mixed cryoglobulinemia, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Goodpasture's syndrome (anti-GBM glomerulonephritis), graft-versus-host disease, Guillain-Barré syndrome (GBM, polyradikuloneuritis), hematological autoimmune diseases, Hashimoto's thyroiditis, hemophilia, acquired hemophilia, hepatitis, autoimmune hepatitis, especially autoimmune chronic hepatitis, idiopathic pulmonary fibrosis (IPF), idiopathic thrombocytopenic purpura, immune thrombocytopenic purpura (Morbus Werlhof disease; ITP), IgA nephropathy, infertility, autoimmune infertility, juvenile rheumatoid arthritis (Steele's disease Still syndrome), Lambert-Eaton syndrome, lichen planus, lichen sclerosus, lupus erythematosus, systemic lupus erythematosus (SLE), lupus erythematosus (disciform type), Lyme arthritis (Lyme disease, Borrelia arthritis), Meniere's disease (Morbus Meniere); mixed connective tissue disease (MCTD), multiple sclerosis (MS, disseminated encephalomyelitis disseminate, Charcot's disease), myasthenia gravis (MG), myositis, polymyositis, neurological autoimmune diseases, neurodermatitis, pemphigus vulgaris, bullous pemphigoid, scar forming pemphigoid; polyarteritis nodosa (periarteritis nodosa) nodosa), polychondritis (polychondritis), polyendocrine (autoimmune) syndrome (PGA syndrome, Schmidt's syndrome), polymyalgia rheumatica, primary agammaglobulinemia, primary biliary cirrhosis (PBC), primary autoimmune cholangitis), progressive systemic sclerosis (PSS), psoriasis, plaque psoriasis, Raynaud's phenomenon, Reiter's syndrome (Reiter's disease (Morbus Reiter), urethral, ​​conjunctival, and synovial syndrome)), rheumatoid arthritis (RA, chronic polyarthritis, rheumatic joint disease, rheumatic fever), sarcoidosis (Beck's disease (MorbusBoeck, Benier-Beck-Schaumann disease, stiff man syndrome, sclerodermia, scleroderma, Sjogren's syndrome, sympathetic ophthalmia; transient gluten intolerance, transplant organ rejection, uveitis, autoimmune uveitis, vasculitis, vitiligo (white catfish, pieboldi skin), and Wegener's disease (Morbus Wegner, Wegener's granulomatosis).

[0212] These and other proteins that act as autoimmune self-antigens are understood to be therapeutic because the intent is to treat a subject, particularly a mammal, and more particularly a human, by vaccinating the subject with an autoantigen that is expressed by the mammal, e.g., human, itself, and that elicits an unwanted immune response that would not occur in a healthy subject. Accordingly, such proteins that act as autoantigens are typically derived from a mammal, particularly a human.

[0213] In this regard, -myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG), all of which are associated with multiple sclerosis (MS); - CD44, preproinsulin, proinsulin, insulin, glutamic acid decarboxylase (GAD65), tyrosine phosphatase-like insulinoma antigen 2 (IA2), zinc transporter (ZnT8), and heat shock protein 60 (HSP60), all of which are associated with type 1 diabetes; -Interphotoreceptor retinoid-binding protein (IRBP), associated with autoimmune uveitis; - the acetylcholine receptor AchR and insulin-like growth factor-1 receptor (IGF-1R), both of which are associated with myasthenia gravis; -M protein (pseudo-autoantigen) from beta-hemolytic streptococci associated with rheumatic fever; -Arthritis-associated macrophage migration inhibitory factor; -Ro / La RNP complex, α- and β-fodrin, pancreatic islet cell autoantigens, poly(ADP) ribose polymerase (PARP), NuMA, NOR-90, Ro60 autoantigen, and p27 antigen, all of which are associated with Sjögren's syndrome; -Ro60 autoantigen, low-density lipoprotein, Sm antigens of the U1 small nuclear ribonucleoprotein complex (B / B', D1, D2, D3, E, F, G), and RNP ribonucleoproteins, all associated with lupus erythematosus; - oxLDL, β(2)GPI, HSP60 / 65, and oxLDL / β(2)GPI, all of which are associated with atherosclerosis; -Cardiac β(1)-adrenergic receptors associated with idiopathic dilated cardiomyopathy (DCM); -Histidyl-tRNA synthetase (HisRS) associated with myositis; -Topoisomerase I associated with scleroderma disease Particularly preferred are autoimmune self-antigens (autoantigens) selected from:

[0214] Furthermore, in other embodiments, the autoimmune autoantigen is associated with a respective autoimmune disease, such as, for example, IL-17, a heat shock protein, and / or any idiotypic pathogenic T cell or chemokine receptor expressed by immune cells involved in the autoimmune response of an autoimmune disease (such as any of the autoimmune diseases described herein).

[0215] Preferably, at least one coding region of an mRNA compound comprising an mRNA sequence according to the present invention comprises at least two, three, four, five, six, seven, eight or more nucleic acid sequences identical to or having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90% and most preferably at least 95% or even 97% sequence identity to any one of the nucleic acid sequences disclosed in the Sequence Listing (or Tables 1 to 5 or Figures 20 to 24 of PCT / EP2016 / 075843, respectively), or fragments or variants of any one of said nucleic acid sequences.

[0216] Preferably, an mRNA sequence comprising at least one coding region as defined herein typically comprises a length of about 50 to about 20,000, or 100 to about 20,000 nucleotides, preferably about 250 to about 20,000 nucleotides, more preferably about 500 to about 10,000, and even more preferably about 500 to about 5,000.

[0217] According to a further embodiment, the mRNA sequence according to the invention is an artificial mRNA sequence as defined herein.

[0218] According to a further embodiment, the mRNA compound comprising the mRNA sequence of the present invention is a modified mRNA sequence, preferably a modified mRNA sequence as described herein. In this regard, the modification as defined herein preferably leads to the stabilization of the mRNA sequence of the present invention. More preferably, the present invention thus provides a stabilized mRNA sequence comprising at least one coding region as defined herein.

[0219] According to one embodiment, an mRNA compound comprising an mRNA sequence of the present invention may be provided as a "stabilized mRNA sequence," i.e., an mRNA that is essentially resistant to in vivo degradation (e.g., by exonucleases or endonucleases). Such stabilization can be achieved, for example, by a modified phosphate backbone of the mRNA of the present invention. A backbone modification in the context of the present invention refers to a modification in which the phosphate of the backbone of a nucleotide contained in the mRNA is chemically modified. In this context, preferred nucleotides that can be used include, for example, phosphorothioate-modified phosphate backbones, in which at least one of the phosphate oxygens contained in the phosphate backbone is preferably replaced with a sulfur atom. The stabilized mRNA may further include, for example, non-ionic phosphate analogs, such as alkyl and aryl phosphonates in which the charged phosphonate oxygen is replaced with an alkyl or aryl group, or phosphodiesters and alkyl phosphotriesters in which the charged oxygen residue exists in an alkylated form. Such backbone modifications typically include, without implying any limitation, modifications from the group consisting of methylphosphonates, phosphoramidates and phosphorothioates (e.g., cytidine-5'-O-(1-thiophosphate)).

[0220] Specific modifications are described below, and preferably have the ability to "stabilize" mRNA as defined herein.

[0221] Chemical modification: The term "mRNA modification" as used herein can refer to chemical modifications, including backbone modifications as well as sugar or base modifications.

[0222] In this context, a modified mRNA (sequence) as defined herein may comprise a nucleotide analogue / modification, such as a backbone modification, a sugar modification or a base modification. A backbone modification in the context of the present invention is a modification in which the phosphate of the backbone of a nucleotide contained in an mRNA compound comprising an mRNA sequence as defined herein is chemically modified. A sugar modification in the context of the present invention is a chemical modification of the sugar of a nucleotide of an mRNA compound comprising an mRNA sequence as defined herein. Furthermore, a base modification in the context of the present invention is a chemical modification of the base moiety of a nucleotide of an mRNA compound comprising an mRNA sequence. In this context, the nucleotide analogue or modification is preferably selected from nucleotide analogues applicable to transcription and / or translation.

[0223] Sugar modification: Modified nucleosides and nucleotides that can be incorporated into modified mRNA compounds containing mRNA sequences as described herein may have modifications in the sugar moiety. For example, the 2' hydroxyl group (OH) may be modified or replaced with any number of different "oxy" or "deoxy" substituents. Examples of "oxy"-2' hydroxyl group modifications include, but are not limited to, alkoxy or aryloxy (-OR, e.g., R = H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or sugar); polyethylene glycols (PEG), -O(CHCHO)CHCHOR; "locked" nucleic acids (LNAs) in which the 2' hydroxyl is linked to the 4' carbon of the same ribose sugar, e.g., by a methylene bridge; and amino groups (-O-amino, where the amino group, e.g., NRR, can be alkylamino, dialkylamino, heterocyclyl, arylamino, diarylamino, heteroarylamino, or diheteroarylamino, ethylenediamine, polyamino) or aminoalkoxy.

[0224] "Deoxy" modifications include hydrogen, amino (e.g., NH; alkylamino, dialkylamino, heterocyclyl, arylamino, diarylamino, heteroarylamino, diheteroarylamino, or amino acid); or the amino group may be attached to the sugar via a linker, where the linker includes one or more of the atoms C, N, and O.

[0225] The sugar group may also contain one or more carbons that have the opposite stereochemistry compared to the corresponding carbon in ribose. Thus, modified mRNA may contain nucleotides that contain, for example, arabinose as the sugar.

[0226] Backbone modifications: In modified nucleosides and nucleotides that can be incorporated into modified mRNA compounds containing mRNA sequences as described herein, the phosphate backbone may be further modified. The backbone phosphate group may be modified by replacing one or more of the oxygen atoms with different substituents. Furthermore, modified nucleosides and nucleotides may include complete replacement of the unmodified phosphate moiety with a modified phosphate as described herein. Examples of modified phosphate groups include, but are not limited to, phosphorothioates, phosphoroselenates, boranophosphates, boranophosphate esters, hydrogen phosphonates, phosphoramidates, alkyl or aryl phosphonates, and phosphate triesters. Phosphorodithioates have both non-linking oxygens replaced by sulfur. The phosphate linker may also be modified by replacing the linking oxygen with nitrogen (bridged phosphoramidates), sulfur (bridged phosphorothioates), or carbon (bridged methylene phosphonates).

[0227] Base modifications: Modified nucleosides and nucleotides that can be incorporated into modified mRNA compounds containing mRNA sequences as described herein may further be modified at the nucleobase portion. Examples of nucleobases found in mRNA include, but are not limited to, adenine, guanine, cytosine, and uracil. For example, the nucleosides and nucleotides described herein may be chemically modified at the major groove surface. In some embodiments, the major groove chemical modification may include an amino group, a thiol group, an alkyl group, or a halo group.

[0228] In a particularly preferred embodiment of the present invention, the nucleotide analogues / modifications are preferably 2-amino-6-chloropurine riboside-5'-triphosphate, 2-aminopurine-riboside-5'-triphosphate; 2-aminoadenosine-5'-triphosphate, 2'-amino-2'-deoxycytidine-triphosphate, 2-thiocytidine-5'-triphosphate, 2-thiouridine-5'-triphosphate, 2'-fluorothymidine-5'-triphosphate, 2'-O-methyl-inosine-5'-triphosphate 4-thiouridine-5'-triphosphate, 5-aminoallylcytidine-5'-triphosphate, 5-aminoallyluridine-5'-triphosphate, 5-bromocytidine-5'-triphosphate, 5-bromouridine-5'-triphosphate, 5-bromo-2'-deoxycytidine-5'-triphosphate, 5-bromo-2'-deoxyuridine-5'-triphosphate, 5-iodocytidine-5'-triphosphate, 5-iodo-2'-deoxycytidine-5'-triphosphate, 5-iodouridine-5'-triphosphate, 5-iodo-2'-deoxyuridine-5'-triphosphate, 5-methylcytidine-5'-triphosphate, 5-methyluridine-5'-triphosphate, 5-propynyl-2'-deoxycytidine-5'-triphosphate, 5-propynyl-2'-deoxy The base modifications are selected from uridine-5'-triphosphate, 6-azacytidine-5'-triphosphate, 6-azauridine-5'-triphosphate, 6-chloropurine riboside-5'-triphosphate, 7-deazaadenosine-5'-triphosphate, 7-deazaguanosine-5'-triphosphate, 8-azaadenosine-5'-triphosphate, 8-azidoadenosine-5'-triphosphate, benzimidazole-riboside-5'-triphosphate, N1-methyladenosine-5'-triphosphate, N1-methylguanosine-5'-triphosphate, N6-methyladenosine-5'-triphosphate, O6-methylguanosine-5'-triphosphate, pseudouridine-5'-triphosphate, or puromycin-5'-triphosphate and xanthosine-5'-triphosphate. Particularly preferred are base-modifying nucleotides selected from the group of base-modified nucleotides consisting of 5-methylcytidine-5'-triphosphate, 7-deazaguanosine-5'-triphosphate, 5-bromocytidine-5'-triphosphate, and pseudouridine-5'-triphosphate.

[0229] In some embodiments, modified nucleosides include pyridin-4-one ribonucleosides, 5-aza-uridine, 2-thio-5-aza-uridine, 2-thiouridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxyuridine, 3-methyluridine, 5-carboxymethyl-uridine, 1-carboxymethyl-pseudouridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyluridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1-taurinomethyl- These include thyl-4-thio-uridine, 5-methyl-uridine, 1-methyl-pseudouridine, 4-thio-1-methyl-pseudouridine, 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, and 4-methoxy-2-thio-pseudouridine.

[0230] In some embodiments, modified nucleosides include 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5-formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-1-methyl -pseudoisocytidine, 4-thio-1-methyl-1-deaza-pseudoisocytidine, 1-methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, and 4-methoxy-1-methyl-pseudoisocytidine.

[0231] In other embodiments, modified nucleosides include 2-aminopurine, 2,6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-aminopurine, 7-deaza-8-aza-2-aminopurine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1-methyladenosine, N6-methyladenosine, N6-isopentenyladenosine, N These include 6-(cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl)adenosine, N6-glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine, 2-methylthio-N6-threonylcarbamoyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, and 2-methoxy-adenine.

[0232] In other embodiments, modified nucleosides include ino...

Claims

1. A lipid nanoparticle, comprising: (i) a cationic lipid having formula III: 【Chemistry 1】 or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein: L １ or L ２ are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, or -S(O) ｘ -, -S-S-, -C(=O)S-, -SC(=O)-, -NR ａ C(=O)-, -C(=O)NR ａ -, -NR ａ C(=O)NR ａ -, -OC(=O)NR ａ -or-NR ａ C(=O)O-, preferably L １ or L ２ is —O(C═O)— or —(C═O)O—; G １ and G ２ are each independently an unsubstituted C １ ~C １２ Alkylene or C １ ~C １２ alkenylene; G ３ is C １ ~C ２４ Alkylene, C １ ~C ２４ Alkenylene, C ３ ~C ８ Cycloalkylene, or C ３ ~C ８ is cycloalkenylene; R ａ is H or C １ ~C １２ is alkyl; R １ and R ２ are each independently C ６ ~C ２４ Alkyl or C ６ ~C ２４ alkenyl; R ３ is H, OR ５ , CN, -C(=O)OR ４ , —OC(═O)R ４ or -NR ５ C(=O)R ４ and R ４ is C １ ~C １２ is alkyl; R ５ is H or C １ ~C ６ is alkyl; and x is 0, 1 or 2; (ii) an mRNA compound comprising an mRNA sequence encoding at least one antigenic peptide or protein, optionally without nucleoside modifications, particularly without base modifications; wherein said mRNA compound is encapsulated in or associated with said lipid nanoparticle.

2. A lipid nanoparticle, comprising: (i) a PEG lipid having the formula (IV): 【Chemistry 2】 [In the formula, R ８ and R ９ are each independently a linear or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, the alkyl chain optionally being interrupted by one or more ester linkages; and w has an average value in the range of 30 to 60; and (ii) an mRNA compound comprising an mRNA sequence encoding at least one antigenic peptide or protein, optionally without nucleoside modifications, particularly without base modifications; wherein said mRNA compound is encapsulated in or associated with said lipid nanoparticle.

3. A lipid nanoparticle, comprising: (i) a cationic lipid having formula I: 【Transformation 3】 or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein: L １ and L ２ are each independently —O(C═O)—, —(C═O)O—, or a carbon-carbon double bond; R １ａ and R １ｂ is, at each occurrence, independently: (a) H or C １ ~C １２ alkyl, or (b) R １ａ is H or C １ ~C １２ alkyl, and R １ｂ together with the carbon atom to which it is attached, the adjacent R １ｂ and together with the carbon atom to which it is attached form a carbon-carbon double bond; R ２ａ and R ２ｂ is, at each occurrence, independently: (a) H or C １ ~C １２ alkyl, or (b) R ２ａ is H or C １ ~C １２ alkyl, and R ２ｂ together with the carbon atom to which it is attached, the adjacent R ２ｂ and together with the carbon atom to which it is attached form a carbon-carbon double bond; R ３ａ and R ３ｂ is, at each occurrence, independently: (a) H or C １ ~C １２ alkyl, or (b) R ３ａ is H or C １ ~C １２ alkyl, and R ３ｂ together with the carbon atom to which it is attached, the adjacent R ３ｂ and together with the carbon atom to which it is attached form a carbon-carbon double bond; R ４ａ and R ４ｂ is, at each occurrence, independently: (a) H or C １ ~C １２ alkyl, or (b) R ４ａ is H or C １ ~C １２ alkyl, and R ４ｂ together with the carbon atom to which it is attached, the adjacent R ４ｂ and together with the carbon atom to which it is attached form a carbon-carbon double bond; R ５ and R ６ are each independently methyl or cycloalkyl; R ７ is independently H or C at each occurrence. １ ~C １２ is alkyl; R ８ and R ９ are each independently C １ ~C １２ alkyl; or R ８ and R ９ together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom; a and d are each independently an integer from 0 to 24; b and c are each independently an integer from 1 to 24; and e is 1 or 2; and (ii) an mRNA compound comprising an mRNA sequence encoding at least one antigenic peptide or protein, optionally containing no nucleoside modifications, particularly no base modifications. wherein said mRNA compound is encapsulated in or associated with said lipid nanoparticle.

4. A lipid nanoparticle, comprising: (i) a cationic lipid having formula II: 【Chemistry 4】 or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein: L １ and L ２ are each independently -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, or -S(O) ｘ -, -S-S-, -C(=O)S-, -SC(=O)-, -NR ａ C(=O)-, -C(=O)NR ａ -, -NR ａ C(=O)NR ａ -, -OC(=O)NR ａ -, -NR ａ C(═O)O—, or a direct bond; G １ is C １ ~C ２ Alkylene, —(C═O)—, —O(C═O)—, —SC(═O)—, —NR ａ C(=O)- or a direct bond G ２ -C(=O)-, -(C=O)O-, -C(=O)S-, -C(=O)NR ａ - or a direct bond; G ３ is C １ ~C ６ alkylene; R ａ is H or C １ ~C １２ is alkyl; R １ａ and R １ｂ is, at each occurrence, independently: (a) H or C １ ~C １２ alkyl; or (b) R １ａ is H or C １ ~C １２ alkyl, and R １ｂ together with the carbon atom to which it is attached, the adjacent R １ｂ and together with the carbon atom to which it is attached form a carbon-carbon double bond; R ２ａ and R ２ｂ is, at each occurrence, independently: (a) H or C １ ~C １２ alkyl; or (b) R ２ａ is H or C １ ~C １２ alkyl, and R ２ｂ together with the carbon atom to which it is attached, the adjacent R ２ｂ and together with the carbon atom to which it is attached form a carbon-carbon double bond; R ３ａ and R ３ｂ is, at each occurrence, independently: (a) H or C １ ~C １２ alkyl; or (b) R ３ａ is H or C １ ~C １２ alkyl, and R ３ｂ together with the carbon atom to which it is attached, the adjacent R ３ｂ and together with the carbon atom to which it is attached form a carbon-carbon double bond; R ４ａ and R ４ｂ is, at each occurrence, independently: (a) H or C １ ~C １２ alkyl; or (b) R ４ａ is H or C １ ~C １２ alkyl, and R ４ｂ together with the carbon atom to which it is attached, the adjacent R ４ｂ and together with the carbon atom to which it is attached form a carbon-carbon double bond; R ５ and R ６ are each independently H or methyl; R ７ is C ４ ~C ２０ is alkyl; R ８ and R ９ are each independently C １ ~C １２ alkyl; or R ８ and R ９ together with the nitrogen atom to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; a, b, c, and d are each independently an integer from 1 to 24; and x is 0, 1 or 2; and (ii) an mRNA compound comprising an mRNA sequence encoding at least one antigenic peptide or protein, optionally containing no nucleoside modifications, particularly no base modifications. wherein said mRNA compound is encapsulated in or associated with said lipid nanoparticle.

5. (iii) A PEG lipid having the formula (IV): 【Transformation 5】 [In the formula, R ８ and R ９ are each independently a linear or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, the alkyl chain optionally being interrupted by one or more ester linkages; and w has an average value in the range of 30 to 60. The lipid nanoparticle of claim 1 , further comprising:

6. The cationic lipid is a compound of formula III, wherein: L １ and L ２ are each independently —O(C═O)— or (C═O)—O—; G ３ is C １ ~C ２４ Alkylene or C １ ~C ２４ alkenylene; and R ３ is H or OR ５ The lipid nanoparticle according to any one of claims 1 to 5,

7. The cationic lipid is a compound of formula III, wherein: L １ and L ２ are each independently —O(C═O)— or (C═O)—O—; and R １ and R ２ each independently having the following structure: 【Transformation 6】 The lipid nanoparticle according to any one of claims 1 to 6, having one of the following:

8. The cationic lipid is a compound of formula III, and wherein R ３ The lipid nanoparticle according to any one of claims 1 to 7, wherein is OH.

9. The cationic lipid has the structure I-1 to I-41, II-1 to II-34, or III-1 to III-36: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 or Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 or Table 14 Table 15 Table 16 Table 17 Table 18 The lipid nanoparticle according to any one of claims 1 to 8, selected from:

10. The cationic lipid is 【Transformation 7】 The lipid nanoparticle according to any one of claims 1 to 9, selected from:

11. In the PEG lipid, R ８ and R ９ The lipid nanoparticle according to any one of claims 1 to 10, wherein is a saturated alkyl chain.

12. The PEG-lipid 【Transformation 8】 The lipid nanoparticle of claim 11, wherein n has an average value in the range of 30 to 60.

13. The lipid nanoparticle of any one of claims 1 to 12, wherein the mRNA compound comprises at least one chemical modification, and the mRNA compound preferably does not comprise a nucleoside modification, and the nucleoside modification is optionally a base modification, and the base modification is optionally a 1-methylpseudouridine modification.

14. The lipid nanoparticle of claim 13, wherein the chemical modification is selected from the group consisting of a sugar modification, a backbone modification, and a lipid modification.

15. The lipid nanoparticle of any one of claims 1 to 14, wherein the mRNA sequence is an artificial mRNA sequence.

16. The lipid nanoparticle of any one of claims 1 to 15, wherein the coding region of the mRNA sequence encoding the at least one antigenic peptide or protein comprises a sequence modification.

17. The lipid nanoparticle of claim 16, wherein the sequence modification is selected from G / C content modification, codon modification, codon optimization, or C optimization of the sequence.

18. The lipid nanoparticle of claim 17, wherein the G / C content of the coding region of the mRNA sequence is increased compared to the G / C content of the corresponding coding sequence of the wild-type mRNA, or the C content of the coding region of the mRNA sequence is increased compared to the C content of the corresponding coding sequence of the wild-type mRNA, or the codon usage in the coding region of the mRNA sequence is adapted to human codon usage, or the codon compatibility index (CAI) is increased or maximized in the coding region of the mRNA sequence, and wherein the encoded amino acid sequence of the mRNA sequence is preferably unmodified compared to the encoded amino acid sequence of the wild-type mRNA.

19. The mRNA sequence is a) a 5'-CAP structure, and / or b) a poly(A) sequence, and / or c) poly(C) sequence The lipid nanoparticle of any one of claims 1 to 18, further comprising:

20. The lipid nanoparticle of claim 19, wherein the mRNA sequence comprises a poly(A) sequence, and the poly(A) sequence comprises a sequence of about 25 to about 400 adenosine nucleotides, preferably a sequence of about 50 to about 400 adenosine nucleotides, more preferably a sequence of about 50 to about 300 adenosine nucleotides, even more preferably a sequence of about 50 to about 250 adenosine nucleotides, and most preferably a sequence of about 60 to about 250 adenosine nucleotides.

21. The lipid nanoparticle of any one of claims 1 to 19, wherein the mRNA sequence further comprises at least one histone stem loop.

22. The at least one histone stem-loop has the following formula (V) or (VI): Formula (V) (stem-loop sequence without stem boundary elements): 【Chemistry 9】 Formula (VI) (stem-loop sequence with stem border elements): 【Chemistry 10】 [During the ceremony a stem 1 or stem 2 border element N1-6 is a contiguous sequence of 1 to 6, preferably 2 to 6, more preferably 2 to 5, even more preferably 3 to 5, and most preferably 4 to 5 or 5 N, where each N is independently selected from a nucleotide selected from A, U, T, G and C, or a nucleotide analog thereof; Stem 1 [N ０－２ GN ３－５ ] is a contiguous sequence of 5 to 7 nucleotides that is reverse complementary or partially reverse complementary to element stem 2; In the formula, N ０－２ is a contiguous sequence of 0 to 2, preferably 0 to 1, more preferably 1 N, wherein each N is independently selected from a nucleotide selected from A, U, T, G and C or a nucleotide analog thereof; In the formula, N ３－５ is a contiguous sequence of 3 to 5, preferably 4 to 5, more preferably 4 N, wherein each N is independently selected from a nucleotide selected from A, U, T, G and C or a nucleotide analog thereof; and Loop sequence [N ０－４ (U / T)N ０－４ ] is located between element stem 1 and stem 2 and is a continuous sequence of 3 to 5 nucleotides, more preferably 4 nucleotides; In the formula, each N ０－４ is, independently of the others, a contiguous sequence of 0 to 4, preferably 1 to 3, more preferably 1 to 2 N, wherein each N is, independently of the others, selected from a nucleotide selected from A, U, T, G and C or a nucleotide analog thereof; and wherein U / T represents uridine, or optionally thymidine; Stem 2 [N ３－５ CN ０－２ ] is a contiguous sequence of 5 to 7 nucleotides that is reverse complementary or partially reverse complementary to element stem 1; In the formula, N ３－５ is a contiguous sequence of 3 to 5, preferably 4 to 5, more preferably 4 N, wherein each N is independently selected from a nucleotide selected from A, U, T, G and C or a nucleotide analog thereof; In the formula, N ０－２ is a contiguous sequence of 0 to 2, preferably 0 to 1, more preferably 1 N, wherein each N is independently selected from a nucleotide selected from A, U, T, G, and C, or a nucleotide analog thereof; and wherein C is cytidine or an analog thereof, optionally substituted with guanosine or an analog thereof, provided that its complementary nucleotide guanosine in stem 1 is substituted with cytidine.

23. 23. The lipid nanoparticle of claim 21 or 22, wherein the at least one histone stem loop comprises a nucleic acid sequence according to SEQ ID NO: 224305 and / or most preferably an RNA sequence according to SEQ ID NO: 224306.

24. 24. The lipid nanoparticle of any one of claims 19 to 23, wherein the mRNA sequence comprises a poly(A) sequence, preferably comprising 10 to 200, 10 to 100, 40 to 80 or 50 to 70 adenosine nucleotides, and / or a poly(C) sequence, preferably comprising 10 to 200, 10 to 100, 20 to 70, 20 to 60 or 10 to 40 cytosine nucleotides.

25. The mRNA sequence preferably contains, in the 5' to 3' direction, the following elements: a) a 5'-CAP structure, preferably m7GpppN; b) at least one coding region encoding at least one antigenic peptide or protein; c) a poly(A) tail, preferably consisting of 10-200, 10-100, 40-80, or 50-70 adenosine nucleotides; d) optionally, a poly(C) tail, preferably consisting of 10-200, 10-100, 20-70, 20-60, or 10-40 cytosine nucleotides; and e) a histone stem-loop, optionally comprising an RNA sequence preferably according to SEQ ID NO: 224306; The lipid nanoparticle of any one of claims 1 to 24, comprising:

26. The lipid nanoparticle of any one of claims 1 to 25, wherein the mRNA sequence comprises a 3'-UTR element.

27. The lipid nanoparticle of claim 26, wherein the at least one 3'-UTR element comprises or consists of a nucleic acid sequence derived from the 3'-UTR of a gene that provides a stable mRNA, or a homologue, fragment or variant thereof.

28. The lipid nanoparticle of claim 26 or 27, wherein the 3'-UTR element comprises a nucleic acid sequence derived from the 3'-UTR of the alpha-globin gene, preferably comprising the corresponding RNA sequence of the nucleic acid sequence according to SEQ ID NO: 224297, a homologue, fragment or variant thereof.

29. The lipid nanoparticle of any one of claims 26 to 28, wherein the at least one 3'-UTR element comprises a nucleic acid sequence derived from the 3'-UTR of a vertebrate albumin gene or a variant thereof, preferably the 3'-UTR of a mammalian albumin gene or a variant thereof, more preferably the 3'-UTR of a human albumin gene or a variant thereof, even more preferably the 3'-UTR of the human albumin gene according to GenBank Accession No. NM_000477.5, or a fragment or variant thereof.

30. The lipid nanoparticle of any one of claims 26 to 29, wherein the 3'-UTR element is derived from a nucleic acid sequence according to SEQ ID NO: 224301 or 224303, preferably the corresponding RNA sequence, or a homologue, fragment or variant thereof.

31. The mRNA sequence preferably contains, in the 5' to 3' direction, the following elements: a) a 5'-CAP structure, preferably m7GpppN; b) at least one coding region encoding at least one antigenic peptide or protein; c) a 3'-UTR element comprising or consisting of a nucleic acid sequence derived from an alpha globin gene, preferably comprising the corresponding RNA sequence of the nucleic acid sequence according to SEQ ID NO: 224297, a homologue, fragment or variant thereof; d) a poly(A) tail, preferably consisting of 10-200, 10-100, 40-80, or 50-70 adenosine nucleotides; e) optionally, a poly(C) tail, preferably consisting of 10-200, 10-100, 20-70, 20-60, or 10-40 cytosine nucleotides; and f) A histone stem-loop, optionally comprising an RNA sequence preferably according to SEQ ID NO: 224306. The lipid nanoparticle of any one of claims 1 to 30, comprising:

32. The lipid nanoparticle of any one of claims 1 to 31, wherein the mRNA sequence comprises a 5'-UTR element.

33. The lipid nanoparticle of claim 32, wherein the 5'-UTR element comprises or consists of a nucleic acid sequence derived from the 5'-UTR of the TOP gene, preferably the corresponding RNA sequence, a homologue, fragment or variant thereof, preferably lacking the 5'-TOP motif.

34. The lipid nanoparticle of claim 33, wherein the 5'-UTR element comprises or consists of a nucleic acid sequence derived from the 5'-UTR of a TOP gene encoding a ribosomal protein, preferably lacking the 5' TOP motif, preferably the corresponding RNA sequence or a homologue, fragment or variant thereof.

35. The lipid nanoparticle of claim 34, wherein the 5'-UTR element comprises or consists of a nucleic acid sequence derived from the 5'-UTR of the TOP gene encoding ribosomal large protein (RPL) or a homologue, fragment or variant thereof, preferably lacking the 5'-TOP motif, more preferably comprising or consisting of an RNA sequence corresponding to the nucleic acid sequence according to SEQ ID NO: 224287.

36. The lipid nanoparticle of claim 35, wherein the 5'-UTR element derived from the 5'-UTR of the TOP gene comprises or consists of the RNA sequence corresponding to the nucleic acid sequence of SEQ ID NO: 224287 or 224289.

37. The mRNA sequence preferably contains, in the 5' to 3' direction, the following elements: a) a 5'-CAP structure, preferably m7GpppN; b) a 5'-UTR element comprising or consisting of a nucleic acid sequence derived from the 5'-UTR of the TOP gene, preferably comprising or consisting of the corresponding RNA sequence of the nucleic acid sequence according to SEQ ID NO: 224287 or 224289, a homologue, fragment or variant thereof; c) at least one coding region encoding at least one antigenic peptide or protein; d) a 3'-UTR element comprising or consisting of a nucleic acid sequence derived from the albumin gene, preferably comprising the corresponding RNA sequence of the nucleic acid sequence according to SEQ ID NO: 224303, a homologue, fragment or variant thereof; e) a poly(A) tail, preferably consisting of 10-200, 10-100, 40-80, or 50-70 adenosine nucleotides; f) optionally, a poly(C) tail, preferably consisting of 10-200, 10-100, 20-70, 20-60, or 10-40 cytosine nucleotides; and g) a histone stem-loop, optionally comprising an RNA sequence preferably according to SEQ ID NO: 224306 The lipid nanoparticle of any one of claims 1 to 36, comprising:

38. The lipid nanoparticle of any one of claims 1 to 37, wherein the antigenic peptide or protein is derived from a pathogenic antigen, a tumor antigen, an allergenic antigen, or an autoimmune autoantigen, or a fragment or variant thereof.

39. The lipid nanoparticle of claim 38, wherein the pathogenic antigen is derived from influenza or rabies virus.

40. The lipid nanoparticle of claim 39, wherein the antigenic peptide or protein is derived from influenza virus hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix protein 1 (M1), matrix protein 2 (M2), nonstructural protein 1 (NS1), nonstructural protein 2 (NS2), nuclear export protein (NEP), polymerase acidic protein (PA), polymerase basic protein PB1, PB1-F2, or polymerase basic protein 2 (PB2), or a fragment or variant thereof.

41. The lipid nanoparticle of claim 40, wherein the antigenic peptide or protein is derived from influenza virus hemagglutinin (HA) or neuraminidase (NA) or a fragment or variant thereof.

42. The lipid nanoparticle of claim 41, wherein the antigenic peptide or protein is at least one full-length protein of hemagglutinin (HA) and / or at least one full-length protein of neuraminidase (NA) of an influenza virus or a mutant thereof.

43. The lipid nanoparticle of any one of claims 39 to 41, wherein the influenza virus is selected from influenza A, B, or C viruses.

44. The lipid nanoparticle of claim 43, wherein the influenza A virus is selected from influenza viruses characterized by a hemagglutinin (HA) selected from the group consisting of H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17 and H18.

45. The lipid nanoparticle of claim 43 or 44, wherein the influenza A virus is selected from influenza viruses characterized by a neuraminidase (NA) selected from the group consisting of N1, N2, N3, N4, N5, N6, N7, N8, N9, N10, and N11.

46. 46. ​​The lipid nanoparticle of any one of claims 43 to 45, wherein the influenza A virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, and H10N7, preferably H1N1, H3N2, H5N1.

47. The lipid nanoparticle of any one of claims 39 to 46, wherein the mRNA sequence comprises at least one coding region encoding at least one antigenic peptide or protein derived from influenza virus hemagglutinin (HA) or a fragment or variant thereof and at least one antigenic peptide or protein derived from influenza virus neuraminidase (NA) or a fragment or variant thereof.

48. 48. The lipid nanoparticle of any one of claims 39 to 47, wherein the mRNA sequence comprises at least one coding region encoding at least one antigenic peptide or protein derived from hemagglutinin (HA) and / or at least one antigenic peptide or protein derived from neuraminidase (NA) of an influenza A virus selected from the group consisting of H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, and H10N7, preferably H1N1, H3N2, H5N1, or a fragment or variant thereof.

49. Lipid nanoparticles according to any one of claims 39 to 48, wherein the mRNA sequence comprises at least one coding region encoding at least one antigenic peptide or protein derived from the hemagglutinin (HA) of influenza A virus according to SEQ ID NOs: 1 to 14031 or 224309 or 224310, or a fragment or variant thereof.

50. The lipid nanoparticle of any one of claims 39 to 49, wherein the mRNA sequence is identical to or at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the RNA sequence according to SEQ ID NOs: 32013-46043, 64025-78055, 224085-224106, 96037-110067, 128049-142079, 160061-174091, 192073-206103. The lipid nanoparticle of any one of claims 39 to 49, comprising at least one RNA sequence selected from RNA sequences or fragments or variants thereof.

51. Lipid nanoparticles according to any one of claims 39 to 50, wherein the mRNA sequence comprises at least one coding region encoding at least one antigenic peptide or protein derived from the hemagglutinin (HA) of influenza B virus according to SEQ ID NOs: 26398 to 28576 or a fragment or variant thereof.

52. The lipid nanoparticle of any one of claims 39 to 51, wherein the mRNA sequence comprises at least one RNA sequence selected from the group consisting of RNA sequences identical to or at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the RNA sequence according to SEQ ID NOs: 58410-60588, 90422-92600, 224107-224112, 122434-124612, 154446-156624, 186458-188636, 218470-220648, or a fragment or variant thereof.

53. The lipid nanoparticle of any one of claims 39 to 52, wherein the mRNA sequence comprises at least one coding region encoding at least one antigenic peptide or protein derived from neuraminidase (NA) of influenza A virus according to SEQ ID NO: 14032 to 26397, 224309, or 224310, or a fragment or variant thereof.

54. The lipid nanoparticle of any one of claims 39 to 53, wherein the mRNA sequence comprises at least one RNA sequence selected from the group consisting of RNA sequences identical to or at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the RNA sequence according to SEQ ID NOs: 46044-58409, 224311, 224312, 78056-90421, 224113, 224313-224317, 110068-122433, 142080-154445, 174092-186457, 206104-218469, or a fragment or variant thereof.

55. Lipid nanoparticles according to any one of claims 39 to 54, wherein the mRNA sequence comprises at least one coding region encoding at least one antigenic peptide or protein derived from neuraminidase (NA) of influenza B virus according to SEQ ID NOs: 28577 to 30504 or a fragment or variant thereof.

56. The lipid nanoparticle of any one of claims 39 to 55, wherein the mRNA sequence comprises at least one RNA sequence or a mixture of RNA sequences selected from RNA sequences identical to or at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the RNA sequence according to SEQ ID NOs: 60589-62516, 92601-94528, 124613-126540, 156625-158552, 188637-190564, 220649-222576, or a fragment or variant thereof.

57. The lipid nanoparticle of any one of claims 39 to 56, wherein the mRNA sequence comprises at least one coding region encoding at least one antigenic peptide or protein, or a fragment or variant thereof, derived from rabies virus glycoprotein G (RAV-G, RAVBV-G or RABV-G), nucleoprotein N (RAV-N), phosphoprotein P (RAV-P), matrix protein M (RAV-M) or RNA polymerase L (RAV-L).

58. 58. The lipid nanoparticle of any one of claims 39 to 57, wherein the mRNA sequence comprises at least one coding region encoding at least one antigenic peptide or protein derived from rabies virus glycoprotein G (RAV-G, RAVBV-G or RABV-G) according to SEQ ID NOs: 30505 to 32012, or a fragment or variant thereof.

59. The lipid nanoparticle of any one of claims 39 to 58, wherein the mRNA sequence comprises at least one RNA sequence selected from the group consisting of RNA sequences identical to or at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the RNA sequence according to SEQ ID NOs: 62517-64024, 224270, 224274, 94529-96036, 224271-224273, 126541-128048, 158553-160060, 190565-192072, 222577-224084, or a fragment or variant thereof.

60. The mRNA sequences are selected from the group consisting of SEQ ID NOs: 224085-224106, 224114-224235, 224085-224106, 224114-224235, 224107-224112, 224236-224263, 224107-224112, 224107-224112, 224236-224263, 224113, 224264-224266, 224309-224347, 224309, 224310, 224311, 224312, 224113, 224313-22431 7, 224113, 224311 to 224317, 224264 to 224266, 224318 to 224347, 224348 to 224357, 224348 to 224357, 224270 to 224284, 224270, 224271 to 224273, 224270 to 224273, 224274 to 224284, 224358 to 224362, 224358, 224359, 224360, 224359, 224360, 224361, 224362, 224363, 224364 NA sequences, preferably at least one coding region according to SEQ ID NOs: 224114-224235, 224236-224263, 224264-224266, 224318-224347, 224348-224357, 224274-224284, 224361, 224362, 224363, 224364, most preferably SEQ ID NOs: 224118, 224117, 224181, 224236, 224200, 224166, 224 236, SEQ ID NO: 224246, SEQ ID NO: 224318, SEQ ID NO: 224336, SEQ ID NO: 224348, SEQ ID NO: 224276, SEQ ID NO: 224280, or a fragment or variant thereof.

61. The lipid nanoparticle of any one of claims 1 to 60, wherein the mRNA compound comprises at least two mRNA sequences, and the at least two mRNA sequences encode two different antigenic peptides and / or proteins.

62. A lipid nanoparticle described in any one of claims 1 to 61, comprising at least two different mRNA compounds, each compound comprising an mRNA sequence encoding at least one antigenic peptide or protein.

63. (iv) neutral lipids; and / or (v) steroids or steroid analogs The lipid nanoparticle of any one of claims 1 to 62, further comprising:

64. The neutral lipid may be selected from the group consisting of distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), and dioleoylphosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoylphosphatidylethanolamine (DSPE), 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1-trans ...

64. The lipid nanoparticle of any one of claims 1 to 63, selected from the group comprising PE, 1-stearoyl-2-oleoylphosphatidylethanolamine (SOPE), and 1,2-dielideyl-sn-glycero-3-phosphoethanolamine (transDOPE).

65. 65. The lipid nanoparticle of any one of claims 1 to 64, wherein the neutral lipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and the molar ratio of the cationic lipid to DSPC is optionally in the range of about 2:1 to 8:

1.

66. 66. The lipid nanoparticle of any one of claims 1 to 65, wherein the steroid is cholesterol and the molar ratio of the cationic lipid to cholesterol is optionally in the range of about 2:1 to 1:

1.

67. A method for preparing lipid nanoparticles according to any one of claims 1 to 66, comprising: (i) providing: a) a cationic lipid of formula (I) as defined above 【Chemistry 11】 or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, and / or a cationic lipid of formula (II) as defined above (above) 【Chemistry 12】 or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, and / or A cationic lipid of formula III as defined above: 【Chemistry 13】 or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof; and / or b) Formula (IV) as defined above: 【Chemistry 14】 PEG lipid having c) at least one mRNA compound comprising an mRNA sequence encoding at least one antigenic peptide or protein, optionally without nucleoside modifications, in particular without base modifications; and d) optionally a steroid; and e) optionally a neutral lipid; (ii) solubilizing the cationic lipid and / or the PEG-lipid and optionally the neutral lipid and / or the steroid or steroid derivative in ethanol; (iii) mixing the ethanolic lipid solution with an aqueous solution containing the mRNA polynucleotides; (iv) removing the ethanol; and optionally (v) isolating or purifying the lipid nanoparticles A method comprising:

68. 68. The method of claim 67, wherein in step (iv) the ethanol is removed by dialysis or diafiltration.

69. 69. The method of claim 67 or 68, wherein in step (v) the lipid nanoparticles are purified by filtration, preferably filtration through a sterile filter.

70. A pharmaceutical composition comprising at least one lipid nanoparticle according to any one of claims 1 to 66.

71. 71. The pharmaceutical composition of claim 70, comprising at least the first and second lipid nanoparticles of any one of claims 1 to 66, wherein the mRNA compound contained in the second lipid nanoparticles is different from the mRNA compound contained in the first lipid nanoparticles.

72. 72. The pharmaceutical composition of claim 70 or 71, further comprising a pharmaceutically acceptable adjuvant or excipient.

73. Lipid nanoparticles according to any one of claims 1 to 66 or pharmaceutical compositions according to any one of claims 70 to 72 for use as a pharmaceutical agent.

74. 74. The lipid nanoparticle or pharmaceutical composition for use according to claim 73, wherein the pharmaceutical agent is for therapeutically or prophylactically generating an immune response in a subject in need thereof.

75. 75. The lipid nanoparticle or pharmaceutical composition for use according to claim 73 or 74, wherein the pharmaceutical agent is for the prevention or treatment of a cancer or tumor disease, an infectious disease, an allergy, or an autoimmune disease or a disorder related thereto.

76. The lipid nanoparticle or pharmaceutical composition for use according to any one of claims 73 to 75, wherein the pharmaceutical agent is a vaccine.

77. The lipid nanoparticle or pharmaceutical composition for use according to any one of claims 73 to 76, wherein the pharmaceutical agent is a tumor, influenza or rabies vaccine.

78. The lipid nanoparticle or pharmaceutical composition for use according to any one of claims 73 to 77, wherein the pharmaceutical agent is a rabies vaccine used in the treatment of rabies.

79. The lipid nanoparticle or pharmaceutical composition for use according to any one of claims 73 to 78, wherein the subject is a vertebrate, preferably a mammal.

80. 80. The lipid nanoparticle or pharmaceutical composition for use according to any one of claims 73 to 79, wherein the pharmaceutical agent is for parenteral administration, and parenteral administration comprises injection.

81. 81. The lipid nanoparticle or pharmaceutical composition for use according to any one of claims 73 to 80, wherein the subject is a bird, preferably a chicken, or a mammal, preferably selected from the group comprising a goat, cow, pig, dog, cat, donkey, monkey, ape, rodent, e.g. mouse, hamster, rabbit, and in particular human.

82. A method for generating an immune response in a subject in need thereof, comprising administering to the subject a lipid nanoparticle described in any one of claims 1 to 66 or a pharmaceutical composition described in any one of claims 70 to 72.

83. A method for preventing or treating a cancer or tumor disease, an infectious disease, an allergic or autoimmune disease or a disorder related thereto in a subject in need thereof, comprising administering to said subject a lipid nanoparticle described in any one of claims 1 to 66 or a pharmaceutical composition described in any one of claims 70 to 72.

84. The lipid nanoparticles of any one of claims 1 to 83, wherein the lipid nanoparticles have a molar ratio (mol%) of 47.4:10:40.9:1.7 (cationic lipid, DSPC, cholesterol and PEG-lipid).

85. The lipid nanoparticles are (i) an mRNA encoding the HA protein of influenza A / Hong Kong / 4801 / 2014 (H3N2) (preferably selected from the group consisting of SEQ ID NOs: 13853, 13854, 13855 and 13856); and / or (ii) an mRNA encoding the HA protein of influenza A / California / 07 / 2009 (H1N1) (preferably selected from the group consisting of SEQ ID NOs: 13836, 13837, 13838, 13839, 13840, 13841, 13842, 13843, and 13844); and / or (iii) an mRNA encoding the HA protein of influenza B / Phuket / 3037 / 2013 (EPI540671) (preferably selected from the group consisting of SEQ ID NOs: 28530, 28531 and 28532); and / or (iv) an mRNA encoding the HA protein of influenza B / Brisbane / 60 / 2008 (preferably selected from the group consisting of SEQ ID NOs: 28524, 28525, 28526, 28527, 28528, and 28529); The lipid nanoparticle of any one of claims 1 to 84, comprising:

86. The lipid nanoparticles are (i) an mRNA encoding the NA protein of influenza A / Hong Kong / 4801 / 2014 (H3N2) (preferably selected from the group consisting of SEQ ID NOs: 26251, 26252, 26253, and 26254); and / or (ii) an mRNA encoding the NA protein of influenza A / California / 7 / 2009(H1N1)pdm09 (preferably selected from the group consisting of SEQ ID NOs: 26238, 26239, 26240, 26241, 26242, and 26243); and / or (iii) an mRNA encoding the NA protein of influenza B / Brisbane / 60 / 2008 (preferably selected from the group consisting of SEQ ID NOs: 30455, 30456, 30457, 30458, 30459, and 30460); The lipid nanoparticle of any one of claims 1 to 85, comprising:

87. The lipid nanoparticles are (i) an mRNA encoding the HA protein of influenza A / Netherlands / 602 / 2009 (H1N1) (preferably selected from the group consisting of SEQ ID NOs: 13848, 13849, and 13850); and / or (ii) an mRNA encoding the HA protein of influenza A / Hong Kong / 4801 / 2014 (H3N2) (preferably selected from the group consisting of SEQ ID NOs: 13853, 13854, 13855, and 13856); and / or (iii) an mRNA encoding the HA protein of influenza B / Brisbane / 60 / 2008 (preferably selected from the group consisting of SEQ ID NOs: 28524, 28525, 28526, 28527, 28528 and 28529); and / or (iv) an mRNA encoding the HA protein of influenza A / Vietnam / 1194 / 2004 (H5N1) (preferably selected from the group consisting of SEQ ID NOs: 13859 and 13860); The lipid nanoparticle of any one of claims 1 to 86, comprising:

88. The lipid nanoparticles are (i) an mRNA encoding the HA protein of influenza A / Hong Kong / 4801 / 2014 (H3N2) (preferably selected from the group consisting of SEQ ID NOs: 13853, 13854, 13855, and 13856); and / or (ii) an mRNA encoding the HA protein of influenza A / California / 07 / 2009 (H1N1) (preferably selected from the group consisting of SEQ ID NOs: 13836, 13837, 13838, 13839, 13840, 13841, 13842, 13843, and 13844); and / or (iii) an mRNA encoding the HA protein of influenza B / Phuket / 3037 / 2013 (EPI540671) (preferably selected from the group consisting of SEQ ID NOs: 28530, 28531, and 28532); and / or (iv) an mRNA encoding the HA protein of influenza B / Brisbane / 60 / 2008 (preferably selected from the group consisting of SEQ ID NOs: 28524, 28525, 28526, 28527, 28528, and 28529); and / or (v) an mRNA encoding the NA protein of influenza A / Hong Kong / 4801 / 2014 (H3N2) (preferably selected from the group consisting of SEQ ID NOs: 26251, 26252, 26253, and 26254); and / or (vi) an mRNA encoding the NA protein of influenza A / California / 7 / 2009(H1N1)pdm09 (preferably selected from the group consisting of SEQ ID NOs: 26238, 26239, 26240, 26241, 26242 and 26243); and / or (vii) an mRNA encoding the NA protein of influenza B / Brisbane / 60 / 2008 (preferably selected from the group consisting of SEQ ID NOs: 30455, 30456, 30457, 30458, 30459, and 30460); The lipid nanoparticle of any one of claims 1 to 87, comprising:

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