Complex AIDS vaccines producing anti-HIV specific neutralizing antibodies and / or anti-HIV cytotoxic t cells

Abstract

In the present invention, the applicant provides a novel method of prophylactically or therapeutically treating acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, where the subject is a human immunodeficiency virus (HIV) serum positive patient. Applicant also provides a novel method of preventing acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) serum negative patient. Applicant also provides a novel method of prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is an elite controller patient that is serum positive for human immunodeficiency virus (HIV).

Description

Field of the Invention

[0001] In the present invention, applicants provide a novel method for the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient. Applicants also provide a novel method for the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient. Applicants also provide a novel method for the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is an elite controller patient who is human immunodeficiency virus (HIV) seropositive. Background of the Invention

[0003] Soon after the human immunodeficiency virus (HIV) was first discovered as the cause of acquired immunodeficiency syndrome (AIDS), a very small group of HIV-infected patients were identified who remained AIDS-free for decades. These so-called HIV elite controllers (ECs) typically had relatively high CD4 + In recent years, extensive research has been conducted to understand the mechanisms by which these rare individuals control HIV, particularly those with elevated T cell counts and the ability to maintain clinically undetectable plasma HIV-1 RNA levels (HIV RNA < 50 copies / mL) for extended periods of time without receiving any antiretroviral therapy (ART).

[0004] Interestingly, the EC state showed low activation properties of T cells and the presence of a unique MHC-1b / E-restricted CD8 + T cell population that can suppress pathogenic HIV antigen presentation CD4 + In addition, recent advances in SIV vaccinology have also highlighted the importance of MHC-1b / E-restricted CD8 + The role of T cell responses in controlling SIV infection in rhesus macaques. These observations provide new strategies for developing HIV vaccines.

[0005] In fact, CD4 + The activated state of T cells is a prerequisite for productive HIV infection in vivo, so the virus is + Replication in T cells is essentially non-productive and often abortive, and it has been hypothesized that this may be achieved by interfering with CD4 + Therefore, some research groups have tried to use the induction of MHC-lb / E-restricted CD8 +Cell-based vaccines to suppress virus-specific CD4 + Activation of T cells.

[0006] For example, Andrieu et al. have developed a gene that can induce MHC-1b / E-restricted CD8 + The vaccine consists of inactivated simian immunodeficiency virus (SIV) particles with a tolerizing adjuvant (e.g., Lactobacillus plantarum). Although this vaccine strategy effectively immunized and induced inhibitory MHC-1b / E-restricted CD8 T cells in Chinese macaques, + T cells, but macaques from India immunized with the same adjuvanted vaccine were not protected.

[0007] Hansen et al. demonstrated that it is possible to uniquely tailor CD8 T cells by modifying cytomegalovirus (CMV) vector determinants that control the priming of unconventional T cells. + T cell responses, thereby maximizing prophylactic or therapeutic protection. Specifically, it was found that the use of such rhesus cytomegalovirus vectors expressing SIV proteins in rhesus macaques (RMs) induced sterile protection against SIV after challenge. However, this protection was only effective in 50% of vaccinated RMs.

[0008] Globally, these results expand the current research paradigm from a focus on preventive HIV vaccines to HIV / AIDS immunotherapy as an important component of the fight against this epidemic. Therefore, in addition to preventive vaccines, there remains a need for an effective therapy to treat individuals living with HIV-1.

[0009] Applicants have recently demonstrated that elevated IFN-α is a key pathogenic mediator of HIV pathogenesis, blocking the initiation of anti-HIV adaptive immune responses.

[0010] Furthermore, they demonstrated that type III interferon receptor (IFNλR) is not constitutively expressed by CD4+ T cells and does not impair antiviral responses, suggesting that type III interferon (IFNλ) could serve as an alternative to elevated IFN-α in anti-HIV immune responses.

[0011] Based on the discovery of the pathogenic effects of type I interferons (especially IFN-α) and the beneficial effects of type III interferons (IFN-III), the applicant proposes to improve the existing vaccine strategies for preventing or treating HIV.

[0012] Therefore, in the present invention, the applicant provides a novel method for the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, comprising administering to the subject a composite vaccine comprising a broadly neutralizing antibody (bnAb) or an antiretroviral (ART) agent, optionally a type III interferon or an agent that stimulates the production of type III interferon, an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling, a tolerogenic vaccine specific for at least one HIV antigen, and / or an effector vaccine comprising at least one HIV immunogen. Therefore, the present invention relates to a composite AIDS vaccine or immunotherapy that produces anti-HIV specific neutralizing antibodies and / or anti-HIV specific cytotoxic T cells. Summary of the Invention

[0013] The present invention relates to a composite vaccine comprising:

[0014] a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0015] b) an effector vaccine comprising at least one HIV immunogen,

[0016] c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and

[0017] d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)

[0018] For use in the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient who has no AIDS symptoms or has AIDS symptoms, and wherein:

[0019] 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject throughout the vaccination process, and

[0020] 2) Among them:

[0021] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0022] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0023] c) Effector vaccines comprising at least one HIV immunogen

[0024] is administered to the subject during the priming phase, and

[0025] 3) Among them:

[0026] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0027] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0028] c) Effector vaccines

[0029] Administered to subjects during a boost phase following a priming phase.

[0030] The present invention also relates to a composite vaccine comprising:

[0031] a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0032] b) an effector vaccine comprising at least one HIV immunogen,

[0033] c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and

[0034] d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)

[0035] For use in preventing acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient, and wherein:

[0036] 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject during the priming phase and the boosting phase throughout the vaccination process, and

[0037] 2) Among them:

[0038] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0039] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0040] c) Effector vaccines comprising at least one HIV immunogen

[0041] is administered to the subject during the priming phase, and

[0042] 3) Among them:

[0043] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0044] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0045] c) Effector vaccines

[0046] Administered to subjects during a boost phase following a priming phase.

[0047] The present invention also relates to a composite vaccine comprising:

[0048] a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0049] b) an effector vaccine comprising at least one HIV immunogen,

[0050] c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and

[0051] d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)

[0052] For use in the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is an elite controller patient who is seropositive for human immunodeficiency virus (HIV), and wherein:

[0053] 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject during the priming phase and the boosting phase throughout the vaccination process, and

[0054] 2) Among them:

[0055] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0056] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0057] c) Effector vaccines comprising at least one HIV immunogen

[0058] is administered to the subject during the priming phase, and

[0059] 3) Among them:

[0060] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0061] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0062] c) Effector vaccines

[0063] Administered to subjects during a boost phase following a priming phase.

[0064] The present invention also relates to a composite vaccine comprising:

[0065] a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0066] b) an effector vaccine comprising at least one HIV immunogen, and

[0067] c) Optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon.

[0068] In some embodiments, the at least one antiretroviral (ART) agent is selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INSTIs), fusion inhibitors (FIs), chemokine receptor antagonists (CCR5 antagonists), and entry inhibitors (CD4-directed post-attachment inhibitors).

[0069] In some embodiments, the Type III interferon is IFN-λ1, IFN-λ2, IFN-λ3, and / or IFN-λ4, wherein the agent that stimulates Type III interferon production comprises a TLR ligand, a RIG-I ligand, and / or an MDA5 ligand.

[0070] In some embodiments, the type III interferon is at least one IFN-λ1, IFN-λ2, IFN-λ3 and / or IFN-λ4 protein, at least one plasmid comprising a DNA sequence encoding IFN-λ1, IFN-λ2, IFN-λ3 and / or IFN-λ4, or at least one RNA molecule or mRNA-LNP encoding IFN-λ1, IFN-λ2, IFN-λ3 and / or IFN-λ4.

[0071] In some embodiments, the agent that neutralizes circulating interferon alpha is an anti-interferon (antiferon), an anti-IFN-alpha antibody, or an anti-IFN-alpha hyperimmune serum; and wherein the agent that blocks interferon alpha signaling is an anti-type I interferon R1 or R2 antibody, or an endogenous regulator of interferon alpha including SOSC1 or the aryl hydrocarbon receptor.

[0072] In some embodiments, the agent that neutralizes circulating interferon alpha or blocks interferon alpha signaling is, or is combined with, an agent that neutralizes circulating interferon beta or blocks interferon beta signaling.

[0073] In some embodiments, the tolerogenic vaccine induces a suppressor MHC-1b / E-restricted CD8 +T cells.

[0074] In some embodiments, the tolerogenic vaccine is a live viral vector selected from cytomegalovirus (CMV), lentivirus, vaccinia virus, adenovirus, and plasmid, and wherein the tolerogenic vaccine comprises at least one HIV immunogen that is an HIV antigen.

[0075] In some embodiments, the tolerogenic vaccine is a cytomegalovirus (CMV) vector comprising:

[0076] a. a first nucleic acid sequence encoding at least one HIV antigen,

[0077] b. Optionally, a second nucleic acid sequence comprising a first microRNA recognition element (MRE) operably linked to a CMV gene that is essential for or enhances CMV growth, wherein the MRE silences expression in the presence of a microRNA expressed by cells of an endothelial lineage; and wherein the CMV vector does not express active UL128 protein or an ortholog thereof, does not express active UL130 protein or an ortholog thereof, does not express active UL146 protein or an ortholog thereof, does not express active UL147 protein or an ortholog thereof, and

[0078] The CMV vector expresses at least one active UL40 protein or its ortholog, at least one active US27 protein or its ortholog and / or at least one active US28 protein or its ortholog.

[0079] In some embodiments, the tolerogenic vaccine comprises at least one HIV immunogen, which is an HIV antigen, and a non-pathogenic bacterium.

[0080] In some embodiments, the HIV antigen is an inactivated virus, an inactivated viral particle, a virus-like particle, an inactivated recombinant viral particle, a conjugate viral protein, or a concatemer viral protein.

[0081] In some embodiments, the non-pathogenic bacteria are live attenuated or killed pathogenic bacteria.

[0082] In some embodiments, the non-pathogenic bacterium is Lactobacillus bacterium, Lactobacillus plantarum, or Mycobacterium bovis.

[0083] In some embodiments, the tolerogenic vaccine comprises at least one lipid nanoparticle (LNP) containing or associated with at least one nucleic acid molecule comprising a single chain trimer of HLA-E with a pathogen-specific antigen.

[0084] In some embodiments, the tolerogenic vaccine comprises at least one HIV immunogen that is an HLA-E binding peptide derived from an HIV antigen selected from the group consisting of gag, pol, env, nef, tat, vif, and rev.

[0085] In some embodiments, the HIV-derived HLA-E binding peptide is selected from SEQ ID NO: 1 to SEQ ID NO: 4, SEQ ID NO: 56 to SEQ ID NO: 58, and SEQ ID NO: 63.

[0086] In some embodiments, the effector vaccine comprising at least one HIV immunogen comprises:

[0087] - a protein-based vaccine comprising at least one HIV-derived trimeric protein, peptide or epitope,

[0088] - A DNA-based vaccine comprising:

[0089] a) non-replicating viral vectors or live attenuated viral vectors, and

[0090] b) at least one DNA sequence encoding at least one HIV-derived protein, peptide or epitope, or at least one DNA sequence encoding at least one antigen-binding fragment of a broadly neutralizing anti-HIV antibody, or at least one DNA sequence encoding a chimeric immunogen,

[0091] - RNA-based vaccines comprising at least one RNA sequence encoding at least one HIV-derived trimeric peptide or protein, and / or

[0092] - A passive vaccine comprising at least one broadly neutralizing anti-HIV antibody.

[0093] In some embodiments, the at least one HIV immunogen is derived from gag, pol, env, nef, tat, vif, and rev.

[0094] In some embodiments, the at least one HIV immunogen is a native Env gp160 trimer, a stabilized Env gp160 trimer, a stabilized Env gp140 trimer (SOS gp140 or SOSIP gp140), a stabilized Env single-chain gp140 trimer, or a stabilized native flexible linked (NFL) Env gp140 trimer.

[0095] In some embodiments, the at least one HIV immunogen is a Tat toxoid as described in patent application WO03013593, which is incorporated herein by reference.

[0096] In some embodiments, the at least one HIV immunogen is in soluble form or displayed on the surface of a nanoparticle.

[0097] In some embodiments, the infectious disease to be prevented or treated is preferably acquired immunodeficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection, or simian immunodeficiency virus (SIV) infection.

[0098] In some embodiments, the combination vaccine produces anti-HIV specific neutralizing antibodies and / or anti-HIV specific cytotoxic cells in the subject.

[0099] definition

[0100] In the present invention, the following terms have the following meanings:

[0101] The word "about" preceding a numerical value encompasses plus or minus 10% or less of the numerical value. It should be understood that the value referred to by "about" itself is also specifically and preferably disclosed.

[0102] As used herein, the term "adjuvant" refers to a substance that helps and enhances the pharmacological effects of a drug or vaccine, or enhances the immunogenic response, including CD8 + Immune response (e.g., with a high percentage of CD8 + A compound or combination of compounds wherein the T cell response is characterized by MHC-Ib / E restriction is used in the treatment of infectious diseases.

[0103] The term "administering" refers to directly administering a compound or composition of the invention, or administering a prodrug, derivative, or analog that will form an equivalent amount of an active compound or substance in vivo. For example, according to some embodiments, the agent is administered to the subject by any effective route. Exemplary routes of administration include, but are not limited to, injection (e.g., subcutaneous, intramuscular, intradermal, intraperitoneal, and intravenous), oral, sublingual, rectal, transdermal, intranasal, vaginal, and inhalation routes.

[0104] The term "antigen" refers to a compound, composition, or substance capable of stimulating the production of antibodies or T-cell responses in an animal, including compositions injected or absorbed into an animal. Antigens react with products of specific humoral or cellular immunity, including those induced by heterologous immunogens. The term "antigen" includes all related antigenic epitopes. "Epitope" or "antigenic determinant" refers to a site on an antigen to which B cells and / or T cells respond. In some embodiments, when an epitope is presented in conjunction with an MHC molecule, T cells will respond to the epitope. Epitopes can be formed by contiguous amino acids or by non-contiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed by contiguous amino acids are generally retained upon exposure to denaturing solvents, while epitopes formed by tertiary folding are generally lost upon treatment with denaturing solvents. Epitopes generally contain at least 3 amino acids, more commonly at least 5, about 9, or about 8-10 amino acids, in a unique spatial conformation. Methods for determining the spatial conformation of epitopes include, for example, X-ray crystallography and two-dimensional nuclear magnetic resonance. In some embodiments, the antigen is a pathogen-specific antigen. In the context of the present disclosure, a pathogen-specific antigen refers to an antigen that can elicit an immune response against a pathogen and / or is unique to a pathogen (e.g., a virus, bacteria, fungus, or protozoa).

[0105] In the context of live viruses or bacteria, the term "attenuated" refers to a reduction (e.g., elimination) in the ability of the virus or bacteria to infect cells or subjects and / or a reduction (e.g., elimination) in the ability to induce or cause disease compared to a wild-type virus or wild-type bacteria. Typically, an attenuated virus or bacteria retains at least some ability to elicit an immune response after administration to an immunocompetent subject. In some cases, an attenuated virus or bacteria is capable of eliciting a protective immune response without causing any signs or symptoms of infection. In some embodiments, the ability of an attenuated virus or bacteria to cause disease in a subject is reduced by at least about 10%, at least about 25%, at least about 50%, at least about 75%, or at least about 90% relative to a wild-type virus or wild-type bacteria.

[0106] The term "CMV" (cytomegalovirus) refers to a member of the β subclass of the herpesvirus family. CMV is a large (approximately 230kB genome) double-stranded DNA virus with host range specific variants, such as MCMV (mouse CMV), RhCMV (rhesus macaque CMV) and HCMV (human CMV). In the context of the present invention, "RhCMV" refers to any strain, isolate or variant of rhesus macaque CMV. In the context of the present invention, "HCMV" refers to any strain, isolate or variant of human CMV.

[0107] The term "decrease" refers to reducing the quality, quantity, or intensity of something. For example, a treatment (e.g., a method provided herein) reduces the infectious load or titer of a pathogen, or one or more symptoms associated with an infection.

[0108] The term "deletion" refers to the removal of a DNA sequence, with the regions flanking the removed sequence being ligated together.

[0109] The term "expression" refers to the translation of a nucleic acid into a protein, such as the translation of an mRNA encoding a tumor-specific or pathogen-specific antigen into a protein.

[0110] The term "expression control sequence" refers to a nucleic acid sequence that regulates and controls the expression of a heterologous nucleic acid sequence that is operably connected to the expression control sequence, for example, the expression of a heterologous polynucleotide that is operably connected to the expression control sequence, that is spliced ​​in the CMV genome and that encodes an antigenic protein. When the expression control sequence controls and regulates transcription of the nucleic acid sequence and (when appropriate) translation, the expression control sequence is operably connected to the nucleic acid sequence. Therefore, the expression control sequence can include suitable promoters, enhancers, transcription terminators, the start codon (ATG) before the protein-coding gene, the splicing signal of the intron, and the correct reading frame of the gene to allow sequence and the terminator codon for correct translation of mRNA. The term "control sequence" is intended to include at least the component that its presence can affect expression, and can also include that its presence is favorable other components, for example, leader sequences and fusion partner sequences. The expression control sequence can include a promoter. Promoter is the minimum sequence that is enough to instruct transcription. Also included are promoter elements that are sufficient to make promoter-dependent gene expression controllable, thereby achieving cell type specificity, tissue specificity, or induction by external signals or reagents; such elements can be located in the 5' or 3' region of the gene. Both constitutive promoters and inducible promoters are included (see, for example, Bitter et al., Methods in Enzymology 153:516-544, 1987). For example, when cloning in a bacterial system, inducible promoters such as pL, plac, ptrp, ptac (ptrp-lac hybrid promoter) of λ phage can be used. In one embodiment, when cloning in a mammalian cell system, promoters derived from mammalian cell genomes (e.g., metallothionein promoters) or promoters derived from mammalian viruses (e.g., retroviral long terminal repeats, adenovirus late promoters, vaccinia virus 7.5K promoters) can be used. Promoters produced by recombinant DNA or synthetic techniques can also be used to provide transcription of nucleic acid sequences. The polynucleotide can be inserted into an expression vector (including a viral vector) that contains a promoter sequence to promote efficient transcription of the inserted gene sequence of the host. The expression vector usually contains a replication origin, a promoter, and a specific nucleic acid sequence that allows phenotypic selection of transformed cells.

[0111] The term "fragment" refers to a portion of a polypeptide that exhibits at least one useful epitope. The phrase "functional fragment of a polypeptide" refers to any polypeptide fragment that retains an activity or a measurable portion of the activity of the polypeptide from which it was derived. For example, fragments can vary in size, from polypeptide fragments capable of binding to an epitope in an antibody molecule to large polypeptides capable of participating in the characteristic induction or programming of phenotypic changes in cells. An epitope is a region of a polypeptide that is capable of binding to an immunoglobulin produced in response to contact with an antigen.

[0112] As used herein, the term "heterologous" refers to a heterologous polypeptide or polynucleotide (eg, antigen or protein) that originates from a different source or species. In some embodiments of the invention, the heterologous sequence is from a different genetic source than the second sequence, such as a virus or other organism.

[0113] The term "immunogenic peptide" (or "antigenic peptide") refers to a peptide that contains an allele-specific motif or other sequence (e.g., an N-terminal repeat) that allows the peptide to bind to an MHC molecule and induce a cytotoxic T lymphocyte ("CTL") response or a B cell response (e.g., antibody production) against the antigen from which the immunogenic peptide is derived. In some embodiments, immunogenic peptides are identified using sequence motifs or other methods (e.g., neural networks or polynomial determination methods known in the art). Typically, an algorithm is used to determine a "binding threshold" for a peptide to select those peptides that have a score that gives them a high probability of binding at a specific affinity and are immunogenic. These algorithms are based on the effect of a specific amino acid at a specific position on MHC binding, the effect of a specific amino acid at a specific position on antibody binding, or the effect of a specific substitution in a peptide containing a motif on binding. In the context of immunogenic peptides, a "conserved residue" refers to a residue that occurs at a specific position with a frequency significantly higher than that expected from random distribution at a specific position in the peptide. In some embodiments, a conserved residue is a residue whose MHC structure can provide a contact point with the immunogenic peptide.

[0114] The term "immunity" refers to the state of being able to mount a protective response after exposure to an immunogenic substance. The protective response can be antibody-mediated or immune cell-mediated and can be directed against a specific pathogen or tumor antigen. Immunity can be acquired actively (e.g., by exposure to an immunogenic substance, either naturally or in a pharmaceutical composition) or passively (e.g., by administering antibodies or in vitro stimulated and expanded T cells).

[0115] With respect to biological components (e.g., nucleic acid molecules, protein organelles, or cells), the terms "isolated" or "non-naturally occurring" refer to biological components that are altered or removed from their natural state. For example, a nucleic acid or peptide naturally occurring in a living animal is not "isolated," but the same nucleic acid or peptide partially or completely separated from coexisting materials in its natural state is "isolated." An isolated nucleic acid or peptide can exist in a substantially purified form or can exist in a non-natural environment, such as a host cell. Typically, a preparation of isolated nucleic acid or peptide comprises a nucleic acid or peptide that is at least about 80% pure, at least about 85% pure, at least about 90% pure, at least about 95% pure, greater than 95% pure, greater than about 96% pure, greater than about 97% pure, greater than about 98% pure, or greater than about 99% pure. "Non-naturally occurring" or "isolated" nucleic acids and proteins include nucleic acids and proteins purified by standard purification methods. The term also includes nucleic acids and proteins prepared by recombinant expression in a host cell and chemically synthesized nucleic acids. An "isolated polypeptide" is one that has been identified and separated and / or recovered from a component of its natural environment.

[0116] The terms "individual" and "patient" are used interchangeably herein and refer to an animal, such as a human, who is receiving treatment (including prophylactic treatment) with an agent of the invention.

[0117] The term "subject" as used herein refers to mammals, primates and / or humans, including all mammals, such as non-human primates (particularly higher primates), sheep, dogs, rodents (such as mice or rats), guinea pigs, goats, pigs, cats, rabbits, cows, and horses.

[0118] The term "mutation" refers to any difference in a nucleic acid or polypeptide sequence from a normal, shared, or "wild-type" sequence. A mutant refers to any protein or nucleic acid sequence that contains a mutation. In addition, cells or organisms with mutations may also be referred to as mutants. Some types of coding sequence mutations include point mutations (differences in a single nucleotide or amino acid), silent mutations (differences in nucleotides that do not result in amino acid changes); deletions (differences in which one or more nucleotides or amino acids are lost up to and including the deletion of the entire coding sequence of a gene); and frameshift mutations (a change in the amino acid sequence caused by a number of nucleotides that is not divisible by 3). Mutations that result in amino acid differences may also be referred to as amino acid substitution mutations. Amino acid substitution mutations can be described by the change in the amino acid at a specific position in the amino acid sequence relative to the wild-type.

[0119] As used herein, an "inactivating mutation" is any mutation in a viral gene that ultimately results in reduced or complete loss of viral protein function.

[0120] The term "operably linked" means that a first nucleic acid sequence is operably linked to a second nucleic acid sequence when the first nucleic acid sequence is in a functional relationship with the second nucleic acid sequence. For example, a promoter is operably linked to a coding sequence if it affects the transcription or expression of the coding sequence. Typically, operably linked DNA sequences are contiguous and, when it is desired to connect two protein coding regions, are in the same reading frame.

[0121] The term "open reading frame" (ORF) refers to a series of nucleotide triplets (codons) encoding amino acids without any internal stop codons. These sequences are typically translatable into peptides.

[0122] As used herein, the terms "prevent," "preventing," and "prevention" refer to preventative measures aimed at reducing the likelihood that a subject will develop a pathological condition or disorder within a given time period. This reduction can be manifested, for example, by delaying the onset of at least one symptom of a pathological condition or disorder in a subject.

[0123] The term "prophylactic" refers to treatment administered to a subject who does not show signs of the disease or who shows only early signs, with the aim of reducing the risk of developing the pathology. Specifically, prophylactic treatment of a subject infected with HIV or SIV refers to treatment that enables the subject to become an elite controller (EC), i.e., to have a relatively high CD4+ count for a prolonged period of time in the absence of any antiretroviral therapy (ART). + T cell count (eg, greater than 500 CD4 + T cells / μL) and / or maintain clinically undetectable plasma HIV-1 RNA levels (e.g., HIV RNA <50 copies / mL).

[0124] The term "therapeutic" refers to treatment administered to a subject who exhibits early signs or definitive signs of disease.

[0125] The term "curative" refers to treatment administered to a subject suffering from a disease with the goal of curing the disease, ie, causing any signs of the disease to disappear or become undetectable.

[0126] The term "polynucleotide" refers to a polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA). Polynucleotides are composed of four bases: adenine, cytosine, guanine, and thymine / uracil (uracil is used in RNA). The coding sequence of a nucleic acid indicates the sequence of the protein encoded by the nucleic acid.

[0127] The terms "protein," "peptide," "polypeptide," and "amino acid sequence" are used interchangeably herein to refer to a polymer of amino acid residues of any length. The polymer may be linear or branched, may contain modified amino acids or amino acid analogs, and may be interrupted by chemical moieties other than amino acids. These terms also encompass amino acid polymers that are modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation to a labeling component or a biologically active component.

[0128] The term "purified" does not require absolute purity but is a relative term. For example, a purified protein preparation is one that is purer than the protein in its native environment within cells or, where appropriate, within a production reaction chamber.

[0129] The term "recombinant" refers to a nucleic acid that has a sequence that is not naturally occurring or that is an artificial combination of two previously separate sequence fragments. This artificial combination can be achieved by chemical synthesis or, more commonly, by artificial manipulation of isolated nucleic acid fragments, such as through genetic engineering techniques.

[0130] The term "sample" or "biological sample" refers to a biological sample, such as a cell or tissue sample body fluid, obtained from a subject. In some cases, the biological sample comprises genomic DNA, RNA (including mRNA and microRNA), protein, or a combination thereof. Examples of samples include, but are not limited to, saliva, blood, serum, urine, spinal fluid, tissue biopsy samples, surgical samples, cells (e.g., PBMCs, leukocytes, lymphocytes, or other immune system cells), and autopsy material.

[0131] The term "sequence identity" refers to the similarity between two nucleic acid sequences or two amino acid sequences, expressed as inter-sequence similarity, also known as sequence identity. Sequence identity is typically measured as a percentage identity (or similarity or homology); the higher the percentage, the more similar the two sequences are.

[0132] Methods of sequence alignment for comparison are well known in the art. Various programs and alignment algorithms are described in Smith and Waterman (Adv. Appl. Math. 2:482, 1981); Needleman and Wunsch (J. Mol. Biol. 48:443, 1970); Pearson and Lipman (PNAS USA 85:2444, 1988); Higgins and Sharp (Gene, 73:237-244, 1988); Higgins and Sharp (CABIOS 5:151-153, 1989); Corpet et al. (Nuc. Acids Res. 16:10881-10890, 1988); Huang et al. (Comp. Appls Biosci. 8:155-165, 1992); and Pearson et al. (Gene, 73:237-244, 1988). al. (Meth. Mol. Biol. 24:307-31, 1994). Altschul et al. (Nature Genet., 6:119-129, 1994) provide detailed considerations on sequence alignment methods and homology calculations. Alignment tools ALIGN (Myers and Miller, CABIOS 4:11-17, 1989) or LFASTA (Pearson and Lipman, 1988) can be used for sequence comparison (Internet 1996, W.R. Pearson and the University of Virginia, fasta20u63 version 2.0u63, release date December 1996). ALIGN compares the entire sequence of each other, while LFASTA compares local similarity regions. These alignment tools and their corresponding tutorials can be found on the NCSA website. Alternatively, for amino acid sequence comparisons exceeding 30 amino acids, the Blast 2 sequence function can be used, using the default BLOSUM62 matrix (gap existence cost of 11 and each residue gap cost of 1) set to default parameters.

[0133] When aligning short peptides (less than about 30 amino acids), alignment should be performed using the Blast 2 sequence function using the PAM30 matrix set to default parameters (open gap penalty 9 and extension gap penalty 1). The BLAST sequence comparison system is available, for example, from the NCBI website and can also be found in Altschul et al., J. Mol. Biol. 215:403-410, 1990; Gish. & States, Nature Genet. 3:266-272, 1993; Madden et al. Meth. Enzymol. 266:131-141, 1996; Altschul et al., Nucleic Acids Res. 25:3389-3402, 1997; and Zhang & Madden, Genome Res. 7:649-656, 1997.

[0134] Protein orthologs are typically characterized by greater than 75% sequence identity to the amino acid sequence of a particular protein, as calculated using ALIGN set to default parameters over the entire length of the alignment. Proteins with greater similarity to a reference sequence exhibit increasing percentage identities when assessed by this method, such as at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, or at least 98% sequence identity. Sequence identity can also be compared over the entire length of a particular domain of a disclosed peptide.

[0135] When comparing sequence identity over a portion significantly less than the entire sequence, homologous sequences typically share at least 80% sequence identity over a short window of 10-20 amino acids, and may share at least 85%, at least 90%, at least 95%, or at least 99% sequence identity, depending on their similarity to the reference sequence. Sequence identity over such short windows can be determined using LFASTA; the method is described on the NCSA website. Those skilled in the art will appreciate that these sequence identity ranges are provided for reference only; it is entirely possible to obtain highly significant homologs outside the ranges provided.

[0136] Due to the degeneracy of the genetic code, nucleic acid sequences that do not show a high degree of identity may still encode similar amino acid sequences.

[0137] It will be appreciated that this degeneracy can be exploited to alter the nucleic acid sequence to produce multiple nucleic acid sequences that each encode substantially the same protein.

[0138] As used herein, the term "treatment" refers to an intervention that improves the signs or symptoms of a disease or pathological condition. For example, in the case of HIV infection, HIV RNA (viral load) and CD4 T lymphocyte (CD4) count are two surrogate markers of antiretroviral therapy (ART) response and HIV disease progression that have been used to manage and monitor HIV infection for decades. Thus, the effectiveness of treatment can be assessed by the plasma viral RNA load of the "treated" person before and after treatment, and if it is reduced by at least about 10%, 20%, 30%, 40%, 50%, more preferably at least about 70%, more preferably at least about 75% or 80% or 85% or 90% or 95% or 98% or 99%, or even more (99.5%, 99.8%, 99.9%, 100%), then the treatment is considered effective, and / or by monitoring the CD4 cell count before and after treatment, and if the absolute CD4 cell count increases by at least about 5%, 10%, 15%, 20%, 25%, more preferably at least about 30%, more preferably at least about 35% or 40% or 45% or 50% or 55% or 60% or 65%, or even more, then the treatment is considered effective. As used herein, the terms "treatment," "treat," and "treating" when referring to a disease, pathological condition, or symptom also refer to any observable beneficial effect of the treatment. The beneficial effect can be demonstrated, for example, by a delay in the onset of clinical symptoms of disease in susceptible subjects, a reduction in the severity of some or all of the clinical symptoms of disease, a slowing of disease progression, a reduction in the number of relapses of disease, an improvement in the subject's overall health or physical condition, or by other parameters well known in the art and specific to a particular disease. Therapeutic treatment is treatment administered to a subject after the onset of signs and symptoms of disease. Prophylactic treatment is treatment administered to a subject who has no signs of disease or who has only early signs of disease in order to reduce the risk of developing the pathology. Specifically, prophylactic treatment of HIV or SIV infection in a subject refers to treatment that enables the subject to become an elite controller (EC), i.e., one who has a relatively high CD4 + T cell count (eg, greater than 500 CD4 + T cells / μL) and / or maintain clinically undetectable plasma HIV-1 RNA levels (e.g., HIV RNA <50 copies / mL). Prophylactic treatment is treatment administered to a subject with a disease with the goal of curing the disease, i.e., causing any signs of the disease to disappear or become undetectable.

[0139] The term "vector" may include a nucleic acid sequence that allows it to replicate in a host cell, such as an origin of replication. The vector may also include one or more selectable marker genes and other genetic elements known in the art, including a promoter element that directs nucleic acid expression. The vector may be a viral vector, such as a CMV vector. The viral vector may be constructed from a wild-type or attenuated virus (including a replication-defective virus). The vector may also be a non-viral vector, including any plasmid known in the art.

[0140] The term "virus" refers to microscopic infectious organisms that reproduce within living cells. Viruses consist primarily of a nucleic acid core (the viral genome) surrounded by a protein coat (the capsid) and can only replicate within living cells. "Viral replication" refers to the production of additional viral particles throughout at least one viral life cycle. Viruses may subvert the normal functions of host cells, causing them to behave in ways determined by the virus. For example, viral infection can cause cells to produce or respond to cytokines that uninfected cells normally do not. The term "lytic" or "acute" viral infection refers to one in which the viral genome replicates and is expressed, producing the polypeptides required for viral capsid production. Mature viral particles exit the host cell, causing the cell to lyse. Some virus species can also enter a "lysogenic" or "latent" infection. During the establishment of latency, viral genome replication occurs, but capsid proteins are not produced and assembled into viral particles.

[0141] The term "microRNA" or "miRNA" as used herein refers to a large class of biomolecules involved in controlling gene expression. For example, in the human heart, liver, or brain, miRNAs play a role in tissue specialization or cell lineage determination. In addition, miRNAs also affect a variety of processes, including early development, cell proliferation and cell death, apoptosis, and fat metabolism. The large number of miRNA genes, diverse expression patterns, and abundant potential miRNA targets indicate that miRNAs may be an important source of genetic diversity.

[0142] Mature miRNAs are typically non-coding RNAs of 18-25 nucleotides that regulate the expression of mRNAs containing sequences complementary to the miRNA. These small RNA molecules are known to control gene expression by regulating the stability and / or translation of mRNAs. For example, miRNAs bind to the 3' UTR of target mRNAs and inhibit translation. MiRNAs can also bind to target mRNAs and mediate gene silencing via the RNAi pathway. MiRNAs can also regulate gene expression by causing chromatin condensation.

[0143] MiRNA silences the translation of one or more specific mRNA molecules by combining with miRNA recognition element (MRE), and MRE refers to any sequence that directly base pairs with miRNA somewhere in the mRNA transcript and interacts. Typically, MRE is present in the 3' untranslated region (UTR) of mRNA, but may also be present in the coding sequence or 5' UTR. MRE is not necessarily fully complementary to miRNA, and typically only has several bases that are complementary to miRNA, and typically comprises one or more mispairings in these complementary bases. MRE can be any sequence that can fully combine with miRNA so that the translation of the gene (for example, CMV gene that is crucial to growth or enhances growth in vivo) that is operably connected to MRE is suppressed by miRNA silencing mechanism (for example RISC). Detailed Description of the Invention

[0145] Second therapeutic use

[0146] The present invention relates to a composite vaccine comprising:

[0147] a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0148] b) an effector vaccine comprising at least one HIV immunogen,

[0149] c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and

[0150] d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)

[0151] For use in the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient who has no AIDS symptoms or has AIDS symptoms, and wherein:

[0152] 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject throughout the vaccination process, and

[0153] 2) Among them:

[0154] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0155] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0156] c) Effector vaccines comprising at least one HIV immunogen

[0157] is administered to the subject during the priming phase, and

[0158] 3) Among them:

[0159] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0160] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0161] c) Effector vaccines

[0162] Administered to subjects during a boost phase following a priming phase.

[0163] The present invention also relates to a composite vaccine comprising:

[0164] a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0165] b) an effector vaccine comprising at least one HIV immunogen,

[0166] c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and

[0167] d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)

[0168] For use in preventing acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient, and wherein:

[0169] 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject throughout the vaccination process, during the priming phase and the boosting phase, and

[0170] 2) Among them:

[0171] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0172] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0173] c) Effector vaccines comprising at least one HIV immunogen

[0174] is administered to the subject during the priming phase, and

[0175] 3) Among them:

[0176] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0177] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0178] c) Effector vaccines

[0179] Administered to subjects during a boost phase following a priming phase.

[0180] The present invention also relates to a composite vaccine comprising:

[0181] a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0182] b) an effector vaccine comprising at least one HIV immunogen,

[0183] c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and

[0184] d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)

[0185] For use in the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is an elite controller patient who is seropositive for human immunodeficiency virus (HIV), and wherein:

[0186] 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject throughout the vaccination process, during the priming phase and the boosting phase, and

[0187] 2) Among them:

[0188] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0189] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0190] c) Effector vaccines comprising at least one HIV immunogen

[0191] is administered to the subject during the priming phase, and

[0192] 3) Among them:

[0193] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0194] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0195] c) Effector vaccines

[0196] Administered to subjects during a boost phase following a priming phase.

[0197] The present invention relates to a composite vaccine comprising:

[0198] a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0199] b) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen,

[0200] c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and

[0201] d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)

[0202] For use in the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient who has no AIDS symptoms or has AIDS symptoms, and wherein:

[0203] 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject throughout the vaccination process, and

[0204] 2) Among them:

[0205] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0206] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0207] c) Tolerogenic vaccines specific for at least one HIV immunogen and / or effector vaccines comprising at least one HIV immunogen

[0208] is administered to the subject during the priming phase, and

[0209] 3) Among them:

[0210] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0211] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0212] c) Tolerogenic and / or effector vaccines, depending on the priming vaccine

[0213] Administered to subjects during a boost phase following a priming phase.

[0214] The present invention also relates to a composite vaccine comprising:

[0215] a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0216] b) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen,

[0217] c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and

[0218] d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)

[0219] For use in preventing acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient, and wherein:

[0220] 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject throughout the vaccination process, during the priming phase and the boosting phase, and

[0221] 2) Among them:

[0222] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0223] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0224] c) Tolerogenic vaccines specific for at least one HIV immunogen and / or effector vaccines comprising at least one HIV immunogen

[0225] is administered to the subject during the priming phase, and

[0226] 3) Among them:

[0227] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0228] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0229] c) Tolerogenic and / or effector vaccines, depending on the priming vaccine

[0230] Administered to subjects during a boost phase following a priming phase.

[0231] The present invention also relates to a composite vaccine comprising:

[0232] a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0233] b) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen,

[0234] c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and

[0235] d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)

[0236] For use in the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is an elite controller patient who is seropositive for human immunodeficiency virus (HIV), and wherein:

[0237] 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject throughout the vaccination process, during the priming phase and the boosting phase, and

[0238] 2) Among them:

[0239] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0240] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0241] c) Tolerogenic vaccines specific for at least one HIV immunogen and / or effector vaccines comprising at least one HIV immunogen

[0242] is administered to the subject during the priming phase, and

[0243] 3) Among them:

[0244] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0245] b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and

[0246] c) Tolerogenic and / or effector vaccines, depending on the priming vaccine

[0247] Administered to subjects during a boost phase following a priming phase.

[0248] The present invention relates to a composite vaccine comprising:

[0249] a) an agent that neutralizes at least one circulating type I interferon or an agent that blocks the signaling of at least one type I interferon,

[0250] b) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen,

[0251] c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and

[0252] d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)

[0253] For use in the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient who has no AIDS symptoms or has AIDS symptoms, and wherein:

[0254] 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject throughout the vaccination process, and

[0255] 2) Among them:

[0256] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0257] b) an agent that neutralizes at least one circulating type I interferon or an agent that blocks at least one type I interferon signaling, and

[0258] c) Tolerogenic vaccines specific for at least one HIV immunogen and / or effector vaccines comprising at least one HIV immunogen

[0259] is administered to the subject during the priming phase, and

[0260] 3) Among them:

[0261] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0262] b) an agent that neutralizes at least one circulating type I interferon or an agent that blocks at least one type I interferon signaling, and

[0263] c) Tolerogenic and / or effector vaccines, depending on the priming vaccine

[0264] Administered to subjects during a boost phase following a priming phase.

[0265] The present invention also relates to a composite vaccine comprising:

[0266] a) an agent that neutralizes at least one circulating type I interferon or an agent that blocks the signaling of at least one type I interferon,

[0267] b) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen,

[0268] c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and

[0269] d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)

[0270] For use in preventing acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient, and wherein:

[0271] 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject throughout the vaccination process, during the priming phase and the boosting phase, and

[0272] 2) Among them:

[0273] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0274] b) an agent that neutralizes at least one circulating type I interferon or an agent that blocks at least one type I interferon signaling, and

[0275] c) Tolerogenic vaccines specific for at least one HIV immunogen and / or effector vaccines comprising at least one HIV immunogen

[0276] is administered to the subject during the priming phase, and

[0277] 3) Among them:

[0278] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0279] b) an agent that neutralizes at least one circulating type I interferon or an agent that blocks at least one type I interferon signaling, and

[0280] c) Tolerogenic and / or effector vaccines, depending on the priming vaccine

[0281] Administered to subjects during a boost phase following a priming phase.

[0282] The present invention also relates to a composite vaccine comprising:

[0283] a) an agent that neutralizes at least one circulating type I interferon or an agent that blocks the signaling of at least one type I interferon,

[0284] b) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen,

[0285] c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and

[0286] d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)

[0287] For use in the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is an elite controller patient who is seropositive for human immunodeficiency virus (HIV), and wherein:

[0288] 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject throughout the vaccination process, during the priming phase and the boosting phase, and

[0289] 2) Among them:

[0290] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0291] b) an agent that neutralizes at least one circulating type I interferon or an agent that blocks at least one type I interferon signaling, and

[0292] c) Tolerogenic vaccines specific for at least one HIV immunogen and / or effector vaccines comprising at least one HIV immunogen

[0293] is administered to the subject during the priming phase, and

[0294] 3) Among them:

[0295] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0296] b) an agent that neutralizes at least one circulating type I interferon or an agent that blocks at least one type I interferon signaling, and

[0297] c) Tolerogenic and / or effector vaccines, depending on the priming vaccine

[0298] Administered to subjects during a boost phase following a priming phase.

[0299] The present invention also relates to a composite vaccine comprising:

[0300] i. Optionally, type III interferon or an agent that stimulates the production of type III interferon,

[0301] ii. agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling,

[0302] iii. at least one broadly neutralizing antibody (bnAb), and

[0303] iv. Optionally, at least one antiretroviral (ART) agent

[0304] For the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof.

[0305] method

[0306] The present invention relates to a method for prophylactically treating or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient without AIDS symptoms or with AIDS symptoms, and the combined vaccine method comprises:

[0307] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject throughout the vaccination process, and

[0308] 2) In the initiation phase, the subject is administered:

[0309] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0310] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0311] c) an effector vaccine comprising at least one HIV immunogen, and

[0312] 3) A boost phase following the priming phase, comprising administering to the subject:

[0313] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0314] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0315] c) Effector vaccines, which are dependent on priming vaccines.

[0316] The present invention also relates to a method for preventing acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient, the method comprising:

[0317] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject during the priming and boosting phases throughout the vaccination process, and

[0318] 2) In the initiation phase, the subject is administered:

[0319] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0320] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0321] c) an effector vaccine comprising at least one HIV immunogen, and

[0322] 3) A boost phase following the priming phase, comprising administering to the subject:

[0323] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0324] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0325] c) Effector vaccines, which are dependent on priming vaccines.

[0326] The present invention also relates to a method for prophylactically or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is an elite controller patient who is seropositive for human immunodeficiency virus (HIV), the method comprising:

[0327] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject during the priming and boosting phases throughout the vaccination process, and

[0328] 2) In the initiation phase, the subject is administered:

[0329] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0330] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0331] c) an effector vaccine comprising at least one HIV immunogen,

[0332] 3) A boost phase following the priming phase, comprising administering to the subject:

[0333] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0334] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0335] c) Effector vaccines.

[0336] The present invention relates to a method for prophylactically treating or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient without AIDS symptoms or with AIDS symptoms, and the combined vaccine method comprises:

[0337] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject throughout the vaccination process, and

[0338] 2) In the initiation phase, the subject is administered:

[0339] a) type III interferon or an agent that stimulates the production of type III interferon,

[0340] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0341] c) an effector vaccine comprising at least one HIV immunogen, and

[0342] 3) A boost phase following the priming phase, comprising administering to the subject:

[0343] a) type III interferon or an agent that stimulates the production of type III interferon,

[0344] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0345] c) Effector vaccines, which are dependent on priming vaccines.

[0346] The present invention also relates to a method for preventing acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient, the method comprising:

[0347] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject during the priming and boosting phases throughout the vaccination process, and

[0348] 2) In the initiation phase, the subject is administered:

[0349] a) type III interferon or an agent that stimulates the production of type III interferon,

[0350] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0351] c) an effector vaccine comprising at least one HIV immunogen, and

[0352] 3) A boost phase following the priming phase, comprising administering to the subject:

[0353] a) type III interferon or an agent that stimulates the production of type III interferon,

[0354] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0355] c) Effector vaccines, which are dependent on priming vaccines.

[0356] The present invention also relates to a method for prophylactically treating or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is an elite controller patient who is seropositive for human immunodeficiency virus (HIV), the method comprising:

[0357] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject during the priming and boosting phases throughout the vaccination process, and

[0358] 2) In the initiation phase, the subject is administered:

[0359] a) type III interferon or an agent that stimulates the production of type III interferon,

[0360] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0361] c) an effector vaccine comprising at least one HIV immunogen,

[0362] 3) A boost phase following the priming phase, comprising administering to the subject:

[0363] a) type III interferon or an agent that stimulates the production of type III interferon,

[0364] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0365] c) Effector vaccines.

[0366] The present invention relates to a method for prophylactically treating or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient without AIDS symptoms or with AIDS symptoms, and the combined vaccine method comprises:

[0367] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject throughout the vaccination process, and

[0368] 2) In the initiation phase, the subject is administered:

[0369] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0370] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0371] c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and

[0372] 3) A boost phase following the priming phase, comprising administering to the subject:

[0373] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0374] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0375] c) Tolerogenic and / or effector vaccines, which depend on the priming vaccine.

[0376] The present invention also relates to a method for preventing acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient, the method comprising:

[0377] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject during the priming and boosting phases throughout the vaccination process, and

[0378] 2) In the initiation phase, the subject is administered:

[0379] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0380] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0381] c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and

[0382] 3) A boost phase following the priming phase, comprising administering to the subject:

[0383] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0384] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0385] c) Tolerogenic and / or effector vaccines, which depend on the priming vaccine.

[0386] The present invention also relates to a method for prophylactically or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is an elite controller patient who is seropositive for human immunodeficiency virus (HIV), the method comprising:

[0387] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject during the priming and boosting phases throughout the vaccination process, and

[0388] 2) In the initiation phase, the subject is administered:

[0389] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0390] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0391] c) an effector vaccine comprising at least one HIV immunogen,

[0392] 3) A boost phase following the priming phase, comprising administering to the subject:

[0393] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0394] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0395] c) Effector vaccines.

[0396] The present invention also relates to a composite vaccine / composition / pharmaceutical composition / drug, comprising:

[0397] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0398] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0399] c) Effector vaccines comprising at least one HIV immunogen.

[0400] The present invention also relates to a composite vaccine / composition / pharmaceutical composition / drug, which comprises

[0401] a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon,

[0402] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0403] c) Tolerogenic vaccines specific for at least one HIV immunogen and / or effector vaccines comprising at least one HIV immunogen.

[0404] The present invention relates to a method for prophylactically treating or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient without AIDS symptoms or with AIDS symptoms, and the combined vaccine method comprises:

[0405] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject throughout the vaccination process, and

[0406] 2) In the initiation phase, the subject is administered:

[0407] a) type III interferon or an agent that stimulates the production of type III interferon,

[0408] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0409] c) a tolerogenic vaccine specific for at least one HIV immunogen that lyses infected CD4+ cells expressing HIV peptides under HLA-E restriction, and / or an effector vaccine comprising at least one HIV immunogen that lyses infected CD4+ cells expressing HIV peptides under HLA-Ia (A, B, C) restriction, and

[0410] 3) A boost phase following the priming phase, comprising administering to the subject:

[0411] a) type III interferon or an agent that stimulates the production of type III interferon,

[0412] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0413] c) Tolerogenic and / or effector vaccines, which depend on the priming vaccine.

[0414] The present invention also relates to a method for preventing acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient, the method comprising:

[0415] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject during the priming and boosting phases throughout the vaccination process, and

[0416] 2) In the initiation phase, the subject is administered:

[0417] a) type III interferon or an agent that stimulates the production of type III interferon,

[0418] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0419] c) a tolerogenic vaccine specific for at least one HIV immunogen that lyses infected CD4+ cells expressing HIV peptides under HLA-E restriction, and / or an effector vaccine comprising at least one HIV immunogen that lyses infected CD4+ cells expressing HIV peptides under HLA-Ia (A, B, C) restriction, and

[0420] 3) A boost phase following the priming phase, comprising administering to the subject:

[0421] a) type III interferon or an agent that stimulates the production of type III interferon,

[0422] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0423] c) Tolerogenic and / or effector vaccines, which depend on the priming vaccine.

[0424] The present invention also relates to a method for prophylactically treating or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is an elite controller patient who is seropositive for human immunodeficiency virus (HIV), the method comprising:

[0425] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject during the priming and boosting phases throughout the vaccination process, and

[0426] 2) In the initiation phase, the subject is administered:

[0427] a) type III interferon or an agent that stimulates the production of type III interferon,

[0428] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0429] c) an effector vaccine comprising at least one HIV immunogen which lyses infected CD4+ cells expressing HIV peptides under HLA-Ia (A, B, C) restriction,

[0430] 3) A boost phase following the priming phase, comprising administering to the subject:

[0431] a) type III interferon or an agent that stimulates the production of type III interferon,

[0432] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0433] c) Effector vaccines.

[0434] The present invention relates to a method for prophylactically treating or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient without AIDS symptoms or with AIDS symptoms, and the combined vaccine method comprises:

[0435] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject throughout the vaccination process, and

[0436] 2) In the initiation phase, the subject is administered:

[0437] a) type III interferon or an agent that stimulates the production of type III interferon,

[0438] b) an agent that neutralizes at least one circulating type I interferon or an agent that blocks the signaling of at least one type I interferon,

[0439] c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and

[0440] 3) A boost phase following the priming phase, comprising administering to the subject:

[0441] a) type III interferon or an agent that stimulates the production of type III interferon,

[0442] b) an agent that neutralizes at least one circulating type I interferon or an agent that blocks the signaling of at least one type I interferon,

[0443] c) Tolerogenic and / or effector vaccines, which depend on the priming vaccine.

[0444] The present invention also relates to a method for preventing acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient, the method comprising:

[0445] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject during the priming and boosting phases throughout the vaccination process, and

[0446] 2) In the initiation phase, the subject is administered:

[0447] a) type III interferon or an agent that stimulates the production of type III interferon,

[0448] b) an agent that neutralizes at least one circulating type I interferon or an agent that blocks the signaling of at least one type I interferon,

[0449] c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and

[0450] 3) A boost phase following the priming phase, comprising administering to the subject:

[0451] a) type III interferon or an agent that stimulates the production of type III interferon,

[0452] b) an agent that neutralizes at least one circulating type I interferon or an agent that blocks the signaling of at least one type I interferon,

[0453] c) Tolerogenic and / or effector vaccines, which depend on the priming vaccine.

[0454] The present invention also relates to a method for prophylactically or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is an elite controller patient who is seropositive for human immunodeficiency virus (HIV), the method comprising:

[0455] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject during the priming and boosting phases throughout the vaccination process, and

[0456] 2) In the initiation phase, the subject is administered:

[0457] a) type III interferon or an agent that stimulates the production of type III interferon,

[0458] b) an agent that neutralizes at least one circulating type I interferon or an agent that blocks the signaling of at least one type I interferon,

[0459] c) an effector vaccine comprising at least one HIV immunogen,

[0460] 3) A boost phase following the priming phase, comprising administering to the subject:

[0461] a) type III interferon or an agent that stimulates the production of type III interferon,

[0462] b) an agent that neutralizes at least one circulating type I interferon or an agent that blocks the signaling of at least one type I interferon,

[0463] c) Effector vaccines.

[0464] The present invention relates to a method for prophylactically treating or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient without AIDS symptoms or with AIDS symptoms, and the combined vaccine method comprises:

[0465] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject throughout the vaccination process, and

[0466] 2) In the initiation phase, the subject is administered:

[0467] a) type III interferon or an agent that stimulates the production of type III interferon,

[0468] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0469] c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and

[0470] 3) A boost phase following the priming phase, comprising administering to the subject:

[0471] a) type III interferon or an agent that stimulates the production of type III interferon,

[0472] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0473] c) Tolerogenic and / or effector vaccines, which depend on the priming vaccine.

[0474] The present invention also relates to a method for preventing acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient, the method comprising:

[0475] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject during the priming and boosting phases throughout the vaccination process, and

[0476] 2) In the initiation phase, the subject is administered:

[0477] a) type III interferon or an agent that stimulates the production of type III interferon,

[0478] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0479] c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and

[0480] 3) A boost phase following the priming phase, comprising administering to the subject:

[0481] a) type III interferon or an agent that stimulates the production of type III interferon,

[0482] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0483] c) Tolerogenic and / or effector vaccines, which depend on the priming vaccine.

[0484] The present invention also relates to a method for prophylactically or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is an elite controller patient who is seropositive for human immunodeficiency virus (HIV), the method comprising:

[0485] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject during the priming and boosting phases throughout the vaccination process, and

[0486] 2) In the initiation phase, the subject is administered:

[0487] a) type III interferon or an agent that stimulates the production of type III interferon,

[0488] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0489] c) an effector vaccine comprising at least one HIV immunogen,

[0490] 3) A boost phase following the priming phase, comprising administering to the subject:

[0491] a) type III interferon or an agent that stimulates the production of type III interferon,

[0492] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0493] c) Effector vaccines.

[0494] Optionally, the methods of the present invention comprise a preliminary step (prior to the priming phase) of administering to the subject at least one broadly neutralizing antibody (bnAb) or antiretroviral (ART) agent during a first period of time.

[0495] In some embodiments, the present invention relates to a method for prophylactically treating or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient without AIDS symptoms or with AIDS symptoms; or a method for preventing acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient; the combined vaccine method comprises:

[0496] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject throughout the vaccination process, and

[0497] 2) In the initiation phase, the subject is administered:

[0498] a) type III interferon or an agent that stimulates the production of type III interferon,

[0499] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0500] c) a tolerogenic vaccine specific for at least one HIV immunogen, and

[0501] 3) A boost phase following the priming phase, comprising administering to the subject:

[0502] a) type III interferon or an agent that stimulates the production of type III interferon,

[0503] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0504] c) Tolerogenic vaccines.

[0505] In some embodiments, the present invention relates to a method for prophylactically treating or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient without AIDS symptoms or with AIDS symptoms; or a method for preventing acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient; the combined vaccine method comprises:

[0506] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject throughout the vaccination process, and

[0507] 2) In the initiation phase, the subject is administered:

[0508] a) type III interferon or an agent that stimulates the production of type III interferon,

[0509] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0510] c) an effector vaccine comprising at least one HIV immunogen, and

[0511] 3) A boost phase following the priming phase, comprising administering to the subject:

[0512] a) type III interferon or an agent that stimulates the production of type III interferon,

[0513] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0514] c) Effector vaccines.

[0515] In some embodiments, the present invention relates to a method for prophylactically treating or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient without AIDS symptoms or with AIDS symptoms; or a method for preventing acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient; the combined vaccine method comprises:

[0516] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) to the subject throughout the vaccination process, and

[0517] 2) In the initiation phase, the subject is administered:

[0518] a) type III interferon or an agent that stimulates the production of type III interferon,

[0519] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0520] c) a tolerogenic vaccine specific for at least one HIV immunogen and an effector vaccine comprising at least one HIV immunogen, and

[0521] 3) A boost phase following the priming phase, comprising administering to the subject:

[0522] a) type III interferon or an agent that stimulates the production of type III interferon,

[0523] b) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0524] c) Tolerogenic and effector vaccines.

[0525] The present invention also relates to a method for prophylactically treating or therapeutically treating acquired immunodeficiency syndrome (AIDS) by vaccinating a subject in need thereof, the method comprising administering to the subject:

[0526] v. Type III interferon or an agent that stimulates the production of type III interferon,

[0527] vi. an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[0528] vii. at least one broadly neutralizing antibody (bnAb), and

[0529] viii. Optionally, at least one antiretroviral (ART) agent.

[0530] In some embodiments, the method is a method of prophylactic treatment or therapeutic treatment.

[0531] Due to the huge variation that the HIV genome produces because of mutation, recombination, insertion and / or deletion, HIV is divided into different groups, subgroups, types, hypotypes and genotypes. Due to the continuous mutation of the HIV genome, HIV is divided into two large groups (HIV-1 and HIV-2) and many subgroups. The main difference between each group and each subgroup is the viral envelope. HIV-1 is divided into a large group (M), and the M group is divided into at least nine kinds of different subtypes on the gene. These subtypes are A, B, C, D, F, G, H, J and K subtypes. In addition, many other subtypes are also present, and these subtypes are produced by the above-mentioned subtypes in vivo recombination (for example CRF).

[0532] In some embodiments, the HIV antigen is associated with a specific HIV group, subgroup, type, subtype, or combination of subtypes.

[0533] In some embodiments, the HIV virus is HIV-1 or HIV-2, preferably HIV-1. In some embodiments, the HIV-1 virus is group M subtype B (HXB2).

[0534] Technical effects of the composite vaccine of the present invention

[0535] Without wishing to be bound by any particular theory or mechanism of action, the methods and composite vaccines provided herein have the following technical effects and advantages:

[0536] - They can control the pathogenic effects of elevated IFN-α on activated CD4+ T cells and initiate adaptive immune responses (this is primarily achieved through agents that neutralize circulating IFN-α or agents that block IFN-α signaling),

[0537] - They can preserve the antiviral activity of interferon (this is primarily achieved through type III interferon or agents that stimulate the production of type III interferon, which can partially replace interferon alpha)

[0538] - they can control viral replication (this is primarily achieved by administering broadly neutralizing antibodies (bnAbs) or antiretroviral (ART) agents throughout the vaccine approach),

[0539] - They can induce anti-HIV specific adaptive immune responses (this is mainly achieved by effector and / or tolerogenic vaccines).

[0540] Without wishing to be bound by any particular theory or mechanism of action, the tolerogenic vaccine may result in the induction of HIV-specific CD8+ regulatory (or suppressor) T cells. In this case, the method and combination vaccine may provide a functional treatment.

[0541] "Functional cure" refers to treatment that enables HIV-infected patients to become elite controllers (EC) or achieve elite controller (EC) status. For example, "functional cure" can enable HIV-infected patients to have relatively high CD4 counts for an extended period of time without any antiretroviral therapy (ART). + T cell count (eg, greater than 500 CD4 + T cells / μL) and / or maintain clinically undetectable plasma HIV-1 RNA levels (e.g., HIV RNA <50 copies / mL).

[0542] Without wishing to be bound by any particular theory or mechanism of action, the effector vaccine may result in the induction of broad HIV-specific cytotoxic T lymphocytes (CTLs) and / or broadly neutralizing antibodies (bnAbs). In this case, the method and combination vaccine provide a method for complete treatment.

[0543] "Sterilizing cure" refers to treatment that results in an uninfected or HIV-infected patient reaching a state in which HIV replication is undetectable in the patient's blood sample. In some embodiments, "sterilizing cure" refers to treatment that results in an uninfected or HIV-infected patient reaching a state in which cells containing replication-competent HIV proviral DNA are undetectable in the patient's blood sample.

[0544] ART drugs

[0545] As used herein, the term "antiretroviral therapy" or "ART" or "highly active antiretroviral therapy" or "HAART" refers to any combination of antiretroviral (ARV) agents that maximally suppress the HIV virus (e.g., reduce viral load, reduce HIV proliferation, etc.) and prevent HIV disease progression. There are several classes of HIV drugs, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), post-binding inhibitors (or entry inhibitors), protease inhibitors (PIs), CCR5 antagonists, integrase strand transfer inhibitors (INSTIs), and fusion inhibitors (FIs).

[0546] In one embodiment, the antiretroviral (ART) agent is selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INSTIs), fusion inhibitors (FIs), chemokine receptor antagonists (CCR5 antagonists), and entry inhibitors (CD4-directed post-attachment inhibitors).

[0547] Non-limiting examples of antiretroviral (ART) agents include:

[0548] - Nucleoside reverse transcriptase inhibitors (NRTIs), such as:

[0549] Abacavir

[0550] Didanosine( EC)

[0551] Emtricitabine (Emtriva)

[0552] Lamivudine

[0553] Stavudine

[0554] Tenofovir disoproxil fumarate DF

[0555] Tenofovir alafenamide AF

[0556] Zidovudine

[0557] - Non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as:

[0558] Delavirdine

[0559] Efavirenz

[0560] Etravirine

[0561] Nevirapine ( XR)

[0562] οRilpivirine

[0563] Doravirine

[0564] -Protease inhibitors (PIs), such as:

[0565] Atazanavir

[0566] Darunavir

[0567] Fosamprenavir

[0568] Indinavir

[0569] Lopinavir / ritonavir

[0570] Nelfinavir

[0571] Ritonavir

[0572] Saquinavir

[0573] Tipranavir

[0574] -Integrase inhibitors (INSTIs), such as:

[0575] Raltegravir ( HD)

[0576] oDolutegravir

[0577] Elvitegravir

[0578] - Chemokine receptor antagonists (CCR5 antagonists), e.g.

[0579] Maraviroc

[0580] -Fusion inhibitors (FI), e.g.

[0581] Enfuvirtide

[0582] -Entry inhibitors, e.g.

[0583] Ibalizumab

[0584] and any combination thereof.

[0585] In one embodiment, the ART agent of the present invention comprises multiple ART agents, or a combination of multiple ART agents. These ART agents are, for example, selected from the ART agents listed above.

[0586] In general, initial treatment regimens typically include a combination of two NTRIs with a third active antiretroviral agent, which may be an INSTI, NNRTI, or PI. A booster may sometimes be included, which may be cobicistat. or ritonavir

[0587] In one embodiment, the ART agent of the present invention comprises a combination of at least two ART agents, preferably selected from the ART agents listed above.

[0588] In one embodiment, the ART agents of the present invention comprise a combination of two, three, four, five or six ART agents, preferably selected from the ART agents listed above.

[0589] ART combination products are known in the art, some of which are approved as complete daily treatment regimens.

[0590] Non-limiting examples of antiretroviral (ART) agents (combination ART or combined ART (cART)) include the following ART combinations:

[0591] -Elvitegravir + Cobicistat + Emtricitabine + Tenofovir DF

[0592] -Elvitegravir + cobicistat + emtricitabine + tenofovir AF

[0593] -Darunavir + Cobicistat + Emtricitabine + Tenofovir AF

[0594] -Rilpivirine + Emtricitabine + Tenofovir AF

[0595] -Rilpivirine + Emtricitabine + Tenofovir DF

[0596] - Bictegravir + emtricitabine + tenofovir AF

[0597] - Dolutegravir + Abacavir + Lamivudine

[0598] - Dolutegravir + Rilpivirine

[0599] - Dolutegravir + Lamivudine

[0600] -Efavirenz + Emtricitabine + Tenofovir DF

[0601] -Efavirenz + Lamivudine + Tenofovir DF

[0602] - Doravirine + Lamivudine + Tenofovir DF

[0603] -Emtricitabine + Tenofovir AF

[0604] -Emtricitabine + Tenofovir DF

[0605] -Abacavir + Lamivudine

[0606] - Lamivudine + Tenofovir DF

[0607] -Abacavir + Lamivudine + Zidovudine

[0608] - Zidovudine + Lamivudine

[0609] - Atazanavir + Cobicistat

[0610] -Darunavir ethanolate + cobicistat

[0611] Preferably, the antiretroviral (ART) agent is an ART combination or combined ART (cART) comprising at least two nucleoside reverse transcriptase inhibitors (NRTIs) and at least one non-nucleoside reverse transcriptase inhibitor (NNRTI) or integrase inhibitor (INSTI).

[0612] Preferably, the antiretroviral (ART) agent is an ART combination or combined ART (cART) selected from the following:

[0613] - Emtricitabine (NRTI) + tenofovir alafenamide (NRTI) + rilpivirine (NNRTI), or

[0614] - Emtricitabine (NRTI) + tenofovir alafenamide (NRTI) + bictegravir (INSTI), or

[0615] - Emtricitabine (NRTI) + tenofovir disoproxil fumarate (NRTI) + efavirenz (NNRTI).

[0616] In some embodiments, prior to the first time period of the present invention, the subject has received at least one dose of at least one antiretroviral (ART) agent, or is currently receiving antiretroviral therapy, or is currently receiving combined antiretroviral therapy (cART) comprising at least one antiretroviral (ART) agent. The at least one antiretroviral (ART) agent may be the same as or different from the antiretroviral (ART) agent administered in the method of the present invention.

[0617] In some embodiments, the at least one antiretroviral (ART) agent already received is the same as the antiretroviral (ART) agent administered in the methods of the present invention. In this case, when treated according to the methods of the present invention, the subject can continue to receive the at least one antiretroviral (ART) agent he / she has previously received.

[0618] In some embodiments, the at least one antiretroviral (ART) agent received is different from the antiretroviral (ART) agent administered in the methods of the present invention.

[0619] In some embodiments, the subject has received at least one dose of combination antiretroviral therapy (cART) prior to being administered at least one antiretroviral (ART) agent of the present invention, and the cART includes a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), and a protease inhibitor (PI).

[0620] Preferably, if, before the first time period of the present invention, the subject has received at least one dose of at least one antiretroviral (ART) agent, or is receiving antiretroviral therapy or is receiving combined antiretroviral therapy (cART) comprising at least one antiretroviral (ART) agent, then during the first time period of the present invention, at least one antiretroviral (ART) agent is administered to the subject, preferably the same at least one antiretroviral (ART) agent that he has previously received.

[0621] Broadly neutralizing antibodies (bnAbs)

[0622] As used herein, the term "broadly neutralizing antibodies" (bnAbs) refers to antibodies that have the potential to provide comprehensive protection against HIV infection. Specifically, broadly neutralizing antibodies are able to broadly protect against heterologous HIV-1 strains.

[0623] Broadly neutralizing antibodies (bnAbs) can be isolated from HIV-seropositive subjects.

[0624] In some embodiments, the methods of the invention comprise administering at least one broadly neutralizing anti-HIV antibody.

[0625] Broadly neutralizing anti-HIV antibodies may, for example, bind to one or more epitopes contained in the CDR2 domain of the viral CD4 receptor, the CD4 binding site, gp41, gpl20, the V1V2 region of the HIV-1 envelope, or the V3 glycan.

[0626] Non-limiting examples of broadly neutralizing anti-HIV antibodies include UB-421 (semzuvolimab), 10E8.4 / iMab, VRC07, CAP256V2LS, VRC07-523LS, PGT121, VH3810109 (also known as GSK3810109 or N6-LS), PGT121.414.LS, PGDM1400LS, PGDM1400, 3BNC117-LS-J, 3BNC117-LS, 3BNC117, 10-1074-LS-J, 10-1074-LS, 10-1074, SAR441236, Elipovimab, VRC01, or VRC01-LS.

[0627] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the CDR2 domain of the viral CD4 receptor include UB-421 (semzuvolimab).

[0628] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the CD4 binding site include VRC07, VRC07-523LS, 3BNC117-LS-J, 3BNC117-LS, 3BNC117, SAR441236, VRC01, or VRC01-LS.

[0629] Non-limiting examples of broadly neutralizing anti-HIV antibodies targeting gp41 include 10E8.4 / iMab.

[0630] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target gpl20 include VH3810109 (also known as GSK3810109 or N6-LS).

[0631] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the V1V2 region of the HIV-1 envelope include CAP256V2LS, PGDM1400LS, PGDM1400, SAR441236.

[0632] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the V3 glycan include PGT121, PGT121.414.LS, 10-1074-LS-J, 10-1074-LS, 10-1074, and ipavirizumab.

[0633] When the methods of the present invention comprise administering at least one broadly neutralizing anti-HIV antibody, it is preferred that two or more different broadly neutralizing anti-HIV antibodies be administered.

[0634] Preferably, the at least one broadly neutralizing anti-HIV antibody is a combination of 2, 3, 4, 5, 6, 7, 8, 9 or 10 broadly neutralizing anti-HIV antibodies.

[0635] When a combination of several broadly neutralizing anti-HIV antibodies is used, the at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 broadly neutralizing anti-HIV antibodies preferably bind to different epitopes, more preferably bind to different targets selected from the group consisting of the CDR2 domain of the viral CD4 receptor, the CD4 binding site, gp41, gp120, the V1V2 region of the HIV-1 envelope and the V3 glycan.

[0636] In some embodiments, the at least one broadly neutralizing anti-HIV antibody targets the CD4 binding site and the V1V2 region of the HIV-1 envelope. For example, the at least one broadly neutralizing anti-HIV antibody can be SAR441236.

[0637] In some embodiments, the at least one broadly neutralizing anti-HIV antibody targets the CD4 binding site, the V1V2 region and the V3 glycan of the HIV-1 envelope. For example, the at least one broadly neutralizing anti-HIV antibody can be PGDM1400LS or PGDM1400.

[0638] In some embodiments, the at least one broadly neutralizing anti-HIV antibody is a combination of antibodies selected from:

[0639] -3BNC117-LS and 10-1074-LS;

[0640] -3BNC117-LS-J and 10-1074-LS-J;

[0641] -PGT121.414.LS and VRC07-523LS;

[0642] -PGDM1400LS, VRC07-523LS, and PGT121.414.LS; and

[0643] -CAP256V2LS, VRC07-523LS, and PGT121.

[0644] In some embodiments, the methods of the invention comprise administering a nucleic acid sequence encoding at least one broadly neutralizing anti-HIV antibody.

[0645] Type III interferons

[0646] As used herein, the term "type III interferon," also known as interferon-λ (IFN-λ), refers to naturally occurring and / or recombinant cytokines in the type III interferon-λ family. There are four IFN-λ members in humans: IFN-λ1 / IL-29, IFN-λ2 / IL-28A, IFN-λ3 / IL-28B, and IFN-λ4.

[0647] In some embodiments, the Type III interferon is IFN-λ.

[0648] In some embodiments, the IFN-λ comprises at least one IFN-λ subtype (eg, IFN-λ1, IFN-λ2, IFN-λ3, IFN-λ4).

[0649] In some embodiments, the IFN-λ is selected from IFN-λ1, IFN-λ2, IFN-λ3, IFN-λ4, or a combination thereof.

[0650] In some embodiments, human IFN-λ1 has the following accession number NP_742152.1. In some embodiments, human IFN-λ2 has the following accession number NP_742150.1. In some embodiments, human IFN-λ3 has the following accession number NP_001333866.1 (isoform 1) or NP_742151.2 (isoform 2). In some embodiments, human IFN-λ4 has the following accession number NP_001263183.2.

[0651] In some embodiments, the interferon-λ is IFN-λ1. In some embodiments, the interferon-λ is IFN-λ2. In some embodiments, the interferon-λ is IFN-λ3. In some embodiments, the interferon-λ is IFN-λ4.

[0652] In some embodiments, interferon-λ is chemically modified to improve certain properties, such as serum half-life. In one embodiment, the interferon-λ of the present invention is pegylated (i.e., interferon-λ is covalently linked to polyethylene glycol or the like). Methods for preparing pegylated proteins are well known in the art, for example, see Chapman A et al., 2002, Advanced Drug Delivery Reviews 54: 531-545.

[0653] In some embodiments, the Type III interferon is pegylated interferon IFN-λ. In some embodiments, the Type III interferon is pegylated interferon IFN-λ-1a.

[0654] In some embodiments, the type III interferon is pegylated interferon-λ (also known as "pegylated interferon lambda" or "λPEG-rIL-29") from Eiger BioPharmaceuticals Inc. Such pegylated interferon-λ is well known in the art and is described, for example, in US 8,454,947 and WO 2013 / 028233, the contents of which are incorporated herein by reference.

[0655] In other embodiments, the Type III interferon or the agent that stimulates the production of a Type III interferon is a nucleic acid sequence, such as RNA, mRNA, DNA, or plasmid encoding a Type III interferon.

[0656] The type III interferon or the agent that stimulates the production of type III interferon can be at least one RNA molecule, such as at least one mRNA molecule encoding IFN-λ1, IFN-λ2, IFN-λ3 and / or IFN-λ4.

[0657] In some embodiments, the type III interferon or the agent that stimulates the production of type III interferon is at least one RNA molecule, such as at least one mRNA molecule, carried by a lipid nanoparticle (LNP). The type III interferon or the agent that stimulates the production of type III interferon can be at least one RNA molecule within or associated with a lipid nanoparticle (LNP).

[0658] In some embodiments, the Type III interferon or the agent that stimulates the production of Type III interferon is an RNA-LNP encoding IFN-λ1, IFN-λ2, IFN-λ3, and / or IFN-λ4.

[0659] In some embodiments, the lipid nanoparticle (LNP) comprising the RNA molecule encoding type III interferon further comprises a molecule that is targeted to dendritic cells (DC). For example, the lipid nanoparticle may comprise or express a molecule that is recognized or bound by a receptor expressed by a dendritic cell (DC). Therefore, the lipid nanoparticle can deliver the RNA molecule encoding type III interferon to the dendritic cell (DC), thereby increasing the type III interferon produced by the dendritic cell (DC).

[0660] In some embodiments, interferon-λ is a functional mimetic of interferon-λ1. In some embodiments, interferon-λ is a functional mimetic of interferon-λ2. In some embodiments, interferon-λ is a functional mimetic of interferon-λ3. In some embodiments, interferon-λ is a functional mimetic of interferon-λ4.

[0661] As used herein, the term "functional mimetic" refers to a molecule that has the same or similar biological effect as a naturally occurring protein. For example, an interferon-λ functional mimetic can activate the interferon-λ receptor and drive the transcription of IFN-stimulated genes.

[0662] In some embodiments, the interferon-λ functional mimetic is a fragment of IFN-λ1. In some embodiments, the interferon-λ functional mimetic is a fragment of IFN-λ2. In some embodiments, the interferon-λ functional mimetic is a fragment of IFN-λ3. In some embodiments, the interferon-λ functional mimetic is a fragment of IFN-λ4.

[0663] In some embodiments, the interferon-λ functional mimetic is an antibody. Such interferon-λ functional mimetic antibodies can trigger the same or similar biological effects as naturally occurring proteins. For example, the antibody can bind to an epitope on the interferon-λ receptor, activate receptor signaling and drive transcription of IFN-stimulated genes. The heterodimeric receptor complex of interferon-λ (IFNLR) comprises IFNLR1 (IFNLRA, IL-28RA) and IL10R2 (IL-10RB). IFNLR1 confers ligand specificity and promotes receptor assembly, while IL10R2 is shared by IL-10 family members and is required for signaling.

[0664] In some embodiments, the interferon-λ derivative is a small molecule chemical entity (e.g., a chemical entity with a molecular weight of less than 900 Daltons). Methods for screening chemical libraries to identify small molecule chemical entities that may become potential drug candidates are known in the art. For example, a chemical library can be tested in a ligand-receptor binding assay.

[0665] In some embodiments, the agent that stimulates the production of Type III interferon is an agent that stimulates a pattern recognition receptor (PRR).

[0666] Pattern-recognition receptors (PRRs) primarily include Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-1-like receptors (RLRs), and C-type lectin receptors (CLRs). They recognize distinct microbial signatures or host-derived danger signals and trigger immune responses, such as interferon production.

[0667] In some embodiments, agents that stimulate type III interferon production include toll-like receptor (TLR) ligands (eg, TLR3, TLR5, TLR7 / 8, and TLR9), RIG-I ligands, and MDA-5 ligands.

[0668] In some embodiments, the agent that stimulates the production of type III interferon comprises poly I:C, CpG, and / or Tat protein.

[0669] In some embodiments, an agent that stimulates the production of type III interferon does not induce the production of type I interferon.

[0670] In some embodiments, the agent that stimulates the production of type III interferon comprises at least one agent selected from the group consisting of a TLR ligand, a RIG-I ligand, and an MDA5 ligand.

[0671] Anti-IFN-α agents

[0672] The term "interferon alpha" (IFN-α) or "interferon-α" as used herein refers to a family of more than 20 related but different members or subtypes, including IFN-α1 / 13, IFN-α2, IFN-α4, IFN-α5, IFN-α6, IFN-α7, IFN-α8, IFN-α10, IFN-α14, IFN-α16, IFN-α17, and IFN-α21. These members are encoded by a cluster on chromosome 9 and all bind to the same IFN receptor. Among them, IFN-α2 has three recombinant variants (α2a, α2b, α2c) depending on the cell source, and IFN-α2b is the main variant in the human genome. However, there is evidence that each subtype has different binding abilities to IFNAR, thereby regulating signal transduction events and biological effects in target cells.

[0673] In the context of the present invention, the term "interferon-α" or "IFN-α" may refer to any subtype of IFN-α, such as IFN-α1 / 13, IFN-α2, IFN-α4, IFN-α5, IFN-α6, IFN-α7, IFN-α8, IFN-α10, IFN-α14, IFN-α16, IFN-α17, IFN-α21.

[0674] In one embodiment, the interferon-α blocking agent or anti-IFN-α agent described herein is an agent that neutralizes circulating IFN-α and / or an agent that blocks IFN-α signaling, and / or an agent that depletes IFN-α producing cells, and / or an agent that blocks IFN-α production.

[0675] In one embodiment, the interferon-α blocking agents described herein include at least one agent selected from the group consisting of an agent that neutralizes circulating IFN-α, and / or an agent that blocks IFN-α signaling, and / or an agent that depletes IFN-α producing cells, and / or an agent that blocks IFN-α production.

[0676] In one embodiment, the agent that neutralizes circulating IFN-α, and / or blocks IFN-α signaling, and / or depletes IFN-α producing cells, and / or blocks IFN-α production is an IFN-α antagonist.

[0677] In some embodiments, the interferon-α blocking agent is selected from the group consisting of an agent that neutralizes circulating interferon α, an agent that blocks interferon-α signaling, an agent that depletes IFN-α producing cells, and / or an agent that blocks IFN-α production, wherein the agent that neutralizes circulating interferon α is selected from the group consisting of active anti-IFN-α vaccines including IFN-α-kinoid, vaccines based on IFN-α DNA or IFN-α RNA, or passive anti-IFN-α vaccines including anti-IFN-α antibodies or anti-IFN-α hyperimmune serum, wherein the agent that blocks interferon-α signaling is selected from the group consisting of active anti-IFNAR1 or anti-IFNAR2 vaccines such as those based on IFNAR1 or IFNAR2 DNA or those based on IFNAR1 or IFNAR2. RNA vaccines, passive anti-IFNAR1 or anti-IFNAR2 vaccines such as anti-type I interferon R1 or R2 antibodies, and endogenous regulators of IFN-α such as SOSC1 or aryl hydrocarbon receptor, wherein the agent that depletes IFN-α-producing cells is an agent that depletes plasmacytoid dendritic cells (pDCs), and wherein the agent that blocks IFN-α production is an agent that blocks pDCs from producing IFN-α.

[0678] In some embodiments, the interferon-α blocking agent is an agent that neutralizes circulating interferon α, selected from active anti-IFN-α vaccines including IFN-α-kinoid, vaccines based on IFN-α DNA or IFN-α RNA, or passive anti-IFN-α vaccines including anti-IFN-α antibodies or anti-IFN-α hyperimmune serum, and the agent that blocks interferon-α signaling is selected from active anti-IFNAR1 or anti-IFNAR2 vaccines such as IFNAR1 or IFNAR2 DNA-based or IFNAR1 or IFNAR2 RNA-based vaccines, passive anti-IFNAR1 or anti-IFNAR2 vaccines such as anti-type I interferon R1 or R2 antibodies, and endogenous regulators of IFN-α such as SOCS1 or aryl hydrocarbon receptor.

[0679] The term "interferon alpha antagonist" as used herein refers to a substance that interferes with or inhibits the biological activity of IFN-α. "IFN-α biological activity" as used herein refers to any activity that occurs after IFN-α binds to its receptor IFNAR (IFNAR1 / IFNAR2 heterodimer). For example, such binding can activate the JAK-STAT signaling cascade and trigger tyrosine phosphorylation of multiple proteins including JAK, TYK2 and STAT proteins. Therefore, agents that block interferon alpha signaling can neutralize the fixation of IFN-α to its receptor and / or block the signaling cascade induced by binding of IFN-α to its receptor. In some embodiments, the IFN-α antagonist is selected from an active anti-IFN-α vaccine (e.g., IFN-α-kinoid, a vaccine based on IFN-α DNA or IFN-α RNA) or a passive anti-IFN-α vaccine (e.g., an anti-IFN-α antibody or an anti-IFN-α hyperimmune serum). For example, see et al. (2018). Cytokine Growth Factor Rev 40:99-112.

[0680] In some embodiments, the methods of the invention comprise administering to a subject an agent that neutralizes at least one circulating Type I interferon or an agent that blocks signaling of at least one Type I interferon.

[0681] In some embodiments, the agent that neutralizes circulating interferon alpha or blocks interferon alpha signaling is an agent that neutralizes at least one circulating type I interferon or blocks signaling of at least one type I interferon.

[0682] In humans, type I interferons include IFN-α, IFN-β, IFN-ω, IFN-ε, IFN-κ, and any subtype thereof. In the present invention, type I interferon can be any type I interferon selected from IFN-α, IFN-β, IFN-ω, IFN-ε, IFN-κ, and any subtype thereof.

[0683] In some embodiments, the agent that neutralizes circulating interferon alpha or blocks interferon alpha signaling is an agent that neutralizes any circulating type I interferon or blocks signaling of any type I interferon.

[0684] In some embodiments, the agent that neutralizes circulating interferon alpha or blocks interferon alpha signaling is at least one agent that neutralizes circulating IFN-alpha and at least one other type I interferon or blocks IFN-alpha signaling and at least one other type I interferon signaling.

[0685] In some embodiments, the agent that neutralizes circulating interferon alpha or blocks interferon alpha signaling is at least one agent that neutralizes circulating IFN-alpha and at least one interferon selected from IFN-beta, IFN-omega, IFN-epsilon, and IFN-κ, or at least one agent that blocks IFN-alpha signaling and signaling of at least one interferon selected from IFN-beta, IFN-omega, IFN-epsilon, and IFN-κ.

[0686] In some embodiments, the agent that neutralizes circulating interferon alpha or blocks interferon alpha signaling is an agent that neutralizes both circulating IFN-alpha and IFN-beta or blocks both IFN-alpha and IFN-beta signaling.

[0687] The at least one agent that neutralizes circulating IFN-α and at least one other type I interferon or blocks IFN-α signaling and at least one other type I interferon signaling can be a single agent, compound or molecule, or a combination of multiple agents, compounds or molecules.

[0688] In some embodiments, an agent that neutralizes circulating interferon alpha or blocks interferon alpha signaling is combined or used in combination with an agent that neutralizes circulating interferon beta or blocks interferon beta signaling.

[0689] Agents that neutralize circulating IFNα

[0690] In one embodiment, the agent that neutralizes circulating IFN-α is a passive anti-IFN-α vaccine, such as an anti-IFN-α antibody or an anti-IFN-α hyperimmune serum.

[0691] In one embodiment, the agent that neutralizes circulating IFN-α is an anti-IFN-α antibody, preferably a neutralizing antibody, preferably a chimeric humanized or human antibody. The anti-IFN-α antibody can be a monoclonal antibody or a polyclonal antibody, preferably a monoclonal antibody. The anti-IFN-α antibody can be a single domain antibody (sdAb) or a nanobody, for example, obtained from a camelid such as a dromedary camel, camel, llama or alpaca.

[0692] Examples of anti-IFN-α antibodies include, but are not limited to, sifalimumab, rontalizumab, S95021 (as described in Duguet et al. Journal of Translational Autoimmunity 4 (2021) 100093, which is incorporated herein by reference), MMHA-1 clone, MMHA-2 clone, MMHA-6 clone, MMHA-8 clone, MMHA-9 clone, MMHA-11 clone, MMHA-13 clone, and MMHA-17 clone.

[0693] In one embodiment, the agent that neutralizes circulating IFN-α is anti-IFN-α hyperimmune serum.

[0694] In one embodiment, the agent described herein that neutralizes circulating IFN-α is an IFN-α ligand inhibitor.

[0695] In one embodiment, the agent that neutralizes circulating IFN-α is a soluble receptor that binds IFN-α.

[0696] In another embodiment, the agent that neutralizes circulating IFN-α is an active anti-IFN-α vaccine.

[0697] An "active anti-IFN-α vaccine" refers to a compound or composition that can induce the production of anti-IFN-α antibodies. For example, an "active anti-IFN-α vaccine" refers to a compound or composition that, upon administration to a subject, can induce the subject to produce anti-IFN-α autoantibodies.

[0698] The active ingredients of active anti-IFN-α vaccines can be peptides, proteins, DNA or RNA molecules.

[0699] For example, the active ingredient in active anti-IFN-α vaccines is an IFN-α kinoid. A kinoid is an immunogenic, inactivated and / or non-toxic IFN derivative. Typically, it exists as a heterocomplex formed by chemically conjugating the IFN derivative to a carrier.

[0700] Kinoids can be used as immunogens to induce high-affinity autoantibodies against a given IFN. Therefore, immunization with kinoids can induce high-titer neutralizing antibodies against the corresponding IFN.

[0701] In one embodiment, the agent described herein that neutralizes circulating IFN-α is an IFN-α-kinoid, e.g.

[0702] The active ingredient of an active anti-IFN-α vaccine may also be a DNA molecule, such as partial or full-length IFN-α DNA, or an RNA molecule, such as partial or full-length IFN-α RNA.

[0703] Active anti-IFN-α vaccines can induce the production of antibodies that bind to one or more IFN-α subtypes. For example, the RNA molecules used in an IFN-α RNA-based vaccine can be specific for a single IFN-α subtype. Alternatively, an active anti-IFN-α vaccine can comprise at least two RNA molecules corresponding to at least two IFN-α subtypes.

[0704] Agents that block IFNα signaling

[0705] In another embodiment, the interferon-α blocking agent is an agent that blocks IFN-α signaling.

[0706] In one embodiment, the agent that blocks IFN-α signaling is an agent that antagonizes the type I IFN signaling pathway.

[0707] In one embodiment, an agent described herein that blocks IFN-α signaling is an IFNAR antagonist.

[0708] In one embodiment, the agent that blocks IFN-α signaling is an IFNAR1 antagonist. In another embodiment, the agent that blocks IFN-α signaling is an IFNAR2 antagonist.

[0709] In one embodiment, the agent that blocks IFN-α signaling is a passive anti-IFNAR1 or anti-IFNAR2 vaccine, such as an anti-type I interferon R1 or R2 antibody.

[0710] In one embodiment, the agent that blocks IFN-α signaling is an antibody that binds to IFNAR1 or IFNAR2.

[0711] In another embodiment, the agent that blocks IFN-α signaling is an active anti-IFNAR1 or anti-IFNAR2 vaccine, such as an IFNAR1 or IFNAR2 DNA-based or an IFNAR1 or IFNAR2 RNA-based vaccine.

[0712] An "active anti-IFNAR1 or anti-IFNAR2 vaccine" refers to a compound or composition that can induce the production of anti-IFNAR1 or anti-IFNAR2 antibodies. For example, an "active anti-IFNAR1 or anti-IFNAR2 vaccine" refers to a compound or composition that, upon administration to a subject, can induce the subject to produce anti-IFNAR1 or anti-IFNAR2 autoantibodies.

[0713] The active ingredient of an active anti-IFNAR1 or anti-IFNAR2 vaccine may be a DNA molecule, such as partial or full-length IFNAR1 or IFNAR2 DNA, or an RNA molecule, such as partial or full-length IFNAR1 or IFNAR2 RNA.

[0714] In one embodiment, the agent that blocks IFN-α signaling can be an inhibitor of the type I IFN signaling pathway. Type I IFN signaling pathway inhibitors are well known in the art and include but are not limited to JAK1 / 2 / 3 inhibitors and STAT inhibitors. Therefore, in one embodiment, the agent that blocks IFN-α signaling is selected from JAK1 / 2 / 3 inhibitors, STAT inhibitors, and tyrosine kinase 2 (TYK2) inhibitors. Non-limiting examples of JAK1 / 2 / 3 inhibitors include Ruxolitinib, Tofacitinib, and Baricitinib. Non-limiting examples of TYK2 inhibitors include BMS-986165 inhibitors.

[0715] In one embodiment, the agent that blocks IFN-α signaling can be an endogenous negative regulator of the type I IFN signaling pathway. Endogenous negative regulators are well known in the art and include, but are not limited to, SOCS1 / 3, FOXO3, aryl hydrocarbon receptor (AhR), or other negative regulators. Therefore, in one embodiment, the agent that blocks interferon signaling is selected from SOCS1 / 3, FOXO3, or aryl hydrocarbon receptor (AhR).

[0716] In one embodiment, the agent that blocks IFN-α signaling is a PASylation antagonist. PASylation antagonists of type I IFN are known in the art, for example, see Nganou-Makamdop et al. (2018). PLoS Pathog 14(8): e1007246.

[0717] Agents that deplete interferon-alpha-producing cells

[0718] In one embodiment, an IFN-α antagonist described herein is an agent that depletes IFN-α producing cells.

[0719] As used herein, the term "IFN-α producing cell" refers to any cell that can produce IFN-α. Specifically, it is well known in the art that plasmacytoid dendritic cells (pDCs) are the main producers of IFN-α. Therefore, in one embodiment, the agent that depletes IFN-α producing cells depletes pDCs.

[0720] In one embodiment, the agent that depletes IFN-α producing cells is an antibody. In one embodiment, the antibody depletes pDC, such as an anti-CD123 antibody (ie, anti-IL-3RA).

[0721] Agents that block IFNα production

[0722] In one embodiment, an IFN-α antagonist described herein is an agent that blocks the production of IFN-α.

[0723] In one embodiment, the agent that blocks IFN-α production is an antibody. In one embodiment, the antibody blocks pDC production of IFN-α. The antibody can be, for example, an anti-BDCA2 (blood DC antigen 2) antibody.

[0724] Specific examples of interferon-α blocking agents

[0725] In some embodiments, the interferon-alpha blocking agent is selected from:

[0726] - an anti-IFN-α antibody, preferably sifalimumab, longlimumab, S95021 (as described in Duguet et al. Journal of Translational Autoimmunity 4 (2021) 100093), MMHA-1 clone, MMHA-2 clone, MMHA-6 clone, MMHA-8 clone, MMHA-9 clone, MMHA-11 clone, MMHA-13 clone or MMHA-17 clone,

[0727] - Anti-IFN-α hyperimmune serum,

[0728] -IFN-α-kinoid, e.g.

[0729] - IFN-α DNA-based or IFN-α RNA-based vaccines,

[0730] - soluble receptors that bind to IFN-α,

[0731] - an IFNAR1 or IFNAR2 antagonist, preferably an antibody that binds to IFNAR1 or IFNAR2, such as the anti-IFNAR1 MAb Anifrolumab (

[0732] AstraZeneca), or the anti-IFNAR antibodies described in WO 2022 / 087274 (the contents of which are incorporated herein by reference),

[0733] - IFNAR1 or IFNAR2 DNA-based or IFNAR1 or IFNAR2 RNA-based vaccines,

[0734] - a type I IFN signaling pathway inhibitor selected from a STAT inhibitor, a JAK1 / 2 / 3 inhibitor (e.g., ruxolitinib, tofacitinib, or baricitinib), and a TYK2 inhibitor (e.g., BMS-986165),

[0735] - an endogenous negative regulator of the type I IFN signaling pathway selected from SOCS1 / 3, FOXO3, aryl hydrocarbon receptor (AhR) or another negative regulator,

[0736] -PASylation antagonists,

[0737] - an antibody that depletes pDC, preferably an anti-CD123 (i.e., anti-IL-3RA) antibody,

[0738] -Antibodies that block the production of IFN-α by pDCs, preferably anti-BDCA2 (blood DC antigen 2) antibodies.

[0739] In some embodiments, the interferon-α blocking agent is an antibody, preferably a monoclonal antibody, preferably a neutralizing antibody, preferably a chimeric humanized or human antibody.

[0740] In some embodiments, the interferon-α blocking agent is an antigen-binding polypeptide, such as an antigen-binding fragment of an antibody.

[0741] In one embodiment, the interferon-α blocking agent is an anti-IFN-α antibody, preferably a monoclonal antibody, preferably a neutralizing antibody, preferably a chimeric humanized or human antibody. In some embodiments, the interferon-α blocking agent is sifalimumab, longlimumab or S95021.

[0742] In one embodiment, the interferon-alpha blocking agent is a human monoclonal antibody that binds to type I interferon receptor subunit 1. In one embodiment, the interferon-alpha blocking agent is anirutumab ( AstraZeneca).

[0743] Anti-IFN-β agents

[0744] In some embodiments, an agent that neutralizes circulating interferon alpha or blocks interferon alpha signaling also neutralizes circulating IFN-beta or also blocks IFN-beta signaling.

[0745] In some embodiments, an agent that neutralizes circulating interferon alpha or blocks interferon alpha signaling is combined or used in combination with an agent that neutralizes circulating interferon beta or blocks interferon beta signaling.

[0746] The term "interferon beta" (IFN-β) or "interferon beta" refers to a family of drugs consisting of two related but distinct members, IFN-β1 and IFN-β3. They both bind to the same IFN receptor, the IFN-α receptor (IFNAR), a cell surface receptor complex composed of two chains: IFNAR1 and IFNAR2 (the IFNAR1 / IFNAR2 heterodimer). Binding of IFN-β to the IFNAR receptor triggers signaling events and biological effects in target cells.

[0747] As used herein, the term "interferon beta" (IFN-β) or "interferon beta" refers to a family of two related but distinct members, IFN-β1 and IFN-β3. They both bind to the same IFN receptor, the IFN-α receptor (IFNAR), a cell surface receptor complex composed of two chains: IFNAR1 and IFNAR2 (IFNAR1 / IFNAR2 heterodimer).

[0748] The binding of IFN-β to IFNAR receptors triggers signal transduction events and biological effects in target cells.

[0749] In one embodiment, an interferon-β blocking agent described herein is an agent that neutralizes circulating IFN-β and / or an agent that blocks IFN-β signaling.

[0750] In one embodiment, the interferon-β blocking agents described herein include at least one agent selected from an agent that neutralizes circulating IFN-β and an agent that blocks IFN-β signaling.

[0751] In one embodiment, the agent that neutralizes circulating IFN-β and / or the agent that blocks IFN-β signaling is an IFN-β antagonist.

[0752] The term "interferon beta antagonist" as used herein refers to a substance that interferes with or inhibits the biological activity of IFN-β. "IFN-β biological activity" as used herein refers to any activity produced after IFN-β binds to its receptor IFNAR (IFNAR1 / IFNAR2 heterodimer). For example, such binding can activate the JAK-STAT signaling cascade and trigger tyrosine phosphorylation of multiple proteins (including JAK, TYK2 and STAT proteins). Therefore, interferon signaling blocking agents can neutralize the fixation of IFN-β to its receptor, and / or block the signaling cascade induced by binding of IFN-β to its receptor. In some embodiments, the IFN-β antagonist is selected from an active anti-IFN-β vaccine (e.g., IFN-β-kinoid, IFN-β DNA-based or IFN-β RNA-based vaccine) or a passive anti-IFN-β vaccine (e.g., anti-IFN-β antibodies or anti-IFN-β high immune serum).

[0753] In one embodiment, the agent that neutralizes circulating IFN-β is a passive anti-IFN-β vaccine, such as an anti-IFN-β antibody or an anti-IFN-β hyperimmune serum.

[0754] In one embodiment, the interferon-β blocking agent is an agent that neutralizes circulating IFN-β, wherein the agent that neutralizes circulating IFN-β is an anti-IFN-β antibody or an anti-IFN-β hyperimmune serum.

[0755] In one embodiment, the agent that neutralizes circulating IFN-β is an anti-IFN-β antibody, preferably a neutralizing antibody, preferably a chimeric humanized or human antibody. The anti-IFN-β antibody can be a monoclonal antibody or a polyclonal antibody, preferably a monoclonal antibody.

[0756] Non-limiting examples of anti-IFN-β antibodies include:

[0757] - anti-human IFN-β neutralizing monoclonal antibody, clone 10B10 (Invivogen),

[0758] -polyclonal anti-human IFN-β antibody (R&D systems),

[0759] - monoclonal anti-human IFN-β antibodies clone #76703, clone #MMHB-3 and clone #937912 (R&D systems),

[0760] - Neutralizing polyclonal anti-human IFN-β goat IgG (PBL assay sciences).

[0761] In one embodiment, the agent that neutralizes circulating IFN-β is anti-IFN-β hyperimmune serum.

[0762] In one embodiment, an agent described herein that neutralizes circulating IFN-β is an IFN-β ligand inhibitor.

[0763] In one embodiment, the agent that neutralizes circulating IFN-β is a soluble receptor that binds IFN-β.

[0764] In another embodiment, the interferon-β blocking agent is an active anti-IFN-β vaccine.

[0765] An "active anti-IFN-β vaccine" refers to a compound or composition that can induce the production of anti-IFN-β antibodies. For example, an "active anti-IFN-β vaccine" refers to a compound or composition that, upon administration to a subject, can induce the subject to produce anti-IFN-β autoantibodies.

[0766] The active ingredients of active anti-IFN-β vaccines can be peptides, proteins, DNA or RNA molecules.

[0767] For example, the active ingredient in active anti-IFN-β vaccines is an IFN-β kinoid. A kinoid is an immunogenic, inactivated and / or non-toxic IFN derivative. Typically, it exists as a heterocomplex formed by chemically conjugating the IFN derivative to a carrier.

[0768] Kinoids can be used as immunogens capable of inducing high-affinity autoantibodies against a given IFN. Thus, immunization with kinoids can induce high-titer neutralizing antibodies against the corresponding IFN.

[0769] The active ingredient of an active anti-IFN-β vaccine may also be a DNA molecule, such as partial or full-length IFN-β DNA, or an RNA molecule, such as partial or full-length IFN-β RNA.

[0770] In one embodiment, the interferon-β blocking agent is an agent that blocks IFN-β signaling, wherein the IFN-β signaling blocking agent is selected from anti-type I interferon R1 or R2 antibodies, SOSC1, and aryl hydrocarbon receptor.

[0771] In one embodiment, the agent that blocks IFN-β signaling as described herein is an IFNAR antagonist. In one embodiment, the agent that blocks IFN-β signaling is an IFNAR1 antagonist. In another embodiment, the agent that blocks IFN-β signaling is an IFNAR2 antagonist.

[0772] In one embodiment, the agent that blocks IFN-β signaling is an antibody that binds to IFNAR1 or IFNAR2.

[0773] In one embodiment, the agent that blocks IFN-β signaling is an agent that antagonizes the type I IFN signaling pathway.

[0774] In one embodiment, the agent that blocks IFN-β signaling can be an inhibitor of the type I IFN signaling pathway. Type I IFN signaling pathway inhibitors are well known in the art and include, but are not limited to, JAK1 / 2 / 3 inhibitors and STAT inhibitors. Therefore, in one embodiment, the agent that blocks IFN-β signaling is selected from JAK1 / 2 / 3 inhibitors, STAT inhibitors, and tyrosine kinase 2 (TYK2) inhibitors. Non-limiting examples of JAK1 / 2 / 3 inhibitors include ruxolitinib, tofacitinib, and baricitinib.

[0775] Non-limiting examples of TYK2 inhibitors include the BMS-986165 inhibitor.

[0776] In one embodiment, the agent that blocks IFN-β signaling can be an endogenous negative regulator of the type I IFN signaling pathway. Endogenous negative regulators are well known in the art and include, but are not limited to, SOCS1 / 3, FOXO3, aryl hydrocarbon receptor (AhR), or other negative regulators. Therefore, in one embodiment, the agent that blocks interferon signaling is selected from SOCS1 / 3, FOXO3, or aryl hydrocarbon receptor (AhR).

[0777] In one embodiment, the agent that blocks IFN-β signaling is a PASylation antagonist. PASylation antagonists of type I IFN are known in the art, for example, see Nganou-Makamdop et al. (2018). PLoS Pathog 14(8): e1007246.

[0778] Tolerogenic vaccines / CD8 vaccines

[0779] As used herein, the term "vaccine" refers to an immunogenic product or composition that can be administered to a mammal (e.g., a human) to confer immunity (e.g., passive or active immunity) against a disease or other pathological condition. Vaccines can be used for prevention or treatment, i.e., prophylactic or therapeutic. Thus, vaccines can be used to reduce the likelihood of developing a disease (e.g., an infection), or to reduce the severity of the symptoms of a disease or condition, to limit the progression of a disease or condition (e.g., an infection), or to limit the recurrence of a disease or condition.

[0780] The terms "tolerogenic vaccine" and "CD8 vaccine" are used indiscriminately herein.

[0781] In one embodiment, the tolerogenic vaccine is a prophylactic vaccine. In another embodiment, the tolerogenic vaccine is a therapeutic vaccine. As used herein, the therapeutic vaccine can be a prophylactic vaccine or a therapeutic vaccine. In some embodiments, the tolerogenic vaccine is a prophylactic vaccine. In other embodiments, the tolerogenic vaccine is a therapeutic vaccine.

[0782] In one embodiment, the tolerogenic vaccine induces immune tolerance to at least one HIV-associated antigen. In one embodiment, the tolerogenic vaccine is therefore specific for at least one HIV immunogen, which is an HIV antigen.

[0783] The terms "immunotolerance" and "Ts" are used herein as synonyms. Immune tolerance refers to the physiological ability of the immune system to recognize an antigen and produce anergy, which is usually associated with other immunological changes when the same antigen is subsequently encountered. In the present invention, the main feature of immune tolerance is CD8 + T cell activity that suppresses CD4 T cells that present at least one HIV-associated antigen + T cell activation. In general, whenever one or more HIV-associated antigens engage CD4 + Upon specific activation of T cells presenting epitopes derived from HIV-associated antigens, the MHC-1b / E-restricted CD8 + T cells can produce CD4 + Specific inhibition / prevention of T cell activation.

[0784] In some embodiments, a tolerogenic vaccine specific for at least one HIV immunogen lyses infected CD4+ cells expressing at least one HIV peptide under HLA-E restriction.

[0785] In one embodiment, the tolerogenic vaccine of the present invention elicits inhibitory MHC-1b / E-restricted CD8 + In another embodiment, the tolerogenic vaccine of the present invention comprises inhibitory MHC-1b / E-restricted CD8 + T cells or mainly inhibitory MHC-lb / E-restricted CD8 + T cell composition.

[0786] As used herein, "consisting essentially of" with respect to a cell population refers to an inhibitory MHC-1b / E-restricted CD8 + The T cell population is the only therapeutic agent or biologically active agent in the composition.

[0787] In one embodiment, inhibitory MHC-1b / E-restricted CD8 + T cells are generated by inducing HLA-1a-depleted dendritic cells, natural killer cells, or B cells ex vivo or in vivo.

[0788] In one embodiment, inhibitory MHC-1b / E-restricted CD8 + T cells are cytolytic CD8 + In one embodiment, inhibitory MHC-1b / E-restricted CD8 + T cells are non-cytolytic CD8 + T cells.

[0789] In one embodiment, the tolerogenic vaccine is an active vaccine. In another embodiment, the tolerogenic vaccine is a passive vaccine.

[0790] As used herein, the term "active vaccine" refers to a vaccine that induces active immunity, which is the process of exposing the body to an antigen to produce an adaptive immune response. This response takes days or weeks to develop but can persist for a long time, even lifelong. The term "passive vaccine" refers to a vaccine that induces passive immunity, which is the process of providing, for example, antibodies or cells to protect against infection. This provides immediate but short-lived protection, lasting from a few weeks to a few months.

[0791] In some embodiments, the tolerogenic vaccine is a vaccine that elicits inhibitory MHC-1b / E-restricted CD8 + T cell vaccine, the vaccine is selected from:

[0792] - an active vaccine which is a live viral vector comprising at least one pathogen-specific antigen, wherein the live viral vector is selected from the group consisting of cytomegalovirus, lentivirus, vaccinia virus, adenovirus and plasmid;

[0793] - active vaccines comprising at least one pathogen-specific antigen and at least one non-pathogenic bacterium, preferably at least one attenuated or inactivated pathogenic bacterium;

[0794] - an active vaccine, which is an ex vivo generated population of dendritic cells, natural killer cells or B cells that present at least one MHC-1b / E-restricted antigen and at least one MHC-II-restricted antigen, wherein the MHC-1b / E-restricted antigen is a pathogen-specific antigen;

[0795] - Passive vaccines, which are autologous MHC-1b / E-restricted CD8 produced ex vivo +T cell populations that recognize MHC-1b / E-restricted pathogen-specific antigens;

[0796] - an active vaccine, which is at least one lipid nanoparticle (LNP) containing or associated with at least one nucleic acid molecule comprising a single chain trimer with a pathogen-specific antigen or peptide and HLA-E.

[0797] Lentivirus and plasmids

[0798] According to one embodiment of the present invention, the tolerogenic vaccine is a live viral vector comprising at least one HIV-associated antigen.

[0799] In one embodiment, the live viral vector as described above is an active vaccine.

[0800] In one embodiment, the live viral vector as described above is selected from the group consisting of cytomegalovirus, lentivirus, vaccinia virus, adenovirus and plasmid.

[0801] In one embodiment, the live viral vector as described above is a recombinant vector selected from the group consisting of a recombinant cytomegalovirus, a recombinant lentivirus, a recombinant vaccinia virus, a recombinant adenovirus and a recombinant plasmid.

[0802] Live viral vectors can be replicating or non-replicating.

[0803] According to one embodiment, the live viral vector is a recombinant vaccinia virus. Recombinant vaccinia viruses have been generated from different vaccinia virus strains. For example, a variety of highly attenuated, host-restricted, non-replicating or poorly replicating poxvirus strains have been developed as the basis for recombinant vaccine development, including orthopoxvirus, modified vaccinia Ankara (MVA), NYVAC, fowlpox virus, ALVAC, and TROVAC.

[0804] Live CMV vector

[0805] According to one embodiment of the present invention, the tolerogenic vaccine is a CMV vector.

[0806] CMV vector construction

[0807] In one embodiment, the CMV vector is an active vaccine.

[0808] In one embodiment, the CMV vector comprises a nucleic acid sequence encoding at least one human immunodeficiency virus (HIV) antigen.

[0809] In one embodiment, the tolerogenic vaccine is a recombinant CMV expressing at least one HIV-associated antigen, wherein the antigen is a heterologous antigen. Thus, in one embodiment, the HIV-associated antigen can be derived from any protein that is not naturally expressed by CMV.

[0810] In one embodiment, the CMV vector does not express active UL128 and UL130 proteins or their orthologs.

[0811] As used herein, the term "ortholog" refers to homologous genes of CMV that infect other species.

[0812] In one embodiment, the CMV vector does not express active UL146 and UL147 proteins or their orthologs.

[0813] In one embodiment, the CMV vector expresses at least one active UL40 protein, and / or at least one active US27 protein, and / or at least one active US28 protein. In one embodiment, the at least one active UL40 protein, the at least one active US27 protein, and the at least one active US28 protein may be orthologs or homologs of UL40, US27, and US28.

[0814] In some examples, the CMV vector does not express active UL128, UL130, UL146, or UL147 protein due to a mutation in the nucleic acid sequence encoding UL128, UL130, UL146, or UL147, or an ortholog thereof.

[0815] The term "mutation" as used herein may refer to any mutation that results in the non-expression of active UL128, UL130, UL146 or UL147 proteins. Such mutations may include point mutations, frameshift mutations, deletions of sequences encoding the protein (truncation mutations) or deletions of all nucleic acid sequences encoding the protein, or any other mutations. For example, CMV comprising the mutation is described in WO2014138209, which is incorporated herein by reference in its entirety.

[0816] In a further example, the vector does not express active UL128, UL130, UL146 or UL147 protein or its orthologs due to the presence of a nucleic acid sequence in the vector comprising an antisense or RNAi sequence (siRNA or miRNA) that inhibits the expression of UL128, UL130, UL146 or UL147 protein or its orthologs.

[0817] In one embodiment, mutations and / or antisense and / or RNAi can be used in any combination to generate a CMV vector lacking active UL128, UL130, UL146 or UL147, or orthologs thereof.

[0818] In one embodiment, the CMV vector comprises all of the above modifications and further comprises a nucleic acid sequence that functions as a miRNA response element (MRE) that silences expression in the presence of an endothelial cell-expressed miRNA.

[0819] The terms "miRNA response element (miRNA response element)" or "MRE" used herein refer to any sequence that directly base pairs with a miRNA somewhere on an mRNA transcript and interacts. Therefore, miRNA can silence the translation of one or more specific mRNA molecules by combining with a miRNA recognition element (MRE). MRE is usually located in the 3' untranslated region (UTR) of mRNA, but can also be located in a coding sequence or 5'UTR. MRE is not necessarily completely complementary to miRNA, and usually has only a few bases complementary to miRNA, and one or more mismatches are usually present in these complementary bases. MRE can be any sequence that can fully combine with miRNA, thereby suppressing the translation of genes operably connected to MRE. Examples of such genes include but are not limited to IE2 and UL79 genes or their orthologs, or any CMV genes that are crucial to growth or promote growth in vivo. For example, the CMV comprising the MRE is described in WO201875591, which is incorporated herein by reference in its entirety.

[0820] In one embodiment, the MRE can be any miRNA recognition element that silences expression in the presence of a miRNA expressed by endothelial cells. In one embodiment, the MRE of the vector silences expression in the presence of one or more of miR-126-3p, miR-130a, miR-210, miR-221 / 222, miR-378, miR-296, and miR-328.

[0821] In one embodiment, the MRE is silenced in the presence of miR-126-3p.

[0822] In one embodiment, the MRE silences the expression of UL122 (IE2) and UL79 in the presence of miR-126-3p.

[0823] Those skilled in the art can select the MRE sequence of checking, supposition or sudden change from the literature, and this sequence expectation induces silence when the miRNA expressed in endothelial cells or myeloid cells (for example macrophage) exists.Then, those skilled in the art can obtain expression construct, wherein reporter gene (for example fluorescent protein, enzyme or other reporter genes) is driven to express by promoter (for example constitutive active promoter or cell-specific promoter).Then the MRE sequence can be incorporated into the expression construct.This expression construct can be transfected into suitable cell, and target miRNA is transfected into cell.Reporter gene does not express and shows, and in the situation that there is miRNA, MRE has silenced gene expression.

[0824] In one embodiment, the CMV vector comprises a first nucleic acid sequence encoding at least one HIV-associated antigen and does not express active UL128, UL130, UL146 and UL147 proteins or their orthologs, but expresses at least one active UL40, US27 and / or US28 protein or its orthologs.

[0825] In another embodiment, the CMV vector comprises a first nucleic acid sequence encoding at least one HIV-associated antigen, and optionally comprises a second nucleic acid sequence comprising a first microRNA recognition element (MRE) operably linked to a CMV gene that is essential for or enhances CMV growth, wherein the MRE is silenced in the presence of a microRNA expressed by endothelial lineage cells, does not express active UL128, UL130, UL146 and UL147 proteins or their orthologs, and expresses at least one active UL40, US27 and / or US28 protein or its ortholog.

[0826] In one embodiment, the CMV vector may contain additional inactivating mutations known in the art to provide a different immune response, such as a US11 inactivating mutation or a UL82 (pp71) inactivating mutation, or any other inactivating mutation.

[0827] In one embodiment, the CMV vector can also include at least one inactivating mutation in one or more viral genes, which are known in the art to encode viral proteins that are crucial for viral propagation in vivo (i.e., spread between cells) or enhance viral propagation in vivo. Such inactivating mutations can be caused by the absence of point mutations, frameshift mutations, truncation mutations, or the entire nucleic acid sequence encoding viral proteins. Inactivating mutations include any mutations in viral genes that ultimately result in a reduction in viral protein function or a complete loss of function.

[0828] In one embodiment, the CMV vectors described herein may include mutations that prevent inter-host transmission, thereby preventing the virus from infecting immunocompromised subjects or other subjects who may develop complications from CMV infection. In another embodiment, the CMV vectors described herein may also include mutations that result in immunodominant and non-immunodominant epitope presentation and non-classical MHC restriction. Such CMV mutations are described, for example, in U.S. Patent Publications 2013-0136768, 2014-0141038, and PCT Application Publication WO 2014 / 138209, all of which are incorporated herein by reference.

[0829] In one embodiment, the mutations of the CMV vectors described herein do not affect the ability of the vector to reinfect a subject previously infected with CMV. Thus, in one embodiment, the CMV vector is capable of repeatedly infecting an organism.

[0830] In one embodiment, the CMV vector is a human CMV (hCMV) or rhesus CMV (RhCMV) vector.

[0831] Vector preparation

[0832] In one embodiment, the CMV vectors disclosed herein can be prepared by inserting DNA comprising sequences encoding HIV-associated antigens into essential or nonessential regions of the CMV genome.

[0833] In one embodiment, the method can also include deleting one or more regions from the CMV genome. In one embodiment, the method can also include in vivo recombination. Therefore, the method can include in the presence of a donor DNA comprising a heterologous DNA flanked by a DNA sequence homologous to the CMV genome, transfecting cells with CMV DNA in a cytocompatibility medium, thereby introducing the heterologous DNA into the CMV genome, and then optionally reclaiming the CMV modified by in vivo recombination.

[0834] In one embodiment, the method can also include cutting CMV DNA to obtain the CMV DNA of cutting, heterologous DNA is connected to the CMV DNA of cutting to obtain CMV-heterologous DNA hybrid, with this CMV-heterologous DNA hybrid transfection cell, optionally reclaim the CMV modified in the presence of heterologous DNA subsequently. Due to in vivo recombination being understood, the method therefore also provides a kind of plasmid, this plasmid comprises non-naturally occurring donor DNA in CMV, the foreign polypeptide of this donor DNA encoding CMV, this donor DNA is located in the fragment of CMV DNA (this fragment is originally colinear with the essential or non-essential region of CMV genome), makes the DNA of CMV essential or non-essential region be located at the flank of donor DNA. Heterologous DNA can be inserted into CMV, with any direction generation recombinant CMV, thus realize the stable integration of this DNA, and express when needed.

[0835] In one embodiment, the DNA encoding HIV-associated antigens in the recombinant CMV vector may further comprise a promoter. The promoter may be from any source, such as a herpes virus, including an endogenous CMV promoter, such as HCMV, RhCMV, mouse CMV (MCMV), or other CMV promoters. The promoter may also be a non-viral promoter, such as the EF1a promoter. The promoter may be a truncated transcriptionally active promoter comprising a region transactivated by a transactivator protein provided by the virus, and a minimal promoter region of a full-length promoter derived from the truncated transcriptionally active promoter. The promoter may be composed of a combination of a DNA sequence corresponding to a minimal promoter and an upstream regulatory sequence. The minimal promoter consists of a CAP site plus a TATA box (a minimal sequence for basal transcription levels, non-regulated transcription levels); the "upstream regulatory sequence" consists of an upstream element and an enhancer sequence. In addition, the term "truncated" means that the full-length promoter is not completely present, i.e., some portions of the full-length promoter have been removed. The truncated promoter can be derived from a herpes virus, such as MCMV or HCMV, such as HCMV-IE or MCMV-IE. Based on base pairs, the size of the truncation can be reduced by up to 40% or even up to 90% relative to the full-length promoter. The promoter can also be a modified non-viral promoter. Regarding the HCMV promoter, reference can be made to U.S. Patent Nos. 5,168,062 and 5,385,839, the contents of which are incorporated herein by reference. Regarding expression by transfecting cells with plasmid DNA, reference can be made to Feigner et al. (1994), J. Biol. Chem. 269, 2550-2561, the contents of which are incorporated herein by reference. Regarding direct injection of plasmid DNA as a simple and effective vaccination method for a variety of infectious diseases, reference can be made to Ulmer et al. (1993), Science. 259: 1745-49, which is incorporated herein by reference. Therefore, the use of vectors by direct injection of vector DNA also falls within the scope of the present invention.

[0836] The present invention also discloses an expression cassette that can be inserted into a recombinant virus or plasmid containing a truncated transcriptionally active promoter. The expression cassette can also contain a functional truncated polyadenylation signal, such as the SV40 polyadenylation signal, which is truncated but still functional. Considering that nature provides a larger signal, it is surprising that the truncated polyadenylation signal is functional. The truncated polyadenylation signal solves the problem of limited insert size for recombinant viruses (such as CMV). The expression cassette can also contain DNA that is heterologous to the virus or system into which it is inserted; and the DNA can be heterologous DNA as described herein.

[0837] For the disclosed HIV-associated antigens to be expressed in a vector, the protein coding sequence of the HIV-associated antigen should be "operably linked" to regulatory sequences or nucleic acid control sequences that direct the transcription and translation of the protein.

[0838] Non-pathogenic bacteria

[0839] According to another embodiment of the present invention, the tolerogenic vaccine comprises at least one HIV-associated antigen and a non-pathogenic bacterium.

[0840] In one embodiment, the tolerogenic vaccine comprises at least one HIV-associated antigen and at least one non-pathogenic bacterium.

[0841] In one embodiment, the tolerogenic vaccine comprising at least one HIV-associated antigen and a non-pathogenic bacterium is an active vaccine.

[0842] Non-pathogenic bacteria

[0843] As used herein, the term "non-pathogenic bacteria" refers to bacteria that generally do not induce any pathology in mammals, preferably humans.

[0844] In one embodiment, the non-pathogenic bacteria are alive.

[0845] In one embodiment, the non-pathogenic bacteria described herein are commensal bacteria.

[0846] As used herein, the term "commensal bacteria" refers to microorganisms that reside on epithelial cell-lined body surfaces and are exposed to the external environment (e.g., the gastrointestinal tract and respiratory tract, vagina, skin, etc.). Among the many proposed health benefits of commensal gut bacteria, their ability to interact with the host immune system is well established. Commensal bacteria are well known to those skilled in the art. Non-limiting examples include Bacillus sp. (e.g., B. coagulans), Lactobacillus sp., Bifidobacterium animalis, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium lactis, Escherichia coli, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus johnsonii, Lactobacillus plantarum, Lactobacillus spp. plantarum), Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus brevis, Lactobacillus gasseri, Lactobacillus salivarius, Lactobacillus salivarius salicinius, Lactobacillus delbureckii, Lactobacillus delbureckii bulgaricus, Lactobacillus delbureckii lactis, Lactococcus lactis, Streptococcus thermophilus, etc.

[0847] In one embodiment, the commensal bacteria are selected from the group consisting of Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium bifidum, Bifidobacterium breve, Lactococcus lactis, Streptococcus thermophilus, Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus reuteri.

[0848] In one embodiment, the commensal bacteria is a Lactobacillus species, preferably Lactobacillus plantarum.

[0849] In another embodiment, the commensal bacteria is a Lactobacillus species, preferably Lactobacillus rhamnosus.

[0850] In another embodiment, the bacterium is a Mycobacterium, preferably Mycobacterium bovis.

[0851] In one embodiment, a combination of non-pathogenic bacteria may be used, such as two or more commensal bacteria.

[0852] In another embodiment, the non-pathogenic bacteria described herein are selected from attenuated or inactivated pathogenic bacteria.

[0853] As used herein, the term "pathogenic bacteria" refers to bacteria that induce pathology in humans. Such bacteria are well known to those skilled in the art and include, in particular, Listeria species (e.g., Listeria monocytogenes), Corynebacterium species, Mycobacterium species, Rhococcus species, Eubacteria species, Bortadella species, and Nocardia species. Preferably, the pathogenic bacteria is selected from the genus Mycobacterium, more preferably Mycobacterium bovis.

[0854] As used herein, the term "attenuated pathogenic bacteria" refers to bacteria that have been rendered less toxic than their wild-type counterparts due to one or more mutations or one or more attenuation treatments (e.g., chemical treatment and / or continuous passage in a specific culture medium). Such attenuated pathogenic bacteria are well known to those skilled in the art. Non-limiting examples of attenuated pathogenic bacteria include attenuated Salmonella typhimurium and mycobacteria. Methods for preparing such inactivated pathogenic bacteria are common knowledge in the art. Examples of such methods include phage-mediated lysis, chemical inactivation (e.g., formaldehyde treatment), heat inactivation, physical inactivation (e.g., lyophilization (e.g., extended freeze drying) or UV or gamma irradiation or microwave exposure), or any combination thereof.

[0855] In one embodiment, the non-pathogenic bacteria described herein may or may not be recombinant.

[0856] In one embodiment, the attenuated pathogenic bacteria described herein are attenuated derivatives of pathogenic bacteria, such as BCG. In one embodiment, the attenuated derivative of the pathogenic bacteria corresponds to a recombinant Salmonella typhimurium or a recombinant Mycobacterium (e.g., BCG) that expresses or produces at least one HIV protein. In another embodiment, the derivative of the pathogenic bacteria does not express any HIV protein.

[0857] Tolerogenic adjuvants

[0858] In one embodiment, the non-pathogenic bacteria described herein are used as a tolerogenic adjuvant for a tolerogenic vaccine. Thus, in one embodiment, the non-pathogenic bacteria are a tolerogenic adjuvant.

[0859] As used herein, the term "tolerogenic adjuvant" refers to an entity that, when administered by mucosal or intradermal or intraepithelial route together with an appropriate HIV-associated antigen as defined below, will induce and preferably maintain a state of immunological tolerance to the antigen, thereby enabling treatment of HIV infection in humans.

[0860] In one embodiment, when the tolerogenic adjuvant is combined with HIV-associated antigens, it induces or maintains immune tolerance to the viral antigens, thereby treating the associated HIV.

[0861] In one embodiment, non-pathogenic bacteria, in particular probiotics and commensal bacteria, may be used as tolerogenic adjuvants within the scope of the present invention.In one embodiment, Lactobacillus, preferably Lactobacillus plantarum and / or Lactobacillus rhamnosus, may be used as tolerogenic adjuvants in the context of the present invention.

[0862] In another embodiment, Mycobacterium, preferably Mycobacterium bovis, may be used as a tolerogenic adjuvant in the context of the present invention.

[0863] In one embodiment, a combination of non-pathogenic bacteria, such as two or more commensal bacteria, may be used as a tolerance adjuvant in the context of the present invention.

[0864] In another embodiment, instead of or in addition to attenuation, the pathogenic bacteria described herein may be inactivated for use as a tolerance adjuvant in the context of the present invention, although attenuated pathogenic bacteria may also be used after inactivation.

[0865] In some embodiments, the tolerogenic adjuvant comprising non-pathogenic bacteria or attenuated pathogenic bacteria further comprises a prebiotic.

[0866] As used herein, "prebiotics" refers to substances that induce the growth or activity of certain bacteria. Prebiotics vary in nature and include, for example, sugars such as oligosaccharides and polysaccharides.

[0867] Any prebiotic can be used in combination with the non-pathogenic bacteria or attenuated pathogenic bacteria described herein.

[0868] In some embodiments, the tolerogenic adjuvant comprises at least one prebiotic selected from the group consisting of fructooligosaccharides (FOS), galactooligosaccharides (GOS), inulin, transgalactooligosaccharides (TOS), bene synergy1 (SYN1), fructooligosaccharide-inulin, lactulose, oat fiber, germinated barley, hydrolyzed guar gum, resistant starch, psyllium ovata, β-glucan, and pectin.

[0869] In vitro generation of APCs presenting MHC-1b / E-restricted antigens

[0870] According to another embodiment of the present invention, the tolerogenic vaccine is an ex vivo generated population of dendritic cells, natural killer cells or B cells presenting MHC-II and MHC-lb / E-restricted antigens.

[0871] In one embodiment, an ex vivo generated population of dendritic cells, natural killer cells, or B cells presenting MHC-II and MHC-lb / E-restricted antigens is an active vaccine.

[0872] In one embodiment, the MHC-lb / E-restricted antigen is an HIV-associated pathogen-specific antigen.

[0873] In one embodiment, the HIV-associated antigen or HIV-specific antigen is an HIV- or SIV-derived MHC Ib / E binding antigen.

[0874] In one embodiment, the HIV-derived MHC Ib / E binding antigen described herein is selected from SEQ ID NO: 1 to SEQ ID NO: 4, SEQ ID NO: 56 to SEQ ID NO: 58, and SEQ ID NO: 63.

[0875] In one embodiment, the HIV-derived MHC Ib / E binding antigen has an amino acid sequence selected from the group consisting of RMYSPVSIL (SEQ ID NO: 1), PEIVIYDYM (SEQ ID NO: 2), TALSEGATP (SEQ ID NO: 3), RIRTWKSLV (SEQ ID NO: 4), VLKYWWNLL (SEQ ID NO: 56) (Env), ILPCRIKQI (SEQ ID NO: 57) (Env), AISPRTLNA (SEQ ID NO: 58) (Gag), and RMYSPTSIL (SEQ ID NO: 63).

[0876] In some embodiments, the MHC-II restricted peptide or antigen is an HLA-DR restricted peptide or antigen. Examples of HLA-DR restricted peptides include, for example, an HLA-DR binding antigen having one of the following sequences: QGQMVHQAISPRTLN (SEQ ID NO: 7) (Gag p24), GEIYKRWIILGLNKI (SEQ ID NO: 8) (Gag p24), KRWIILGLNKIVRMY (SEQ ID NO: 9) (Gag p24), FRKYTAFTIPSINNE (SEQ ID NO: 10) (Pol RT), PEIVIYDYM (SEQ ID NO: 16) (Pol), or RIRTWKSLV (SEQ ID NO: 17) (Pol).

[0877] In one embodiment, the HLA-DR restricted peptide is derived from HIV, preferably from HIV-1.

[0878] In one embodiment, the HLA-DR restricted peptide is an HIV-derived HLA-DR binding antigen having an amino acid sequence selected from the group consisting of: sequence QGQMVHQAISPRTLN (SEQ ID NO:7) (Gag p24), sequence GEIYKRWIILGLNKI (SEQ ID NO:8) (Gag p24), sequence KRWIILGLNKIVRMY (SEQ ID NO:9) (Gag p24), and sequence FRKYTAFTIPSINNE (SEQ ID NO:10) (Pol RT).

[0879] In one embodiment, the dendritic cells, natural killer cells or B cell populations presenting MHC-II and MHC-lb / E-restricted peptides are allogeneic cell populations. In a preferred embodiment, the dendritic cells, natural killer cells or B cell populations presenting MHC-II and MHC-lb / E-restricted peptides are autologous cell populations.

[0880] As used herein, "allogeneic cells" refer to cells that are isolated from one subject (the donor) and infused into another subject (the recipient or host).

[0881] As used herein, "autologous cells" refer to cells that have been isolated and infused back into the same subject (recipient or host).

[0882] Therefore, the present invention also relates to a method for generating ex vivo a population of dendritic cells, natural killer cells or B cells that present MHC-II and MHC-lb / E restricted peptides.

[0883] In one embodiment, the method of generating ex vivo a population of dendritic cells, natural killer cells, or B cells that present MHC-II and MHC-1b / E-restricted peptides comprises:

[0884] a. Optionally, reducing MHC-1a expression in immature dendritic cells, natural killer cells or B cells using an agent that inhibits TAP expression or activity,

[0885] b. loading immature dendritic cells with HLA-DR and / or MHC-lb / E-restricted peptides, and

[0886] c. Maturating the loaded immature dendritic cells, natural killer cells or B cells.

[0887] Isolation of MO-DC precursors

[0888] In one embodiment, immature dendritic cells are generated from monocytic dendritic cell precursors (MO-DC) precursors.

[0889] As used herein, the term "monocyte dendritic cell precursors" refers to monocytes and other bone marrow precursors (e.g., myeloid precursors). These cells can be isolated from any tissue in which they reside, particularly lymphoid tissues such as the spleen, bone marrow, lymph nodes, and thymus. Monocyte dendritic cell precursors can be isolated from umbilical cord blood. Monocyte dendritic cell precursors can also be isolated from peripheral blood mononuclear cells or bone marrow samples using any technique known in the art. Monocyte dendritic cell precursors can also be isolated from frozen samples. Methods for isolating MO-DC precursors and immature dendritic cells from the various sources mentioned above (including blood and bone marrow) can be performed in a variety of ways. Typically, a cell population is collected from an individual and enriched for MO-DC precursors. For example, a mixed cell population containing MO-DC precursors can be obtained from peripheral blood by leukapheresis, apheresis, density centrifugation, differential lysis, filtration, antibody selection (e.g., flow cytometry, positive or negative selection), or preparation of a buffy coat. In one embodiment, the MO-DC precursors are not activated, and thus, in one embodiment, the method selected must not activate the MO-DC precursors. For example, if antibody selection is selected to enrich for precursors in a cell population, the selected antibodies must not activate the cells (e.g., by inducing calcium influx, which may be caused by cross-linking of molecules on the antibody-bound surface). Typically, during antibody selection, the antibodies used will eliminate macrophages, B cells, natural killer cells, T cells, etc. Antibodies can also be used to positively select for monocyte-like cells that express CD14.

[0890] In one embodiment, MO-DC precursors and immature dendritic cells can be obtained from autologous PBMCs (peripheral blood mononuclear cells). In one embodiment, MO-DC precursors and immature dendritic cells can be obtained from autologous tissue. In one embodiment, MO-DC precursors and immature dendritic cells can be obtained from HLA-matched healthy individuals.

[0891] In one embodiment, immature dendritic cells can be obtained from induced pluripotent stem cells (iPS). In one embodiment, immature dendritic cells can be obtained from CD34 + In one embodiment, immature dendritic cells can be obtained from human dendritic cell lines. In one embodiment, immature dendritic cells can be obtained from CD34 + Dendritic cell precursor cell lines are obtained. A non-limiting example of a cell line that can be used to generate immature dendritic cells is the CD34 + Human acute myeloid leukemia cell line (MUTZ-3), see, eg, Masterson et al., (2002) Blood, 100:701-703.

[0892] In another embodiment, MO-DC precursors and immature dendritic cells can be obtained from HLA-matched healthy individuals, converted into immature dendritic cells, matured, activated, and administered to HLA-matched subjects in need thereof.

[0893] Generation of immature dendritic cells

[0894] In one embodiment, cells from unactivated MO-DC precursors or CD34 + Dendritic cell precursor-enriched cell populations are cultured ex vivo or in vitro for differentiation, maturation, and / or expansion.

[0895] Briefly, ex vivo differentiation typically involves culturing MO-DC precursors or CD34 + Dendritic cell precursors, or containing unactivated MO-DC precursors or CD34 + Cell populations of dendritic cell precursors. Such differentiation agents typically include granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin 4 (IL-4), interleukin 6 (IL-6), interleukin 3 (IL-3), stem cell factor (SCF), Fms-related tyrosine kinase 3 ligand (Flt3-L) or a combination thereof. Such differentiation agents can be used alone or in combination. For example, GM-CSF can be used alone or in combination with one or more cytokines (e.g., IL-4, IL-6, IL-3, SC and / or Flt3-L). In one embodiment, unactivated MO-DC precursors or CD34 + Dendritic cell precursors differentiate into immature dendritic cells that can induce the activation and proliferation of a large number of T cells.

[0896] Suitable culture conditions for generating and maintaining immature dendritic cell precursors are well known in the art. Such culture media include, but are not limited to, RPMI 1640, DMEM, X-VIVO The culture medium may be supplemented with cytokines such as cytokines. The culture medium may be supplemented with serum, amino acids, vitamins, divalent cations, etc. to promote cell differentiation into dendritic cells. In one embodiment, dendritic cell precursors may be cultured in a serum-free medium. Such culture conditions may optionally exclude any animal-derived products. Typically, GM-CSF is added to the culture medium at a concentration of about 2 to about 200 ng / ml, or typically 20 ng / ml GM-CSF, and IL-4 is added to the culture medium at a concentration of about 2 to about 200 ng / ml, or typically 20 ng / ml IL-4. IL-6 is added to the culture medium at a concentration of about 2 to about 200 ng / ml, or typically 20 ng / ml IL-6. IL-3 is added to the culture medium at a concentration of about 2 to about 200 ng / ml, or typically 20 ng / ml IL-3, SCF is added to the culture medium at a concentration of about 10 to about 1000 ng / ml, or typically 100 ng / ml SCF, and Flt3-L is added to the culture medium at a concentration of about 10 to about 1000 ng / ml, or typically 100 ng / ml Flt3-L. When precursor cells differentiate into immature dendritic cells, they typically exhibit a typical cell surface protein expression pattern of immature dendritic cells. For example, these cells typically express CD14 - , HLA-DR + 、CD11c + 、CD83 - , and express low levels of CD86. A non-limiting example of the generation of immature dendritic cell precursors is described in Example 2. At this stage, immature dendritic cells are able to capture soluble antigens through specialized uptake mechanisms.

[0897] Reduction in MHC-1a expression

[0898] In one embodiment, MHC-Ia expression in immature dendritic cells or dendritic cells is reduced by an agent that inhibits TAP expression or activity.

[0899] According to one embodiment, the immature dendritic cells or dendritic cells express reduced levels of the major histocompatibility molecule Ia (MHC-Ia) on their surface. According to one embodiment, the immature dendritic cells or dendritic cells do not express the major histocompatibility molecule Ia (MHC-Ia) on their surface.

[0900] "MHC class 1a presentation" refers to "classical" presentation through HLA-A, HLA-B and / or HLA-C molecules, while MHC class Ib presentation refers to "non-classical" antigen presentation through HLA-E, HLA-F, HLA-G and / or HLA-H molecules.

[0901] Methods for inhibiting MHC-1a expression are well known. For example, inhibition of the TAP transporter (transporter associated with antigen processing) can reduce MHC-1a expression, thereby promoting HLA-E expression on the surface of dendritic cells.

[0902] Exemplary methods of inhibiting TAP transporters in the endoplasmic reticulum include, but are not limited to, CRISPR-CAS-9 technology, silencing RNA, transfection of DCs with UL-10 viral protein from CMV (cytomegalovirus), or use of viral proteins.

[0903] Examples of viral genes or proteins that silence TAP expression include, but are not limited to, HSV-1 ICP47 protein, varicella virus UL49.5 protein, cytomegalovirus US6 protein, or gammaherpes virus EBV BNLF2a protein, and HIV nef protein.

[0904] Another approach is to use chemical products to inhibit the expression of MHC class 1a molecules without altering HLA-E expression on the surface of tolerogenic DCs. Examples of chemical products include, but are not limited to, 5'-methyl-5'-thioadenosine or leptomycin B.

[0905] In one embodiment, the TAP inhibitor is RNA synthesized from the pGem4Z vector containing the UL49.5 gene from BHV-1.

[0906] In one embodiment, the TAP inhibitor can be efficiently introduced into immature dendritic cells by electroporation. In another embodiment, the TAP inhibitor can be efficiently introduced into immature dendritic cells by transfection.

[0907] Depletion of MHC-1a can be monitored by methods known in the art. For example, antibodies can be used to monitor whether immature dendritic cells or dendritic cells are MHC-1a - / 低 .

[0908] Loading of MHC-1a-depleted immature dendritic cells

[0909] In one embodiment, the immature dendritic cells or dendritic cells can be loaded (or pulsed) in the presence of at least one predetermined antigen. In one embodiment, the expression of MHC-1a in the immature dendritic cells or dendritic cells has been previously reduced. In another embodiment, the expression of MHC-1a in the immature dendritic cells has not been previously reduced.

[0910] In one embodiment, the immature dendritic cells or dendritic cells present peptides or antigens that specifically bind to HLA-DR and / or MHC-1b / E molecules. Thus, in one embodiment, the immature dendritic cells or dendritic cells can be loaded (or pulsed) by contacting the immature dendritic cells or dendritic cells with a predetermined peptide or antigen before, after, or during maturation. In one embodiment, the immature dendritic cells or dendritic cells depleted of MHC-1a present peptides or antigens that specifically bind to HLA-DR and / or MHC-1b / E molecules. Thus, in one embodiment, the immature dendritic cells or dendritic cells depleted of MHC-1a can be loaded (or pulsed) by contacting the immature dendritic cells with a predetermined peptide or antigen before, after, or during maturation.

[0911] Suitable predetermined antigens for use in the present invention may include any infectious disease-associated antigen. Infectious disease-associated antigens are described below and include, for example, MHC-Ib / E peptides or antigens of HIV or SIV.

[0912] Methods for contacting dendritic cells with antigens are generally known in the art (see Steel and Nutman, J. Immunol. 160:351-60 (1998); Tao et al., J. Immunol. 158:4237-44 (1997); Dozmorov and Miller, Cell Immunol. 178:187-96 (1997); Inaba et al., J Exp Med. 166:182-94 (1987); Macatonia et al., J Exp Med. 169:1255-64 (1989); De Bruijn et al., Eur. J. Immunol. 22:3013-20 (1992), the disclosures of which are incorporated herein by reference). Generally, as described above, immature dendritic cells obtained by the method of the present invention can be cultured under appropriate culture conditions in the presence of a predetermined antigen. Optionally, immature dendritic cells can be mixed with a predetermined antigen in a typical dendritic cell culture medium with or without GM-CSF and / or a maturation agent. After incubation with the antigen for at least about 10 minutes to about 2 days, the antigen can be removed and the culture medium supplemented with the maturation agent. GM-CSF and other cytokines (e.g., IL-4) can also be added to the culture medium.

[0913] In one embodiment, immature dendritic cells or dendritic cells can be transfected with a plasmid encoding an MHC-1b / E molecule. In another embodiment, immature dendritic cells or dendritic cells can be transfected with a plasmid encoding a peptide-MHC-1b / E complex.

[0914] Dendritic cell maturation

[0915] In one embodiment, immature dendritic cells (optionally MHC-1a depleted and previously loaded) can be matured with a maturation agent.

[0916] In one embodiment, immature dendritic cells can be matured into mature dendritic cells. Mature dendritic cells lose the ability to take up antigens, and the cells show upregulated expression of co-stimulatory cell surface molecules and secrete various cytokines. For example, mature dendritic cells can express higher levels of HLA-DR and / or MHC-1b / E antigens, usually identified as MHC-1a - / 低 、CD80 + 、CD83 + and CD86 + Higher MHC expression leads to increased antigen density on the DC surface, while upregulation of the costimulatory molecules CD80 and CD86 enhances T cell activation signals through their costimulatory counterparts on T cells, such as CD28.

[0917] Methods for preparing mature dendritic cells are well known in the art. For example, immature dendritic cells can be matured by contacting them with an effective amount or concentration of a dendritic cell maturation agent. Dendritic cell maturation agents can include, for example, BCG, IFNγ, LPS, TNFα, IL-1β, IL-6, PGE2, Poly I:C, TLR7 / 8 ligands, or combinations thereof.

[0918] For example, immature DCs are typically exposed to an effective amount of LPS for about 1 hour to about 48 hours, preferably 24 hours. Immature dendritic cells can be cultured and matured under suitable maturation culture conditions. Suitable tissue culture media include RPMI 1640, DMEM, X-VIVO Tissue culture medium can be supplemented with amino acids, vitamins, cytokines (such as GM-CSF), divalent cations, etc. to promote cell maturation.

[0919] As an example, dendritic cells can be matured in the presence of IL-1β, IL-6, PGE2, TNF-α, LPS, and Poly I: C. Typically, the following concentrations are used: approximately 2 ng / mL IL-1β, 30 ng / mL IL-6, 1 μg / mL PGE2, 10 ng / mL TNF-α, 250 ng / mL LPS, and 150 ng / mL Poly I: C.

[0920] The maturation of dendritic cells can be monitored by methods known in the art. Cell surface markers can be detected by assay methods familiar in the art, such as flow cytometry, immunohistochemistry, etc. The cytokine production of the cells can also be monitored (e.g., by ELISA, other immunoassays, or oligonucleotide arrays). The mature DCs of the present invention also lose the ability to take up antigens, which can be analyzed by uptake assays familiar to those skilled in the art.

[0921] Final DC

[0922] Therefore, the present invention also relates to a population of mature dendritic cells presenting MHC-II and MHC-lb / E-restricted peptides, which are obtained or obtainable by the above-described ex vivo method.

[0923] Natural killer cells or B cells presenting MHC-lb / E-restricted antigens

[0924] In addition to dendritic cells, other immune cell types can be used to obtain mature immune cell populations that present MHC-II and MHC-lb / E-restricted peptides or antigens.

[0925] In one embodiment, the tolerogenic vaccine is an active vaccine that is an ex vivo generated population of natural killer cells presenting at least one MHC-lb / E-restricted antigen and at least one MHC-II restricted antigen.

[0926] In one embodiment, the natural killer cell is a K562 cell line.

[0927] In some embodiments, natural killer cells are modified to express MHC-lb / E.

[0928] In another embodiment, the tolerogenic vaccine is an active vaccine, which is a population of naive B cells generated ex vivo that presents at least one MHC-lb / E-restricted antigen and at least one MHC-II restricted antigen.

[0929] In one embodiment, the B cell is a cell line.

[0930] In some embodiments, B cells are modified to express MHC-lb / E.

[0931] Therefore, the present invention also relates to a population of mature natural killer cells presenting MHC-II and MHC-lb / E-restricted peptides, which are obtained or obtainable by the above-described ex vivo method.

[0932] The present invention also relates to a population of mature B cells presenting MHC-II and MHC-1b / E-restricted peptides, which are obtained or obtainable by the above-described ex vivo method.

[0933] In vitro generated MHC-1b / E-restricted CD8 + T cells

[0934] According to another embodiment of the present invention, the tolerogenic vaccine is an ex vivo generated MHC-1b / E-restricted CD8 + T cell population.

[0935] In one embodiment, ex vivo generated MHC-1b / E-restricted CD8 + T cell populations are passive vaccines.

[0936] In one embodiment, MHC-1b / E-restricted CD8 + T cell populations recognize MHC-1b / E-restricted HIV-associated antigens.

[0937] Therefore, the present invention also relates to a method for producing MHC-1b / E-restricted CD8 + T cell population methods.

[0938] In one embodiment, ex vivo generation of MHC-1b / E-restricted CD8 + T cell population methods include:

[0939] a. Culturing naive CD8 in the presence of dendritic cells, natural killer cells, or B cell populations presenting MHC-1b / E-restricted peptides + T cells, thereby producing MHC-lb / E-restricted CD8 + T cells, and

[0940] b. Amplification of MHC-1b / E-restricted CD8 + T cells.

[0941] Isolation of T cells

[0942] In one embodiment, CD8 + T cells, preferably naive CD8 + T cells are isolated from a blood sample by any technique known in the art. In one embodiment, CD8 + T cells, preferably naive CD8 + T cells are isolated from PBMC (peripheral blood mononuclear cells) by flow cytometry. In one embodiment, CD8 + T cells, preferably naive CD8 + T cells can be isolated from frozen PBMCs. In one embodiment, CD8 + The T cells are allogeneic T cells, preferably allogeneic naive T cells. In another embodiment, the CD8 +The T cells are autologous T cells, preferably autologous naive T cells. The separation or purification of T cells can be achieved by positive selection or negative selection, including but not limited to the use of antibodies against CD8, CD56, CD57, CD45RO, CD45RA, CCR7, etc. For example, naive CD8 + Isolation of T cells can be performed by a one-step or two-step procedure. The two-step procedure may comprise a first step in which naive T cells are enriched by depletion of non-naive T cells, and a second step in which the enriched naive T cells are labeled with a CD8 antibody for subsequent CD8 + Naive T cells were positively selected.

[0943] Co-culture of naive T cells and MHC-Ib / E dendritic cells

[0944] In one embodiment, CD8 T cells are stimulated with peptide or antigen-pulsed dendritic cells (e.g., MHC-Ib / E antigen-pulsed tolerogenic dendritic cells) in the presence of a stimulatory agent. + T cells, preferably naive CD8 + T cells, more preferably autologous naive CD8 + T cells. After stimulation, the cells can be washed, for example with PBS, stained with anti-CD8 antibodies, and sorted using MHC-peptide pentamers. Purified CD8 + T cells are enriched and can be used for subsequent activation steps.

[0945] In one embodiment, CD8 + T cells (preferably naive CD8 + T cells, more preferably autologous naive CD8 + In one embodiment, the dendritic cells presenting the MHC-1b / E-restricted peptides are co-cultured with T cells and dendritic cells presenting the MHC-1b / E-restricted peptides.

[0946] In one embodiment, the dendritic cells do not express MHC-1a molecules on their surface. In one embodiment, the dendritic cells express less than 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5% of the MHC-1a molecules on their surface (i.e., relative to all MHC molecules expressed on the surface of the dendritic cells). In one embodiment, the dendritic cells express at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the MHC-Ib molecules on their surface. In one embodiment, the dendritic cells express only MHC-Ib molecules on their surface.

[0947] In one embodiment, the dendritic cells express MHC-II molecules on their surface. In one embodiment, the dendritic cells express MHC-II molecules and MHC-Ib molecules on their surface.

[0948] In one embodiment, CD8 + T cells, preferably naive CD8 + T cells, more preferably autologous naive CD8 + T cells are contacted with tolerogenic dendritic cells as described above. Thus, at the end of the culture, the T cells are inhibitory MHC-1b / E-restricted CD8 + T cells and can induce immune tolerance.

[0949] In one embodiment, the MHC-1b / E-restricted CD8 + T cells are cultured for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days or longer. In one embodiment, the cells used to generate the MHC-1b / E-restricted CD8 T cells of the present invention are cultured for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days or longer. + T cells are cultured for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks or longer. In one embodiment, the cells used to generate the MHC-1b / E-restricted CD8 T cells of the present invention are cultured for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks or longer. + The T cells are cultured for at least 1 month, at least 2 months, at least 3 months, or longer.

[0950] In one embodiment, MHC-Ib / E natural killer cells or MHC-Ib / E EB cells are used in place of MHC-Ib / E dendritic cells to generate autologous MHC-Ib / E-restricted CD8 + T cell population.

[0951] Amplification

[0952] In one embodiment, ex vivo generation of MHC-1b / E-restricted CD8 + T cell populations are generated by flow cytometry isolation based on their ability to bind to specific HLA-E antigens or peptides (eg, specific tetramers).

[0953] In one embodiment, the isolated MHC-1b / E-restricted CD8 T cells thus obtained are cultured in the presence of at least one T cell activator. +T cell populations are expanded ex vivo. Examples of T cell activators include, but are not limited to, those to be completed. Alternatively, other examples of T cell activators that can be used during the expansion process include, but are not limited to, mitogens (e.g., PMA / ionomycin), superantigens, anti-CD3 antibodies, and the like. Preferably, the anti-CD3 monoclonal antibody is coated. In one embodiment, the T cell activator can be used in the presence of feeder cells.

[0954] Feeder cells include, but are not limited to, ΔCD3 cells (T cell-depleted helper cells), irradiated PBMCs, irradiated DCs, artificial APCs (antigen presenting cells), Sf9 cells, insect cells, PBMC pools or B cell pools from different subjects, KCD40L cells, EBV-transformed B cell lines, and EBV-transformed lymphoblastoid cells (LCLs).

[0955] In another embodiment, the isolated MHC-1b / E-restricted CD8 T cells obtained by culturing in the presence of an antigen-specific T cell activator (e.g., anti-CD3 / CD28 antibody, PMA / iono, cytokines, etc.) + In one embodiment, the antigen-specific T cell activator can be used in the presence of the above-mentioned feeder cells.

[0956] In one embodiment, the invention is used to expand the ex vivo MHC-1b / E-restricted CD8 + T cells are cultured for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days or longer. In one embodiment, the method for expanding the ex vivo MHC-1b / E-restricted CD8 T cells of the present invention is as follows: + T cells are cultured for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks or longer. In one embodiment, the method for expanding the ex vivo MHC-1b / E-restricted CD8 T cells of the present invention is as follows: + The T cells are cultured for at least 1 month, at least 2 months, at least 3 months, or longer.

[0957] The final T cell

[0958] Therefore, the present invention also relates to MHC-1b / E-restricted CD8+ T cells obtained or obtainable by the ex vivo method as described above.

[0959] LNPs containing single-chain trimers of HLA-E and pathogen-specific antigens

[0960] According to another embodiment of the present invention, the tolerogenic vaccine is a lipid nanoparticle (LNP) containing or associated with a nucleic acid molecule that is a single-chain trimer of HLA-E and a pathogen-specific antigen or peptide.

[0961] The construct comprising a single-chain trimer of HLA-E and a pathogen-specific antigen or peptide is a nucleic acid molecule, such as a DNA or RNA molecule.

[0962] In some embodiments, the construct comprising a single-chain trimer of HLA-E and a pathogen-specific antigen or peptide comprises or consists of:

[0963] - signal peptide,

[0964] - pathogen-specific antigens or peptides,

[0965] - first connector,

[0966] -β2-microglobulin sequence,

[0967] - a second connector, and

[0968] -HLA-E sequence.

[0969] The signal peptide preferably directs the polypeptide to lysosomes.

[0970] Typically, the signal peptide may have the amino acid sequence of SEQ ID NO: 76 and / or the nucleic acid sequence of SEQ ID NO: 77.

[0971] In some embodiments, the pathogen-specific antigen or peptide is an HIV-derived MHC Ib / E binding antigen having an amino acid sequence selected from the group consisting of: sequence RMYSPVSIL (SEQ ID NO: 1), sequence PEIVIYDYM (SEQ ID NO: 2), sequence TALSEGATP (SEQ ID NO: 3), sequence RIRTWKSLV (SEQ ID NO: 4), sequence VLKYWWNLL (SEQ ID NO: 56) (Env), sequence ILPCRIKQI (SEQ ID NO: 57) (Env), sequence AISPRTLNA (SEQ ID NO: 58) (Gag), and sequence RMYSPTSIL (SEQ ID NO: 63).

[0972] The β2-microglobulin is preferably human β2-microglobulin. Typically, the β2-microglobulin may have the amino acid sequence of SEQ ID NO: 78 and / or the nucleic acid sequence of SEQ ID NO: 79.

[0973] The first and second linkers can be any linkers, preferably flexible linkers. In some embodiments, the first and second linkers are glycine-serine linkers (ie, linkers containing multiple glycine and serine residues), or linkers derived therefrom.

[0974] In some embodiments, the first linker has the amino acid sequence (GGGGS)3 (SEQ ID NO:80) and / or the nucleic acid sequence of SEQ ID NO:81.

[0975] In some embodiments, the second linker has the amino acid sequence (GGGGS)4 (SEQ ID NO:82) and / or the nucleic acid sequence of SEQ ID NO:83.

[0976] In some embodiments, the first linker is a "capture" linker in which glycine is replaced by cysteine, i.e., a glycine-serine linker containing cysteine. For example, the first "capture" linker can have the amino acid sequence of SEQ ID NO: 84 and / or the nucleic acid sequence of SEQ ID NO: 85.

[0977] In some embodiments, the HLA-E is HLAE*01:03.

[0978] In some embodiments, the HLA-E chain has the amino acid sequence of SEQ ID NO:59 and / or the nucleic acid sequence of SEQ ID NO:60.

[0979] In other embodiments, the HLA-E chain comprises a Y84C mutation. Specifically, in some embodiments, the HLA-E chain has the amino acid sequence of SEQ ID NO: 61 and / or the nucleic acid sequence of SEQ ID NO: 62.

[0980] Constructs comprising a single-chain trimer of HLA-E and a pathogen-specific antigen may further comprise a disulfide bond "trap" engineered between the cysteine ​​at position 84 of HLA-E and the cysteine ​​contained in the first linker sequence (between the peptide and β2-microglobulin). In such embodiments, the first linker is a first "trap" linker comprising cysteine, such as a "trap" linker having the amino acid sequence of SEQ ID NO: 84.

[0981] Typical constructs comprising single-chain trimers of HLA-E and pathogen-specific antigens or peptides are described in Yang et al. Sci Immunol. 2021 March 25; 6(57) and WO 2022 / 118030, which are incorporated herein by reference.

[0982] In some embodiments, the construct comprising a single-chain trimer of HLA-E and a pathogen-specific antigen or peptide has an amino acid sequence selected from SEQ ID NOs: 64, 66, 68, 70, 72, and 74.

[0983] In some embodiments, the construct comprising a single-chain trimer of HLA-E and a pathogen-specific antigen or peptide has a nucleic acid sequence selected from SEQ ID NOs: 65, 67, 69, 71, 73, and 75.

[0984] Such constructs comprising a single chain trimer of HLA-E and a pathogen-specific antigen or peptide may be contained in a plasmid.

[0985] Transfection or transduction of this plasmid into cells can cause the HLA-E-antigen complex to be expressed on the cell surface (Yang et al. Sci Immunol. 2021 March 25; 6 (57)).

[0986] Without being bound by any theory, administration of lipid nanoparticles (LNPs) containing or conjugated to nucleic acid molecules of a single-chain trimer of HLA-E and a pathogen-specific antigen or peptide to a subject in need thereof can induce the production of dendritic cells, natural killer cells and / or B cells that present MHC-lb / E-restricted antigens in vivo.

[0987] HIV immunogens for tolerance vaccines

[0988] HIV antigens

[0989] The tolerogenic vaccine is specific for at least one HIV immunogen, which is an HIV antigen as described below.

[0990] When the disease to be prevented or treated is acquired immunodeficiency syndrome (AIDS) or simian immunodeficiency virus (SIV) infection, the tolerogenic vaccine comprises or encodes an antigen derived from HIV or SIV, respectively.

[0991] In one embodiment, the HIV or SIV antigen is selected from any HIV or SIV strain.

[0992] In one embodiment, the HIV antigens described herein are HIV-derived antigens. In one embodiment, the HIV antigens described herein are HIV antigens.

[0993] Due to the huge variation that the HIV genome produces because of mutation, recombination, insertion and / or deletion, HIV has been divided into different groups, subgroups, types, hypotypes and genotypes. Due to the continuous mutation of the HIV genome, there are two HIV large groups (HIV-1 and HIV-2) and many subgroups. The main difference between the group and the subgroup is the viral envelope. HIV-1 is divided into a large group (M), and the M group is divided into at least nine genetically different hypotypes. These hypotypes include A, B, C, D, F, G, H, J and K. In addition, many other hypotypes are also present, and these hypotypes are produced by the above-mentioned hypotypes in vivo recombination (for example CRF). In one embodiment, HIV antigens are relevant to the combination of specific HIV group, subgroup, type, hypotype or several hypotypes.

[0994] In one embodiment, the HIV virus is HIV-1 or HIV-2, preferably HIV-1. In another embodiment, the HIV-1 virus is group M subtype B (HXB2).

[0995] In one embodiment, the HIV antigens described herein are non-infectious.

[0996] In one embodiment, the HIV antigen is an inactivated whole HIV virus.

[0997] As used herein, "inactivated whole HIV" refers to intact HIV particles that have been inactivated and are no longer infectious.

[0998] In one embodiment, the HIV antigen is an autologous HIV antigen. In another embodiment, the HIV antigen is not an autologous HIV antigen. In one embodiment, the HIV antigen is made from an inactivated autologous HIV virus.

[0999] As used herein, "antigens made from inactivated autologous HIV virus" refers to antigens comprising or consisting of HIV virus that infects the human being to be treated, which HIV virus has been suitably inactivated so as to be safe for human administration. Thus, in practice, to prepare the vaccine composition of the present invention, an antigen is obtained from the human being to be treated (more specifically, from the CD4 + HIV is isolated from T cells. The isolated HIV is cultured and inactivated.

[1000] In one embodiment, the HIV antigen is selected from HIV gag, HIV env, HIV rev, HIV tat, HIV nef, HIV pol, and HIV vif.

[1001] In one embodiment, the HIV antigen comprises one or more epitopes of HIV gag, HIV env, HIV rev, HIV tat, HIV nef, HIV pol, and HIV vif proteins.

[1002] In one embodiment, the HIV antigen comprises at least HIV gag and / or HIV pol proteins. Alternatively or additionally, the HIV antigen may comprise one or more proteins encoded by gag, such as capsid protein (p24) and matrix protein (p1), and / or one or more proteins encoded by pol, such as integrase, reverse transcriptase, and protease.

[1003] MHC Ib / E binding antigen

[1004] In one embodiment, the HIV antigen described herein is an MHC Ib / E binding antigen. In one embodiment, the pathogen-specific antigen is an MHC Ib / E binding peptide.

[1005] In one embodiment, the HIV antigen described herein is an HIV or SIV derived MHC Ib / E binding peptide. In one embodiment, the HIV antigen is an HIV or SIV derived MHC Ib / E binding antigen.

[1006] In one embodiment, the HIV-derived MHC Ib / E binding antigen or peptide described herein is selected from SEQ ID NO: 1 to SEQ ID NO: 4, SEQ ID NO: 56 to SEQ ID NO: 58 and SEQ ID NO: 63.

[1007] In one embodiment, the HIV-derived MHC Ib / E binding antigen has the amino acid sequence RMYSPVSIL (SEQ ID NO: 1). In one embodiment, the HIV-derived MHC Ib / E binding antigen has the amino acid sequence PEIVIYDYM (SEQ ID NO: 2). In one embodiment, the HIV-derived MHC Ib / E binding antigen has the amino acid sequence TALSEGATP (SEQ ID NO: 3). In one embodiment, the HIV-derived MHC Ib / E binding antigen has the amino acid sequence RIRTWKSLV (SEQ ID NO: 4). In one embodiment, the HIV-derived MHC Ib / E binding antigen has the amino acid sequence VLKYWWNLL (SEQ ID NO: 56). In one embodiment, the HIV-derived MHC Ib / E binding antigen has the amino acid sequence ILPCRIKQI (SEQ ID NO: 57) (Env). In one embodiment, the HIV-derived MHC Ib / E binding antigen has the amino acid sequence AISPRTLNA (SEQ ID NO: 58) (Gag). In one embodiment, the HIV-derived MHC Ib / E binding antigen has the amino acid sequence RMYSPTSIL (SEQ ID NO: 63).

[1008] In some embodiments, the HIV-derived MHC-II HLA-DR binding antigen has the amino acid sequence QGQMVHQAISPRTLN (SEQ ID NO:7) (Gag p24), GEIYKRWIILGLNKI (SEQ ID NO:8) (Gag p24), KRWIILGLNKIVRMY (SEQ ID NO:9) (Gag p24), FRKYTAFTIPSINNE (SEQ ID NO:10) (Pol RT), PEIVIYDYM (SEQ ID NO:16) (Pol), or RIRTWKSLV (SEQ ID NO:17) (Pol).

[1009] Particle antigen

[1010] In one embodiment, the HIV antigen described herein is a particulate antigen.

[1011] In one embodiment, the HIV antigens described herein can be produced by expression of viral nucleic acid sequences advantageously contained in a suitable recombinant microorganism. In one embodiment, the recombinant microorganism is CMV, preferably a CMV vector as described above. In another embodiment, the recombinant microorganism is a bacterium, preferably a bacterium different from the non-pathogenic bacteria described above.

[1012] In one embodiment, the HIV antigens described herein can be codon-optimized. Many viruses, including HIV and other lentiviruses, use a large number of rare codons. By changing these codons to correspond to codons commonly used in the target subject (e.g., humans), the expression of the antigen can be enhanced. For example, rare codons used in HIV proteins can be mutated to codons that occur frequently in highly expressed human genes (Andre et al. (1998) J Virol 72, 1497-1503).

[1013] In one embodiment, the HIV antigens described herein may be consensus or chimeric antigens containing sequence fragments from different pathogen clades or strains.

[1014] A "consensus sequence" represents the most common amino acid at each position in an alignment of available viral sequences.

[1015] A "mosaic immunogen" can be a recombinant protein sequence derived by computer simulation that is optimized to maximize the potential T cell epitopes based on the diversity of the target population and used in combination for complementation.

[1016] In one embodiment, the particulate antigen described herein is a viral antigen.

[1017] In one embodiment, the particulate antigen is selected from the group consisting of a viral particle, a recombinant viral particle, a virus-like particle, a recombinant viral particle, a polymer particle presenting one or more viral peptides or epitopes on its surface, a conjugate viral protein, and a concatemeric viral protein.

[1018] In one embodiment, the particulate antigens described herein can be one or more viral proteins or peptides, recombinant or non-recombinant, in the form of a conjugate or concatemer.

[1019] Immunogenic apoptotic bodies

[1020] In one embodiment, the HIV antigens described herein are derived from immunogenic apoptotic bodies of infected cells or from tissue lysates.

[1021] Infected cells can be derived from a tissue biopsy or from expansion of circulating infected cells.

[1022] For example, immunogenic apoptotic bodies can be obtained from infected cells by releasing apoptotic bodies from infected cells treated with anthracyclines (including doxorubicin, daunorubicin, idarubicin, and mitoxantrone), oxaliplatin, UVC, UVB, or gamma-irradiation.

[1023] Examples of tissue lysates include, but are not limited to, lymph node, synovial fluid, or inflammatory tissue lysates.

[1024] In one embodiment, the immunogenic agent is a CD4 + T cells acquired.

[1025] In some embodiments, the tolerogenic vaccine comprises or consists of Ad26.Mos4.HIV, Ad26.Mos.HIV, ChAdOx1.tHIVconsv1, MVA.tHIVconsv3, MVA.tHIVconsv4, ChAdV63.HIVconsv, and / or MVA.HIVconsv.

[1026] Effector vaccines

[1027] In one embodiment, the effector vaccine is a prophylactic vaccine. In another embodiment, the effector vaccine is a therapeutic vaccine. As used herein, a therapeutic vaccine can be a prophylactic vaccine or a therapeutic vaccine. In some embodiments, the effector vaccine is a prophylactic vaccine. In other embodiments, the effector vaccine is a therapeutic vaccine.

[1028] In one embodiment, the effector vaccine induces an immune response against at least one HIV-associated immunogen. In one embodiment, the effector vaccine is therefore specific for at least one HIV immunogen.

[1029] In some embodiments, an effector vaccine comprising at least one HIV immunogen lyses infected CD4+ cells that express at least one HIV peptide under HLA-Ia (A, B, C) restriction.

[1030] In some embodiments, the effector vaccine comprising at least one HIV immunogen induces broadly neutralizing antibodies (bnAbs) and / or CD8 cytotoxic T cells.

[1031] HIV immunogens for effector vaccines

[1032] Effector vaccines are specific for at least one HIV immunogen.

[1033] When the disease to be prevented or treated is acquired immunodeficiency syndrome (AIDS) or simian immunodeficiency virus (SIV) infection, the effector vaccine comprises or encodes an immunogen derived from HIV or SIV, respectively.

[1034] In one embodiment, the HIV or SIV immunogen is selected from any HIV or SIV strain.

[1035] In one embodiment, the HIV immunogen described herein is an HIV-derived immunogen. In one embodiment, the HIV immunogen described herein is an HIV immunogen.

[1036] Because the HIV genome has huge variation due to mutation, recombination, insertion and / or deletion, HIV is divided into different groups, subgroups, types, hypotypes and genotypes. Because the HIV genome constantly mutates, there are two HIV large groups (HIV-1 and HIV-2) and many subgroups. The main difference between the group and the subgroup is the viral envelope. HIV-1 is divided into a large group (M group), and the M group is divided into at least nine genetically different hypotypes. These hypotypes include A, B, C, D, F, G, H, J and K. In addition, many other hypotypes are produced by the recombination of above-mentioned hypotypes in vivo (for example CRF). In one embodiment, the HIV immunogen is relevant to the combination of specific HIV group, subgroup, type, hypotype or several hypotypes.

[1037] In one embodiment, the HIV virus is HIV-1 or HIV-2, preferably HIV- 1. In another embodiment, the HIV-1 virus is from group M subtype B (HXB2).

[1038] In one embodiment, the HIV immunogens described herein are non-infectious. In one embodiment, the HIV immunogen is an inactivated whole HIV virus.

[1039] In one embodiment, the HIV immunogen is an autologous HIV immunogen. In another embodiment, the HIV immunogen is not an autologous HIV immunogen.

[1040] In one embodiment, the HIV immunogen comprises one or more epitopes of HIV gag, HIV env, HIV rev, HIV tat, HIV nef, HIV pol, and HIV vif proteins.

[1041] In one embodiment, the HIV immunogen comprises at least HIV gag and / or HIV pol proteins. Alternatively or additionally, the immunogen derived from the HIV virus may comprise one or more proteins encoded by gag, such as capsid protein (p24) and matrix protein (p1), and / or one or more proteins encoded by pol, such as integrase, reverse transcriptase, and protease.

[1042] In some embodiments, the HIV immunogen comprises or consists of one or more proteins encoded by env, such as gp120, gp140, gp160, or epitopes thereof.

[1043] In some embodiments, the at least one HIV immunogen is a Tat toxoid as described in patent application WO03013593, which is incorporated herein by reference.

[1044] Preferably, the HIV immunogen is a naturally occurring protein.

[1045] In some embodiments, the HIV immunogen comprises a combination of naturally occurring sequences of one or more HIV proteins.

[1046] Preferably, the HIV immunogen comprises several peptides, antigens or epitopes derived from different HIV strains.

[1047] In some embodiments, the HIV immunogen comprises a conserved element or region of HIV. Preferably, the HIV immunogen comprises a plurality of HIV conserved epitopes. In some embodiments, the HIV immunogen comprises a chimera of HIV conserved epitopes.

[1048] In some embodiments, the HIV immunogen comprises at least one consensus sequence or region of HIV. "Consensus sequence" refers to the most common amino acid at each position in an alignment of available viral sequences. Preferably, the HIV immunogen comprises multiple HIV consensus sequences or epitopes.

[1049] In some embodiments, the HIV immunogen comprises at least one chimeric immunogen. A "chimeric immunogen" can be, for example, a computer-generated recombinant protein sequence that has been optimized to maximize the potential T cell epitopes based on the diversity of the target population and used in combination for complementarity.

[1050] Preferably, the HIV immunogen comprises at least one chimeric immunogen comprising sequences derived from different HIV subtypes, clades, or strains. More preferably, the HIV immunogen comprises a plurality of HIV protein, peptide, or epitope sequences, each sequence derived from a different HIV subtype, clade, or strain. Examples of HIV chimeric immunogens are described further below.

[1051] Aelix's chimeric immunogen

[1052] In some embodiments, the HIV chimeric immunogen is a polypeptide comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 fragments derived from the HIV-1 genome, wherein the fragments are selected from SEQ ID NO: 18 to SEQ ID NO: 33 and variants thereof that are at least 85%, 90% or 95% identical to the sequences of SEQ ID NO: 18 to SEQ ID NO: 33.

[1053]

[1054]

[1055] In some embodiments, the HIV immunogen is a polypeptide comprising the sequence of SEQ ID NO: 18 to SEQ ID NO:33.

[1056] In some embodiments, the fragments derived from the HIV-1 genome selected from SEQ ID NO: 18 to SEQ ID NO: 33 and variants thereof are linked by a triple alanine linker within the HIV immunogen.

[1057] Chimeric immunogens from the University of Oxford

[1058] In other embodiments, the HIV immunogen is a chimeric conserved region polypeptide of an HIV protein.

[1059] Exemplary amino acid sequences of HIV protein chimeric conserved region polypeptides include SEQ ID NOs: 34 to 51. In some examples, the chimeric conserved region polypeptide comprises, consists essentially of, or consists of an amino acid sequence that is at least 85%, 90%, or 95% identical to the amino acid sequence set forth in one of SEQ ID NOs: 34-51.

[1060] In some embodiments, the immunogenic polypeptide comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) of the disclosed chimeric conserved region polypeptides (e.g., one or more of SEQ ID NOs: 34-51). In some examples, two or more chimeric conserved region polypeptides are linked to form a single immunogenic polypeptide (e.g., a chimeric or fusion polypeptide).

[1061] In a specific example, the two or more linked chimeric conserved region polypeptides comprise two or more (e.g., 2, 3, 4, 5, 6, 7, 8) of SEQ ID NOs: 34-41 or sequences that are at least 85%, 90%, or 95% identical to any one of SEQ ID NOs: 34-41. In one example, the immunogenic polypeptide comprises an amino acid sequence comprising, consisting essentially of, or consisting of the entire sequence of SEQ ID NOs: 34-41. In another specific example, the two or more linked conserved region polypeptides comprise two or more (e.g., 2, 3, 4, 5, 6, or 7) of SEQ ID NOs: 34, 35, 36, 39, 40, 41, and 50 or sequences that are at least 85%, 90%, or 95% identical to any one of SEQ ID NOs: 34, 35, 36, 39, 40, 41, and 50. In one example, the immunogenic polypeptide comprises an amino acid sequence comprising, consisting essentially of, or consisting of SEQ ID NOs: 34, 35, 36, 39, 40, 41, and 50. In another example, the two or more linked conserved region polypeptides comprise two or more (e.g., 2, 3, 4, 5, 6, or 7) of SEQ ID NOs: 35, 36, 39, 40, 41, and 50, for example, an immunogenic polypeptide comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NOs: 35, 36, 38, 39, 40, 41, and 50.

[1062] In other specific examples, the two or more conserved region polypeptides connected comprise two or more (e.g., 2, 3, 4, 5, 6, 7, or 8) sequences of SEQ ID NOs: 42-49 or sequences having at least 85%, 90%, or 95% identity to any one of SEQ ID NOs: 42-49. In one example, the immunogenic polypeptide comprises the entire sequence of SEQ ID NOs: 34-42. In another specific example, the two or more conserved regions connected comprise two or more (e.g., 2, 3, 4, 5, 6, or 7) of SEQ ID NOs: 42, 43, 44, 47, 48, 49, and 51. In one example, the immunogenic polypeptide comprises an amino acid sequence comprising, consisting essentially of, or consisting of: the entire sequence of SEQ ID NOs: 42, 43, 44, 47, 48, 49, and 51. In another example, the two or more linked conserved region polypeptides comprise two or more (e.g., 2, 3, 4, 5, or 6) of SEQ ID NOs: 43, 44, 47, 48, 49, and 51, for example, comprise an immunogenic polypeptide comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NOs: 43, 44, 47, 48, 49, and 51.

[1063] In some embodiments, the disclosed immunogenic polypeptides comprise one or more peptide linkers, for example, for connecting two or more conserved region polypeptides to one polypeptide chain. The linker peptide is typically a shorter amino acid sequence that provides a flexible linker to allow polypeptides (e.g., conserved region polypeptides) to be connected without destroying the structure, aggregation (e.g., multimerization) or activity of the polypeptide components. Typically, the linear connecting peptide consists of 2 to 25 amino acids. Typically, the linear connecting peptide is 2 to 15 amino acids long, but in some cases there may be only one, such as a single glycine residue. In one example, the linker polypeptide is 2 to 3 amino acids long, such as one serine and one arginine, or two serine residues and one arginine residue, or two arginine residues and one serine residue, two glycines and one serine, two serines and one glycine, or any combination thereof.

[1064] In some embodiments, the conserved region polypeptides are included in a chimeric or fusion polypeptide (immunogenic polypeptide) in a selected order. In some examples, the order of the conserved region polypeptides is selected to minimize the immune response to the non-naturally occurring peptide linkages in the fusion polypeptide.

[1065] The immunogenic polypeptides disclosed herein can be chemically synthesized by standard methods, or recombinantly produced, for example, by expressing the polypeptide from a nucleic acid molecule encoding the polypeptide. They can also be isolated by methods such as preparative chromatography and immunoseparation.

[1066] Janssen's chimeric immunogen

[1067] In other embodiments, the HIV chimeric immunogen comprises at least two recombinant adenovirus 26 (Ad26) vectors, each vector expressing a different HIV antigen or combination of HIV antigens.

[1068] In some embodiments, the HIV immunogen is an Ad26.Mos4.HIV vaccine, which comprises four recombinant Ad26 vectors, each vector expressing a different HIV antigen or combination of HIV antigens, specifically Ad26.Mos1.Gag-Pol (an Ad26 vector encoding a chimeric Gag-Pol fusion protein having SEQ ID NO: 52), Ad26.Mos2.Gag-Pol (an Ad26 vector encoding a chimeric Gag-Pol fusion protein having SEQ ID NO: 53), Ad26.Mos1.Env (an Ad26 vector encoding a chimeric Env protein having SEQ ID NO: 54), and Ad26.Mos2S.Env (an Ad26 vector encoding a chimeric Env protein having SEQ ID NO: 55).

[1069] In some embodiments, the HIV immunogen comprises at least 2, 3, or 4 recombinant Ad26 vectors, each vector expressing a different HIV antigen or combination of HIV antigens selected from SEQ ID NOs: 52-55 and variants thereof that are at least 85%, 90%, or 95% identical to the sequences of SEQ ID NOs: 52-55.

[1070] Types of effector vaccines

[1071] In some embodiments, the effector vaccine is:

[1072] - protein-based vaccines,

[1073] -DNA-based vaccines

[1074] - RNA-based vaccines, and / or

[1075] - A passive vaccine containing broadly neutralizing anti-HIV antibodies.

[1076] Protein-based vaccines

[1077] In some embodiments, the effector vaccine comprising at least one HIV immunogen is a protein-based vaccine comprising at least one HIV-derived protein, peptide, or epitope.

[1078] Preferably, the HIV immunogen is a native-like protein (NLP) having the native protein conformation.

[1079] In some embodiments, the HIV immunogen is a stabilized recombinant protein.

[1080] For example, when the HIV immunogen is derived from Env, the HIV immunogen can be a stabilized recombinant Env gp140 trimer that mimics the conformation of the native Env trimer. One approach involves stabilizing the gp120-gp41 interaction through intermolecular disulfide bonds (SOS gp140), preferably modified by replacing isoleucine with proline (I559P) to improve trimerization (SOSIP gp140).

[1081] In some embodiments, the HIV immunogen is a single-chain gp140. This single-chain gp140 can be designed to make the Env protein independent of cleavage, for example, by replacing the cleavage site between gp120 and gp41 with a glycine / serine linker. Another strategy similar to the design of single-chain gp140 is to replace the cleavage site with a flexible glycine / serine linker (G4S), thereby generating an Env mimetic that is independent of cleavage, called a natural flexible linker (NFL) trimer. Alternatively, the cleavage site can be replaced with a long linker to generate an uncut pre-fusion optimized (UFO) trimer, which has a natural conformation similar to the SOSIP trimer.

[1082] For example, when the HIV immunogen is derived from Env, the HIV immunogen can be an Env gp160 trimer, a stabilized Env gp160 trimer, a stabilized Env gp140 trimer (SOS gp140 or SOSIP gp140), a stabilized Env single-chain gp140 trimer, or a stabilized native flexible linker (NFL) Env gp140 trimer.

[1083] Preferably, the HIV immunogen comprises multiple proteins, peptides, antigens or epitopes derived from different HIV strains.For example, the HIV immunogen may be a chimeric polypeptide or immunogen as described above.

[1084] In some embodiments, the HIV immunogen is a chimeric immunogen comprising Gag, Pol, and Env proteins, peptides, or epitopes.

[1085] In some embodiments, the at least one HIV immunogen is in a soluble form.

[1086] In some embodiments, the at least one HIV immunogen is displayed on the surface of a nanoparticle, such as a virus-like particle (VLP).

[1087] Non-limiting examples of effector vaccines that are protein-based vaccines comprising HIV gpl20 immunogens include AIDSVAX B / E, CH505TF, CH505w53, CH505w78, CH505 M5, IHV01, or A244.

[1088] AIDSVAX B / E is a bivalent HIV gp120 glycoprotein containing both subtype B (MN) and subtype E (A244) proteins.

[1089] IHV01 is a full-length single-chain (FLSC) gp120-CD4 chimeric subunit HIV-1.

[1090] A244 is the gp120 envelope glycoprotein HIV-1 subtype CRF_01AE A244.

[1091] Non-limiting examples of effector vaccines that are protein-based vaccines comprising an HIV gpl40 immunogen include CN54gpl40, clade C gpl40, chimeric gpl40, HIV type 1 clade C glycoprotein 140, BG505SOSIP.664gpl40, ConM SOSIP, chimeric SOSIP, EDC ConM SOSIP, ConS UFO, EDC ConS UFO, BG505 SOSIP.664gpl40, BG505 SOSIP.GT1.1, gpl45 C.6980, or CD40.HIVRI.Env.

[1092] CN54gp140 is an HIV-1 envelope protein from the clade C strain 97 / CN / 54 isolate.

[1093] CD40.HIVRI.Env is an adjuvanted anti-CD40 mAb fused to Env gp140 HIV clade C ZM-96.

[1094] Other non-limiting examples of protein-based vaccines where the effector vaccine is a trimer-containing HIV immunogen include VRC-HIVRGP096-00-VP (Trimer 4571), ConM SOSIP.v7, CH505 TF chTrimer, or Trimer4571.

[1095] In some embodiments, the effector vaccine comprises or consists of AIDSVAX B / E, CN54 gp140, Clade C gp140, Chimeric gp140, HIV Type 1 Clade C Glycoprotein 140, CH505 TF, CH505w53, CH505w78, CH505 M5, BG505 SOSIP.664 gp140, VRC-HIVRGP096-00-VP (Trimer 4571), ConM SOSIP.v7, ConM SOSIP, Chimeric SOSIP, EDC ConM SOSIP, ConS UFO, EDC ConS UFO, BG505 SOSIP.664 gp140, BG505 SOSIP.GT1.1, IHV01, A244, gp145 C.6980, CD40.HIVRI.Env, CH505 TF chTrimer and / or Trimer 4571.

[1096] RNA-based vaccines

[1097] In some embodiments, the effector vaccine is an RNA-based vaccine comprising at least one RNA sequence encoding at least one HIV-derived protein, peptide, or epitope.

[1098] In some embodiments, the at least one RNA is mRNA.

[1099] Chemical and structural modifications can be made to mRNA to protect it from degradation and facilitate cellular uptake, such as the addition of carrier molecules, including lipid nanoparticles (LNPs).

[1100] In some embodiments, the effector vaccine is an RNA-based vaccine comprising at least one RNA sequence carried by a lipid nanoparticle (LNP).

[1101] Upon administration to a subject, the at least one RNA sequence is capable of synthesizing at least one HIV-derived protein, peptide, antigen or epitope. Preferably, the synthesized protein, peptide or antigen is a native-like protein, such as a trimeric Env protein.

[1102] In some embodiments, the HIV immunogen synthesized from at least one RNA sequence is a chimeric immunogen as described above. In some embodiments, the HIV immunogen synthesized from at least one RNA sequence is a chimeric immunogen comprising Gag, Pol, and Env proteins, peptides, or epitopes.

[1103] Non-limiting examples of effector vaccines of RNA-based vaccines include BG505 MD39.3, BG505 MD39.3gp151, BG505 MD39.3 gp151 CD4KO, eOD-GT8 60mer mRNA vaccine (mRNA-1644), Core-g28v2 60mer mRNA vaccine (mRNA-1644v2-Core), HIVA N01.3, or HTI (HIVACAT).

[1104] In some embodiments, the effector vaccine comprises or consists of BG505 MD39.3, BG505MD39.3 gpl51, BG505 MD39.3 gpl51 CD4KO, eOD-GT8 60mer mRNA vaccine (mRNA-1644), Core-g28v2 60mer mRNA vaccine (mRNA-1644v2-Core), HIVA N01.3, or HTI (HIVACAT).

[1105] DNA-based vaccines

[1106] In some embodiments, the effector vaccine is a DNA-based vaccine encoding at least one HIV-derived protein, peptide, or epitope.

[1107] In some embodiments, the effector vaccine is a DNA-based vaccine comprising a plasmid.

[1108] Non-limiting examples of effector vaccines that are plasmid-containing DNA-based vaccines include DNA-HIV-PT123, Env (A, B, C, A / E) / gag (C) DNA vaccine, Env-C plasmid DNA, DNA-HIV-PT123 HIV-1 vaccine, p24CE, p55gag, or HIVIS DNA.

[1109] DNA-HIV-PT123 is a 3-plasmid DNA vaccine encoding clade C ZM96 Gag, clade C ZM96Env and CN54 Pol-Nef.

[1110] The Env(A,B,C,A / E) / gag(C) DNA vaccine is a multivalent DNA vaccine that encodes Env from HIV-1 clades A, B, C, and A / E, and clade C Gag.

[1111] The DNA-HIV-PT123 HIV-1 vaccine is a DNA vaccine encoding clade C ZM96 Gag, clade CZM96 Env, and CN54 Pol-Nef.

[1112] In some embodiments, the effector vaccine is a DNA-based vaccine comprising a non-replicating viral vector.

[1113] The non-replicating viral vector can be an adenovirus (Ad), such as Ad5, or other serotypes with lower seroprevalence, such as Ad26 or Ad35, or a chimeric form of an adenovirus, such as Ad5H3, or a chimpanzee-adenovirus vector.

[1114] In some embodiments, the non-replicating viral vector is an Ad26, Ad35, Ad5H3, or chimpanzee-adenovirus vector.

[1115] Non-limiting examples of effector vaccines that are DNA-based vaccines comprising an adenoviral vector include Ad4-Env145NFL, Ad4-Env150KN, AdC6-HIVgpl40, or AdC7-HIVgpl40.

[1116] In some embodiments, the viral vector is a poxvirus vector, such as an orthopoxvirus, avipoxvirus, NYVAC, ALVAC (canarypox), TROVAC (fowlpox virus), or a vaccinia virus, such as modified vaccinia virus Ankara (MVA).

[1117] In some embodiments, the viral vector is a recombinant Modified Vaccinia Ankara (MVA) vector.

[1118] Non-limiting examples of effector vaccines that are DNA-based vaccines comprising an MVA vector include MVA-CMDR, MVA HIV-B, MVA-B NHIV, MVA / HIV62B, or MVA-CMDR.

[1119] MVA-CMDR is a non-replicating, highly attenuated vaccinia virus strain that has been genetically engineered to express the HIV-1 genes env gp160 CM235 subtype E and gag and pol CM240 subtype A (integrase deleted, reverse transcriptase non-functional).

[1120] MVA-BNHIV is a monovalent vaccine containing a single modified vaccinia Ankara vector (Bavarian Nordic, ), which encodes Mos1.Env, Mos2S.Env, Mos1.Gag-Pol and Mos2.Gag-Pol HIV-1.

[1121] In some embodiments, the effector vaccine is a DNA-based vaccine comprising a replicating viral vector.

[1122] In some embodiments, the effector vaccine is a DNA-based vaccine comprising a replicating recombinant cytomegalovirus (CMV) vector.

[1123] Non-limiting examples of effector vaccines that are DNA-based vaccines comprising a CMV vector include VIR-1111.

[1124] Other non-replicating viral vectors can also be used, such as pox vectors, canarypox vectors, alphavirus vectors, adeno-associated virus vectors...

[1125] Other examples of effector vaccines that are DNA-based vaccines comprising viral vectors include ALVAC-HIV (vCP1521) (canarypox vector), DREP-HIV-PT1 (alphavirus-based DNA replicon), EBT-101 (adeno-associated virus serotype 9 (AAV9) vector).

[1126] ALVAC-HIV (vCP1521) is a canarypox vector that encodes the protease-encoding portion of the HIV-1 CRF01_AE Env, clade B Gag, and Pol proteins.

[1127] DREP-HIV-PT1 is an alphavirus-based DNA replicon in which the sequences encoding the viral capsid and envelope have been replaced by sequences encoding HIV-1 gp140.

[1128] AdC6-HIVgpl40 and AdC7-HIVgpl40 are chimpanzee adenoviral vectors encoding clade C gpl40 (GLA emulsion).

[1129] EBT-101 is an HIV-1-specific clustered regularly interspaced short palindromic repeats (CRISPR) / Cas9 gene editing system delivered by an adeno-associated virus serotype 9 (AAV9) vector.

[1130] In some embodiments, the effector vaccine is a DNA-based vaccine comprising a sequence encoding at least one HIV-derived protein, peptide, or epitope.

[1131] Once administered to a subject, the sequence encoding at least one HIV-derived protein, peptide or epitope is capable of synthesizing at least one HIV-derived protein, peptide, antigen or epitope. Preferably, the synthesized protein, peptide or antigen is a native-like protein, such as a trimeric Env protein.

[1132] For example, the effector vaccines DREP-HIV-PT1, AdC6-HIVgp140, and AdC7-HIVgp140 contain sequences encoding HIV-1 gp140.

[1133] In some embodiments, the DNA-based vaccine comprises sequences of multiple (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) HIV-derived proteins, peptides, or epitopes. For example, a DNA-based vaccine can comprise sequences of gag, pol, and env epitopes.

[1134] Non-limiting examples of effector vaccines that are DNA-based vaccines that contain sequences of multiple HIV-derived proteins, peptides, or epitopes include, for example, DNA-HIV-PT123, MVA-CMDR, ALVAC-HIV (vCP1521), Env (A, B, C, A / E) / gag (C) DNA vaccine, DNA-HIV-PT123 HIV-1 vaccine, or MVA-BNHIV.

[1135] In some embodiments, the effector vaccine comprises or consists of DNA-HIV-PT123, MVA-CMDR, ALVAC-HIV (vCP1521), VIR-1111, Env (A, B, C, A / E) / gag (C) DNA vaccine, Ad4-Env145NFL, Ad4-Env150KN, Env-C plasmid DNA, DNA-HIV-PT123 HIV-1 vaccine, DREP-HIV-PT1, AdC6-HIVgp140, AdC7-HIVgp140, MVA HIV-B, MVA-BNHIV, p24CE, p55gag, MVA / HIV62B, HIVISDNA, MVA-CMDR and / or EBT-101.

[1136] In some embodiments, the DNA-based vaccine comprises at least one chimeric immunogen sequence as described above. In some embodiments, the chimeric immunogen comprises gag, pol, and / or env sequences.

[1137] Non-limiting examples of effector vaccines that are DNA-based vaccines comprising at least one chimeric immunogenic sequence include, for example, Ad26.Mos4.HIV, MVA chimeric gpl40 protein, Ad26.Mos.HIV, ChAdOx1.tHIVconsv1, ChAdOx1-HTI, MVA-HTI, MVA.tHIVconsv3, MVA.tHIVconsv4, ChAdV63.HIVconsv, or MVA.HIVconsv.

[1138] In some embodiments, the effector vaccine is a DNA-based vaccine comprising an adenoviral vector and at least one chimeric immunogenic sequence, wherein the effector vaccine comprises or consists of Ad26.Mos4.HIV, Ad26.Mos.HIV, ChAdOx1.tHIVconsv1, ChAdOx1-HTI and / or ChAdV63.HIVconsv.

[1139] Ad26.Mos4.HIV is an adenoviral vector Ad26 that encodes four chimeric Env, Gag, and Pol antigens: Mos1.Gag-Pol, Ad26.Mos2.Gag-Pol, Ad26.Mos1.Env, and Ad26.Mos2S.Env.

[1140] Ad26.Mos.HIV is an adenoviral vector Ad26 that encodes three chimeric Env, Gag, and Pol antigens: Ad26.Mos.1.Env, Ad26.Mos1.Gag-Pol, and Ad26.Mos2.Gag-Pol.

[1141] ChAdOx1-HTI is a chimpanzee adenovirus vector encoding the HIVACAT T cell immunogen (HTI).

[1142] In some embodiments, the effector vaccine is a DNA-based vaccine comprising an MVA vector and at least one chimeric immunogenic sequence, wherein the effector vaccine comprises or consists of: an MVA chimeric gpl40 protein, MVA-HTI, MVA.tHIVconsv3, MVA.tHIVconsv4, and / or MVA.HIVconsv.

[1143] MVA chimeric gp140 protein is a recombinant live attenuated MVA virus vector vaccine that has been genetically engineered to express two chimeric Gag, Pol and Env sequences.

[1144] MVA-HTI is an MVA vector encoding HIVA T cell immunogen (HTI).

[1145] In some embodiments, the effector vaccine comprises or consists of Ad26.Mos4.HIV, MVA chimeric gpl40 protein, Ad26.Mos.HIV, ChAdOx1.tHIVconsv1, ChAdOx1-HTI, MVA-HTI, MVA.tHIVconsv3, MVA.tHIVconsv4, ChAdV63.HIVconsv, and / or MVA.HIVconsv.

[1146] In some embodiments, the effector vaccine comprises or consists of Ad26.Mos4.HIV and MVA-BNHIV.

[1147] In some embodiments, the effector vaccine comprises or consists of ChAdOx1.tHIVconsv1, MVA.tHIVconsv3, and MVA.tHIVconsv4.

[1148] In some embodiments, the effector vaccine comprises or consists of: ChAdOx1.HTI and MVA.HTI.

[1149] Broadly neutralizing anti-HIV antibodies

[1150] In some embodiments, the effector vaccine is a passive vaccine comprising at least one broadly neutralizing anti-HIV antibody.

[1151] Broadly neutralizing antibodies (bnAbs) can be isolated from HIV seropositive subjects. Broadly neutralizing antibodies have the potential to provide complete protection against HIV infection. In particular, broadly neutralizing antibodies can broadly protect against heterologous HIV-1 strains.

[1152] Broadly neutralizing anti-HIV antibodies may bind to one or more epitopes in, for example, the CDR2 domain of the viral CD4 receptor, the CD4 binding site, gp41, gpl20, the V1V2 region of the HIV-1 envelope, or the V3 glycan.

[1153] Non-limiting examples of broadly neutralizing anti-HIV antibodies include UB-421 (semzuvolimab), 10E8.4 / iMab, VRC07, CAP256V2LS, VRC07-523LS, PGT121, VH3810109 (also known as GSK3810109 or N6-LS), PGT121.414.LS, PGDM1400LS, PGDM1400, 3BNC117-LS-J, 3BNC117-LS, 3BNC117, 10-1074-LS-J, 10-1074-LS, 10-1074, SAR441236, ipavirizumab, VRC01, or VRC01-LS.

[1154] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the CDR2 domain of the viral CD4 receptor include UB-421 (semzuvolimab).

[1155] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the CD4 binding site include VRC07, VRC07-523LS, 3BNC117-LS-J, 3BNC117-LS, 3BNC117, SAR441236, VRC01, or VRC01-LS.

[1156] Non-limiting examples of broadly neutralizing anti-HIV antibodies targeting gp41 include 10E8.4 / iMab.

[1157] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target gpl20 include VH3810109 (also known as GSK3810109 or N6-LS).

[1158] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the V1V2 region of the HIV-1 envelope include CAP256V2LS, PGDM1400LS, PGDM1400, SAR441236.

[1159] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the V3 glycan include PGT121, PGT121.414.LS, 10-1074-LS-J, 10-1074-LS, 10-1074, and ipavirizumab.

[1160] Preferably, the effector vaccine comprising at least one broadly neutralizing anti-HIV antibody comprises at least two or more different broadly neutralizing anti-HIV antibodies.

[1161] Preferably, the at least one broadly neutralizing anti-HIV antibody is a combination of 2, 3, 4, 5, 6, 7, 8, 9 or 10 broadly neutralizing anti-HIV antibodies.

[1162] When a combination of multiple broadly neutralizing anti-HIV antibodies is used, at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 broadly neutralizing anti-HIV antibodies preferably bind to different epitopes, more preferably bind to different targets selected from the group consisting of the CDR2 domain of the viral CD4 receptor, the CD4 binding site, gp41, gp120, the V1V2 region of the HIV-1 envelope and the V3 glycan.

[1163] In some embodiments, the at least one broadly neutralizing anti-HIV antibody targets the CD4 binding site and the V1V2 region of the HIV-1 envelope. For example, the at least one broadly neutralizing anti-HIV antibody can be SAR441236.

[1164] In some embodiments, the at least one broadly neutralizing anti-HIV antibody targets the CD4 binding site, the V1V2 region and the V3 glycan of the HIV-1 envelope. For example, the at least one broadly neutralizing anti-HIV antibody can be PGDM1400LS or PGDM1400.

[1165] In some embodiments, the at least one broadly neutralizing anti-HIV antibody is a combination of antibodies selected from:

[1166] -3BNC117-LS and 10-1074-LS;

[1167] -3BNC117-LS-J and 10-1074-LS-J;

[1168] -PGT121.414.LS and VRC07-523LS;

[1169] -PGT121, PGDM1400, and VRC07-523LS;

[1170] -PGDM1400LS, VRC07-523LS, and PGT121.414.LS; and

[1171] -CAP256V2LS, VRC07-523LS, and PGT121.

[1172] In one embodiment, the at least one broadly neutralizing anti-HIV antibody is a combination of PGT121, PGDM1400, and VRC07-523LS.

[1173] In other embodiments, the effector vaccine comprises a viral vector comprising a nucleic acid sequence encoding at least one broadly neutralizing anti-HIV antibody.

[1174] An illustrative example of an effector vaccine includes a viral vector comprising a nucleic acid sequence encoding at least one broadly neutralizing anti-HIV antibody, namely AAV8-VRC07, which is an adeno-associated virus (AAV) encoding the VRC07 antibody.

[1175] In some embodiments, the effector vaccine comprises or consists of AAV8-VRC07.

[1176] Overview

[1177] In some embodiments, the effector vaccine comprising at least one HIV immunogen comprises:

[1178] - a protein-based vaccine comprising at least one HIV-derived trimeric protein, peptide or epitope,

[1179] - A DNA-based vaccine comprising:

[1180] a) non-replicating viral vectors, such as adenovirus, or live attenuated viral vectors, such as CMV, and

[1181] b) at least one DNA sequence encoding at least one HIV-derived protein, peptide or epitope, or at least one DNA sequence encoding at least one antigen-binding fragment of a broadly neutralizing anti-HIV antibody, or at least one DNA sequence encoding a chimeric immunogen,

[1182] - RNA-based vaccines comprising at least one RNA sequence encoding at least one HIV-derived trimeric protein, polypeptide or peptide, and / or

[1183] - A passive vaccine containing at least one broadly neutralizing anti-HIV antibody.

[1184] In some embodiments, the effector vaccine comprising at least one HIV immunogen further comprises at least one MHC Ib / E binding antigen, protein, peptide or epitope. In these embodiments, the effector vaccine and the tolerogenic vaccine can be the same molecule, compound, combination or composition.

[1185] For example, the effector vaccine and the tolerizing vaccine may both comprise or consist of Ad26.Mos4.HIV, Ad26.Mos.HIV, ChAdOx1.tHIVconsv1, MVA.tHIVconsv3, MVA.tHIVconsv4, ChAdV63.HIVconsv and / or MVA.HIVconsv.

[1186] Composition / pharmaceutical composition / vaccine / drug

[1187] The present invention also relates to a composite vaccine comprising:

[1188] a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[1189] b) an effector vaccine comprising at least one HIV immunogen, and

[1190] c) Optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon.

[1191] In some embodiments, the agents of the complex vaccine are included in the composition.

[1192] In some embodiments, the composition consists essentially of the agent.

[1193] As used herein, "consisting essentially of an agent," with respect to a composition, means that the agent is the only therapeutic or biologically active agent in the composition.

[1194] In some embodiments, the composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.

[1195] As used herein, "excipient" refers to any or all conventional solvents, dispersion media, fillers, solid carriers, aqueous solutions, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. Generally, the nature of the excipient depends on the specific mode of administration employed. For example, parenteral formulations typically contain injectable liquids, including pharmaceutically and physiologically acceptable liquids such as water, physiological saline, balanced salt solutions, aqueous glucose solutions, glycerol, and the like as vehicles. For solid compositions (e.g., powders, pills, tablets, or capsules), conventional non-toxic solid carriers may include, for example, pharmaceutical grade mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, the pharmaceutical composition to be administered may also contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, preservatives, and pH buffers, such as sodium acetate or sorbitan monolaurate. For human administration, the formulation should meet the sterility, pyrogenicity, general safety, and purity standards required by regulatory agencies (e.g., FDA Office or EMA). In some embodiments, the excipient is an adjuvant, stabilizer, emulsifier, thickener, preservative, antibiotic, organic or inorganic acid or salt thereof, sugar, alcohol, antioxidant, diluent, solvent, filler, binder, adsorbent, buffer, chelating agent, lubricant, colorant or any other component.

[1196] "Pharmaceutically acceptable" means that the ingredients of the pharmaceutical composition are compatible with each other and will not cause harm to the subject to which it is administered. Examples of pharmaceutically acceptable excipients include, but are not limited to, water, saline, phosphate-buffered saline, glucose, glycerol, ethanol, etc., or combinations thereof.

[1197] Pharmaceutically acceptable excipients that can be used in the pharmaceutical combinations of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (e.g., sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[1198] Adjuvants that can be used in the pharmaceutical combinations of the present invention, in particular effector vaccines and / or tolerance vaccines, include, but are not limited to, aluminum hydroxide gel suspension; MPLA-L; aluminum phosphate; GLA-SE; AS01B; alum; MPLA liposomes; alum and 3M-052-AF; aluminum phosphate and ALFQ; AHFG and ALFQ; rehydragel; ALF43; dmLT; hiltonol; or a suspension of alum, imidazoquinoline and aluminum hydroxide.

[1199] Optionally, in some embodiments, the combination vaccine further comprises a Toll-like receptor agonist, such as a TLR4 agonist, a TLR7 agonist, or a TLR9 agonist.

[1200] Type III interferons

[1201] In some embodiments, a Type III interferon and / or an agent that stimulates the production of a Type III interferon is included in the composition.

[1202] In some embodiments, the composition consists essentially of Type III interferon. In some embodiments, the composition consists essentially of an agent that stimulates the production of Type III interferon. In some embodiments, the composition consists essentially of Type III interferon and an agent that stimulates the production of Type III interferon.

[1203] In one embodiment, the composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.

[1204] In some embodiments, the composition is a vaccine composition.In some embodiments, the vaccine composition further comprises at least one adjuvant.

[1205] In some embodiments, a Type III interferon and / or an agent that stimulates the production of a Type III interferon is included in the medicament.

[1206] In one embodiment, the Type III interferon is contained in a medicament. In one embodiment, the agent that stimulates the production of Type III interferon is contained in a medicament. In one embodiment, the Type III interferon and the agent that stimulates the production of Type III interferon are contained in a medicament.

[1207] Type III interferon bound to a delivery vehicle

[1208] In one embodiment, the Type III interferon is associated with a delivery vehicle.

[1209] The term "conjugated" refers to a type III interferon that is physically or chemically coupled, adhered, adsorbed, or coated on a delivery vehicle. Examples of binding include, but are not limited to, covalent bonds and electrostatic complexation. The terms "complexed," "complexed with," and "bound to" are used interchangeably herein. In one embodiment, more than one copy or type of type III interferon is bound to the delivery vehicle.

[1210] Delivery vehicles are well known in the art. For example, the delivery vehicle can be selected from cationic lipids, liposomes, cochleates, virosomes, immunostimulatory complexes, microparticles, microspheres, nanospheres, unilamellar vesicles (LUVs), multilamellar vesicles, emulsions, and polycationic peptides, lipoplexes, polyplexes, lipopolyplexes, water-in-oil (W / O) emulsions, oil-in-water (O / W) emulsions, water-in-oil-in-water (W / O / W) multiple emulsions, microemulsions, nanoemulsions, micelles, dendrimers, virosomes, virus-like particles, polymer nanoparticles (e.g., nanobeads, nanospheres, or nanocapsules), polymer microparticles (e.g., microspheres or microcapsules), chitosan, poly(lactic acid) (PLA) polymers, poly(lactic-co-glycolide) (PLGA) polymers, cyclodextrins, niosomes, or and optionally a pharmaceutically acceptable carrier. In one embodiment, the delivery vehicle is in a form suitable for oral administration, injection, topical administration, or rectal administration.

[1211] In one embodiment, the type III interferon is located within or associated with a nanoparticle, such as a nanobead, nanosphere, or nanocapsule. Preferably, the nanoparticle has a diameter of 50 to 300 nm, more preferably 70 to 200 nm, and even more preferably 100 to 150 nm.

[1212] In some embodiments, the type III interferon is located within or associated with a liposome. The liposome can be, for example, a lipid nanoparticle (LNP).

[1213] In some embodiments, lipid nanoparticles (LNPs) include or are combined with DNA molecules or epitopes. In some embodiments, lipid nanoparticles (LNPs) include or are combined with RNA molecules or epitopes. In some embodiments, lipid nanoparticles (LNPs) include or are combined with DNA and RNA molecules or epitopes.

[1214] Anti-IFNα agents

[1215] In one embodiment, an interferon-alpha blocking agent is included in the composition. In one embodiment, the composition comprises at least one interferon-alpha blocking agent selected from: an agent that neutralizes circulating interferon alpha, and / or an agent that blocks interferon-alpha signaling, and / or an agent that depletes IFN-alpha producing cells, and / or an agent that blocks IFN-alpha production.

[1216] In one embodiment, the composition consists essentially of an agent that neutralizes circulating interferon alpha. In one embodiment, the composition consists essentially of an agent that blocks IFN-alpha signaling. In one embodiment, the composition consists essentially of an agent that depletes IFN-alpha-producing cells. In one embodiment, the composition consists essentially of an agent that blocks IFN-alpha production.

[1217] In one embodiment, the composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.

[1218] In some embodiments, the composition is a vaccine composition.In some embodiments, the vaccine composition further comprises at least one adjuvant.

[1219] In one embodiment, an interferon-alpha blocking agent is included in the medicament.

[1220] In one embodiment, the medicament comprises at least one interferon-alpha blocking agent selected from: an agent that neutralizes circulating interferon alpha, and / or an agent that blocks interferon-alpha signaling, and / or an agent that depletes IFN-alpha producing cells, and / or an agent that blocks IFN-alpha production.

[1221] In one embodiment, an agent that neutralizes circulating interferon alpha is included in the medicament. In one embodiment, an agent that blocks interferon alpha signaling is included in the medicament. In one embodiment, an agent that depletes IFN-alpha-producing cells is included in the medicament. In one embodiment, an agent that blocks IFN-alpha production is included in the medicament.

[1222] In some embodiments, the agent that neutralizes circulating interferon alpha is located within or associated with the liposome. The liposome can be, for example, a lipid nanoparticle (LNP).

[1223] CD8 vaccine

[1224] In one embodiment, a tolerogenic vaccine specific for at least one HIV-associated antigen is included in the composition.

[1225] In one embodiment, the composition consists essentially of a tolerogenic vaccine specific for at least one HIV-associated antigen.

[1226] In one embodiment, the composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.

[1227] In one embodiment, the composition is a vaccine composition.In one embodiment, the vaccine composition further comprises at least one adjuvant.

[1228] In one embodiment, a tolerogenic vaccine specific for at least one HIV-associated antigen is included in the medicament.

[1229] In one embodiment, when the tolerogenic vaccine of the present invention comprises HIV-associated antigens and non-pathogenic bacteria, the HIV-associated antigens and non-pathogenic bacteria are two separate and distinct components, which are contained in a pharmaceutical composition as a mixture. In another embodiment, when the tolerogenic vaccine of the present invention comprises HIV-associated antigens and non-pathogenic bacteria, the HIV-associated antigens and non-pathogenic bacteria are the same component contained in the pharmaceutical composition.

[1230] Antigen bound to delivery vehicle

[1231] In one embodiment, the tolerogenic vaccine is a composition, a pharmaceutical composition, or a medicament, wherein the tolerogenic vaccine is associated with a delivery vehicle.

[1232] In one embodiment, the tolerogenic vaccine comprises at least one HIV-associated antigen and a non-pathogenic bacterium, wherein the at least one HIV-associated antigen and / or the non-pathogenic bacterium are bound to a delivery vehicle. In one embodiment, the at least one HIV-associated antigen is bound to a delivery vehicle. In one embodiment, the non-pathogenic bacterium is bound to a delivery vehicle. In one embodiment, the at least one HIV-associated antigen and the non-pathogenic bacterium are bound to a delivery vehicle.

[1233] The term "conjugated" refers to the physical or chemical coupling, adhesion, adsorption or coating of HIV-associated antigens and / or non-pathogenic bacteria to a delivery vehicle. Examples of binding include, but are not limited to, covalent bonds and electrostatic complexation. The terms "complexed," "complexed with," and "bound to" are used interchangeably herein. In one embodiment, more than one copy or type of HIV-associated antigen is bound to the delivery vehicle. In one embodiment, more than one copy or type of non-pathogenic bacteria is bound to the delivery vehicle.

[1234] Delivery vehicles are well known in the art. For example, the delivery vehicle can be selected from cationic lipids, liposomes, cochleosomes, virosomes, immunostimulatory complexes, microparticles, microspheres, nanospheres, unilamellar vesicles (LUVs), multilamellar vesicles, emulsions, and polycationic peptides, lipoplexes, polyplexes, lipopolyplexes, water-in-oil (W / O) emulsions, oil-in-water (O / W) emulsions, water-in-oil-in-water (W / O / W) multiple emulsions, microemulsions, nanoemulsions, micelles, dendrimers, virosomes, virus-like particles, polymer nanoparticles (e.g., nanobeads, nanospheres, or nanocapsules), polymer microparticles (e.g., microspheres or microcapsules), chitosan, poly(lactic acid) (PLA) polymers, poly(lactic-co-glycolide) (PLGA) polymers, cyclodextrins, vesicles, or and optionally a pharmaceutically acceptable carrier. In one embodiment, the delivery vehicle is in a form suitable for oral administration, injection, topical administration, or rectal administration.

[1235] In one embodiment, the tolerogenic vaccine is within or associated with a nanoparticle, such as a nanobead, nanosphere, or nanocapsule. Preferably, the nanoparticle has a diameter of 50 to 300 nm, more preferably 70 to 200 nm, and even more preferably 100 to 150 nm.

[1236] In some embodiments, the tolerogenic vaccine is located within or associated with a liposome. The liposome can be, for example, a lipid nanoparticle (LNP).

[1237] Microfold cells (M cells) are found in the gut-associated lymphoid tissue (GALT) of Peyer's patches in the small intestine and in the mucosa-associated lymphoid tissue (MALT) elsewhere in the gastrointestinal tract. These cells are known to initiate mucosal immune responses.

[1238] In some embodiments, the delivery vehicle is coated or bound to molecules such as lectins or peptides to enhance delivery to M cells.

[1239] M cells express a specific carbohydrate moiety (α-L-fucose) on their apical surface. Some lectin subtypes, such as Ulex europaeus agglutinin 1 (UEA-1) and Aleuria aurantia lectin, have been shown to be highly specific for α-L-fucose on M cells. Therefore, in some embodiments, the delivery vehicle is coated with or bound to at least one lectin selected from Ulex europaeus agglutinin 1 (UEA-1) and Aleuria aurantia lectin.

[1240] M cells also express claudin 4 and TM4SF3. Delivery systems that utilize surface-bound peptides with high affinity for claudin 4, such as CTGKSC (SEQ ID NO: 11), LRVG (SEQ ID NO: 12), or CKSTHPLSC (CKS9) (SEQ ID NO: 13), can also be used. Thus, in some embodiments, the delivery vehicle is coated or bound to at least one peptide selected from CTGKSC (SEQ ID NO: 11), LRVG (SEQ ID NO: 12), and CKSTHPLSC (CKS9) (SEQ ID NO: 13).

[1241] Effector vaccines

[1242] In one embodiment, an effector vaccine specific for at least one HIV-associated antigen is included in the composition.

[1243] In one embodiment, the composition consists essentially of an effector vaccine specific for at least one HIV-associated antigen.

[1244] In one embodiment, the composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.

[1245] In one embodiment, the composition is a vaccine composition.In one embodiment, the vaccine composition further comprises at least one adjuvant.

[1246] In some embodiments, the effector vaccine is a composition comprising the following adjuvants:

[1247]

[1248]

[1249] In one embodiment, an effector vaccine specific for at least one HIV-associated antigen is comprised in the medicament.

[1250] Antigen bound to delivery vehicle

[1251] In one embodiment, the effector vaccine is a composition, pharmaceutical composition, or medicament, wherein the effector vaccine is associated with a delivery vehicle.

[1252] In one embodiment, the effector vaccine comprises at least one HIV-associated antigen associated with a delivery vehicle.

[1253] The term "conjugated" refers to the physical or chemical coupling, adhesion, adsorption or coating of an HIV-associated antigen on a delivery vehicle. Examples of binding include, but are not limited to, covalent bonds and electrostatic complexation. The terms "complexed," "complexed with," and "bound to" are used interchangeably herein. In one embodiment, more than one copy or type of HIV-associated antigen is bound to the delivery vehicle.

[1254] Delivery vehicles are well known in the art. For example, the delivery vehicle can be selected from cationic lipids, liposomes, cochleosomes, virosomes, immunostimulatory complexes, microparticles, microspheres, nanospheres, unilamellar vesicles (LUVs), multilamellar vesicles, emulsions, and polycationic peptides, lipoplexes, polymer complexes, lipid-polymer complexes, water-in-oil (W / O) emulsions, oil-in-water (O / W) emulsions, water-in-oil-in-water (W / O / W) multiple emulsions, microemulsions, nanoemulsions, micelles, dendrimers, virosomes, virus-like particles, polymer nanoparticles (e.g., nanobeads, nanospheres, or nanocapsules), polymer microparticles (e.g., microspheres or microcapsules), chitosan, poly(lactic acid) (PLA) polymers, poly(lactic-co-glycolide) (PLGA) polymers, cyclodextrins, vesicles, or and optionally a pharmaceutically acceptable carrier.

[1255] In one embodiment, the effector vaccine is located within or associated with a nanoparticle, such as a nanobead, nanosphere, or nanocapsule. Preferably, the nanoparticle has a diameter of 50 to 300 nm, more preferably 70 to 200 nm, and even more preferably 100 to 150 nm.

[1256] In some embodiments, the effector vaccine is located within or associated with a liposome. The liposome can be, for example, a lipid nanoparticle (LNP).

[1257] Combination of type III interferon + anti-IFNa agent

[1258] Another object of the present invention is to provide a composition, such as a pharmaceutical composition, comprising an agent that blocks interferon-α, and a type III interferon and / or an agent that stimulates the production of type III interferon, and optionally at least one pharmaceutically acceptable excipient.

[1259] Another object of the invention is a combination, pharmaceutical composition, kit or medicament comprising an agent that blocks interferon alpha and a type III interferon and / or an agent that stimulates the production of type III interferon.

[1260] In some embodiments, the composition, pharmaceutical composition, combination, pharmaceutical combination, medicament or kit described above is used for the prophylactic or therapeutic treatment of HIV in a subject in need thereof.

[1261] Specific drug combinations

[1262] In some embodiments, the methods of the present invention comprise administering to a subject in need thereof:

[1263] - Ad26.Mos4.HIV (e.g. during the priming phase),

[1264] - MVA-BNHIV (e.g. during the boost phase), and

[1265] -Broadly neutralizing antibodies PGT121, PGDM1400, and VRC07-523LS.

[1266] In some embodiments, the methods of the present invention comprise administering to a subject in need thereof:

[1267] - Pegylated interferon lambda from Eiger BioPharmaceuticals Inc., named "pegylated interferon lambda" or "λPEG-rIL-29,"

[1268] -Anti-IFNAR1 MAb anirumab ( AstraZeneca,

[1269] - Ad26.Mos4.HIV (e.g. during the priming phase),

[1270] - MVA-BNHIV (e.g. during the boost phase), and

[1271] -Broadly neutralizing antibodies PGT121, PGDM1400, and VRC07-523LS.

[1272] In some embodiments, the methods of the present invention comprise administering to a subject in need thereof:

[1273] - Pegylated interferon lambda from Eiger BioPharmaceuticals Inc., named "pegylated interferon lambda" or "λPEG-rIL-29,"

[1274] - anti-IFN-α antibodies, such as sifalimumab, longlimumab, or S95021,

[1275] - Ad26.Mos4.HIV (e.g. during the priming phase),

[1276] - MVA-BNHIV (e.g. during the boost phase), and

[1277] -Broadly neutralizing antibodies PGT121, PGDM1400, and VRC07-523LS.

[1278] In some embodiments, the methods of the present invention comprise administering to a subject in need thereof:

[1279] - RNA-LNPs encoding IFN-λ1, IFN-λ2, IFN-λ3 and / or IFN-λ4,

[1280] - anti-IFN-α antibodies, such as sifalimumab, longlimumab, or S95021,

[1281] - Ad26.Mos4.HIV (e.g. during the priming phase),

[1282] - MVA-BNHIV (e.g. during the boost phase), and

[1283] -Broadly neutralizing antibodies PGT121, PGDM1400, and VRC07-523LS.

[1284] In some embodiments, the methods of the present invention comprise administering to a subject in need thereof:

[1285] - ChAdOx1.tHIVconsv1 (e.g. during the startup phase),

[1286] - MVA.tHIVconsv3 (e.g. during the boost phase), and

[1287] - MVA.tHIVconsv4 (eg during the boost phase).

[1288] In one embodiment, the methods of the present invention comprise administering to a subject in need thereof:

[1289] - Pegylated interferon lambda, named "pegylated interferon lambda" or "λPEG-rIL-29," from Eiger BioPharmaceuticals Inc.

[1290] -Anti-IFNAR1 MAb anirumab ( AstraZeneca,

[1291] - ChAdOx1.tHIVconsv1 (e.g. during the startup phase),

[1292] - MVA.tHIVconsv3 (e.g. during the boost phase), and

[1293] - MVA.tHIVconsv4 (eg during the boost phase).

[1294] In some embodiments, the methods of the present invention comprise administering to a subject in need thereof:

[1295] - Pegylated interferon lambda, named "pegylated interferon lambda" or "λPEG-rIL-29," from Eiger BioPharmaceuticals Inc.

[1296] - anti-IFN-α antibodies, such as sifalimumab, longlimumab, or S95021,

[1297] - ChAdOx1.tHIVconsv1 (e.g. during the startup phase),

[1298] - MVA.tHIVconsv3 (e.g. during the boost phase), and

[1299] - MVA.tHIVconsv4 (eg during the boost phase).

[1300] In some embodiments, the methods of the present invention comprise administering to a subject in need thereof:

[1301] - RNA-LNPs encoding IFN-λ1, IFN-λ2, IFN-λ3 and / or IFN-λ4,

[1302] - anti-IFN-α antibodies, such as sifalimumab, longlimumab, or S95021,

[1303] - Ad26.Mos4.HIV (e.g. during the priming phase),

[1304] - MVA-BNHIV (e.g. during the boost phase), and

[1305] -Broadly neutralizing antibodies PGT121, PGDM1400, and VRC07-523LS.

[1306] In some embodiments, the methods of the present invention comprise administering to a subject in need thereof:

[1307] - ChAdOx1.HTI (e.g. during the startup phase),

[1308] - MVA.HTI (e.g. during the boost phase), and

[1309] - Optionally, vesatolimod (also known as GS-9620) (TLR7 agonist).

[1310] In some embodiments, the methods of the present invention comprise administering to a subject in need thereof:

[1311] - Pegylated interferon lambda, named "pegylated interferon lambda" or "λPEG-rIL-29," from Eiger BioPharmaceuticals Inc.

[1312] -Anti-IFNAR1 MAb anirumab ( AstraZeneca,

[1313] - ChAdOx1.HTI (e.g. during the startup phase),

[1314] - MVA.HTI (e.g. during the boost phase), and

[1315] - Optionally, visammod (also known as GS-9620) (TLR7 agonist).

[1316] In some embodiments, the methods of the present invention comprise administering to a subject in need thereof:

[1317] - Pegylated interferon lambda, named "pegylated interferon lambda" or "λPEG-rIL-29," from Eiger BioPharmaceuticals Inc.

[1318] - anti-IFN-α antibodies, such as sifalimumab, longlimumab, or S95021,

[1319] - ChAdOx1.HTI (e.g. during the startup phase),

[1320] - MVA.HTI (e.g. during the boost phase), and

[1321] - Optionally, visammod (also known as GS-9620) (TLR7 agonist).

[1322] In some embodiments, the methods of the present invention comprise administering to a subject in need thereof:

[1323] - RNA-LNPs encoding IFN-λ1, IFN-λ2, IFN-λ3 and / or IFN-λ4,

[1324] - anti-IFN-α antibodies, such as sifalimumab, longlimumab, or S95021,

[1325] - Ad26.Mos4.HIV (e.g. during the priming phase),

[1326] - MVA-BNHIV (e.g. during the boost phase), and

[1327] -Broadly neutralizing antibodies PGT121, PGDM1400, and VRC07-523LS.

[1328] In some embodiments, the methods of the present invention further comprise administering to a subject in need thereof a tolerogenic vaccine comprising at least one lipid nanoparticle (LNP) containing or conjugated to at least one nucleic acid molecule comprising a single-chain trimer of HLA-E and a pathogen-specific antigen.

[1329] In some embodiments, the effector vaccine is an RNA-based vaccine comprising at least one RNA sequence carried by a lipid nanoparticle (LNP).

[1330] Preferably, the combination vaccine is administered intramuscularly.

[1331] Optionally, the methods of the present invention further comprise administering a Toll-like receptor agonist, such as a TLR4 agonist, a TLR7 agonist, or a TLR9 agonist, to a subject in need thereof.

[1332] Application form

[1333] The above-mentioned combinations, compositions, medicaments or kits may be administered simultaneously, separately or sequentially.

[1334] In one embodiment, the tolerogenic vaccine, the effector vaccine, the agent that blocks interferon-α, the type III interferon, and / or the agent that stimulates the production of type III interferon are administered simultaneously, separately, or sequentially.

[1335] According to some embodiments, the agents, combinations, compositions, medicaments or kits described above are formulated for administration to a subject.

[1336] In some embodiments, the agents, combinations, compositions, medicaments, or kits described above may be administered orally, intragastricly, parenterally, topically, by inhalation spray, rectally, nasally, buccally, transprecutaneously, vaginally, or via an implanted reservoir.

[1337] In some embodiments, oral administration includes mucosal administration. "Mucosal administration" refers to delivery to mucosal surfaces, such as the sublingual, tracheal, bronchi, pharyngeal, esophageal, gastric, and duodenum, small intestine, and large intestine mucosa, including the rectal mucosa. Preferably, the mucosal surface refers to the mucosa of the digestive tract.

[1338] In one embodiment, administration of each part of the composite vaccine, combination, composition, medicament or kit of the invention may be carried out by the same route of administration or by different routes of administration.

[1339] Oral / intragastric

[1340] In some embodiments, the above-described agents, combinations, compositions, drugs or kits are in a form suitable for oral or intragastric administration. Thus, in some embodiments, the above-described combinations, compositions, drugs or kits are administered orally or intragastricly to a subject in the form of, for example, powders, tablets, capsules, or tablets formulated for slow or sustained release.

[1341] Examples of forms suitable for oral or intragastric administration include, but are not limited to, liquid, pasty or solid compositions, and more specifically include tablets, tablets formulated for delayed or sustained release, capsules, pills, dragees, liquids, gels, syrups, slurries, suspensions, and the like.

[1342] In some embodiments, the Type III interferon and / or the agent that stimulates the production of Type III interferon as described above is in a form suitable for oral or intragastric administration. Therefore, in some embodiments, the Type III interferon and / or the agent that stimulates the production of Type III interferon as described above is administered to the subject in an oral or intragastric manner, for example in the form of a capsule or tablet.

[1343] In some embodiments, the agent that neutralizes circulating interferon alpha or blocks interferon alpha signaling as described above is in a form suitable for oral or intragastric administration. Thus, in some embodiments, the agent that neutralizes circulating interferon alpha or blocks interferon alpha signaling as described above is administered to a subject in a form suitable for oral or intragastric administration, for example, in the form of a capsule or tablet.

[1344] In one embodiment, the tolerogenic vaccine as described above is in a form suitable for oral or intragastric administration. Thus, in one embodiment, the tolerogenic vaccine as described above is administered to a subject in an oral or intragastric administration manner, for example in the form of a capsule or tablet.

[1345] In one embodiment, the effector vaccine as described above is in a form suitable for oral or intragastric administration. Thus, in one embodiment, the effector vaccine as described above is administered to a subject in an oral or intragastric administration manner, for example in the form of a capsule or tablet.

[1346] injection

[1347] In some embodiments, the agents, combinations, compositions, medicaments, or kits described above are in a form suitable for parenteral administration.

[1348] In some embodiments, the above-described agents, combinations, compositions, drugs or kits are in a form suitable for injection, such as intravenous, subcutaneous, intramuscular, intraperitoneal, intradermal, transdermal injection or infusion. Therefore, the combination, drug combination, drug or kit of the present invention can be injected into the subject by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection or infusion.

[1349] In some embodiments, the above-described agents, combinations, compositions, drugs or kits are in a form suitable for injection, for example, for intravenous, intramuscular, intraperitoneal injection or infusion. Thus, the above-described combinations, compositions, drugs or kits can be administered to a subject by intravenous, intramuscular, intraperitoneal injection or infusion.

[1350] The sterile injectable form of the above-described medicament, combination, composition, drug or kit can be a solution, aqueous or oily suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic pharmaceutically acceptable diluents or solvents. Available acceptable vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids (such as oleic acid and its glyceride derivatives) and natural pharmaceutically acceptable oils (such as olive oil or castor oil, especially their polyoxyethylated forms) can be used to prepare injections. These oily solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants, which are commonly used to prepare pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers, which are commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[1351] In some embodiments, the above-described type III interferon and / or the agent that stimulates the production of type III interferon is in a form suitable for parenteral administration and / or injection. Therefore, in another embodiment, the above-described type III interferon and / or the agent that stimulates the production of type III interferon is administered to the subject parenterally and / or injected into the subject by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection or infusion, preferably by intravenous injection.

[1352] In some embodiments, the interferon-α blocking agent described above is in a form suitable for parenteral administration and / or injection. Therefore, in another embodiment, the interferon-α blocking agent described above is administered to a subject and / or injected into the subject via intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection or infusion, preferably via intravenous injection.

[1353] In some embodiments, the tolerogenic vaccine described above is in a form suitable for parenteral administration and / or injection. Thus, in another embodiment, the tolerogenic vaccine described above is administered parenterally to a subject and / or injected into a subject by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection or infusion, preferably by intravenous injection.

[1354] In some embodiments, the effector vaccine described above is in a form suitable for parenteral administration and / or injection. Thus, in another embodiment, the effector vaccine described above is administered parenterally to a subject and / or injected into a subject by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection or infusion, preferably by intravenous injection.

[1355] local

[1356] In some embodiments, the above-described agents, combinations, compositions, medicaments or kits are in a form suitable for topical administration. Thus, the above-described agents, combinations, compositions, medicaments or kits are to be administered topically.

[1357] Examples of forms suitable for topical administration include, but are not limited to, liquid, paste or solid compositions, more specifically aqueous solutions, drops, dispersions, sprays, microcapsules, micro- or nanoparticles, polymer patches or controlled-release patches, and the like.

[1358] In some embodiments, the above-mentioned type III interferon and / or the agent stimulating the production of type III interferon is in a form suitable for topical administration. Thus, the above-mentioned tolerogenic vaccine specific for at least one of the above-mentioned HIV-associated antigens of the present invention is to be administered topically.

[1359] In some embodiments, the interferon alpha-blocking agent described above is in a form suitable for topical administration. Thus, the interferon alpha-blocking agent described above is to be administered topically.

[1360] In some embodiments, the tolerogenic vaccine described above is in a form suitable for topical administration. Thus, the tolerogenic vaccine described above of the present invention is to be administered topically.

[1361] In some embodiments, the effector vaccine described above is in a form suitable for topical administration. Thus, the effector vaccine described above of the present invention will be administered topically.

[1362] Transrectal

[1363] In some embodiments, the above-described agents, combinations, compositions, medicaments or kits are in a form suitable for rectal administration. Thus, in some embodiments, the above-described agents, combinations, compositions, medicaments or kits are to be administered rectally.

[1364] Examples of forms suitable for rectal administration include, but are not limited to, suppositories, mini-enemas, enemas, gels, rectal foams, creams, ointments, and the like.

[1365] In some embodiments, the Type III interferon and / or the agent that stimulates the production of Type III interferon described above is in a form suitable for rectal administration. Thus, in some embodiments, the Type III interferon and / or the agent that stimulates the production of Type III interferon described above will be administered rectally.

[1366] In some embodiments, the interferon alpha blocking agent described above is in a form suitable for rectal administration. Thus, in one embodiment, the interferon alpha blocking agent described above is to be administered rectally.

[1367] In some embodiments, the tolerogenic vaccine as described above is in a form suitable for rectal administration. Thus, in one embodiment, the tolerogenic vaccine as described above will be administered rectally.

[1368] In some embodiments, the effector vaccine as described above is in a form suitable for rectal administration. Thus, in one embodiment, the effector vaccine as described above will be administered rectally.

[1369] Frequency of application

[1370] In some embodiments, the medicament is administered daily. In some embodiments, the methods disclosed herein involve repeated administration at intervals less than once daily. For example, in certain embodiments, the methods disclosed herein involve administering the medicament every other day, five times a week, four times a week, three times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. In some embodiments of the methods disclosed herein, the methods involve administering the medicament once a month, once every two months, once every three months, once every four months, once every five months, once every six months, or once a year.

[1371] In some embodiments, the Type III interferon agent and / or the agent that stimulates the production of Type III interferon is administered once daily for 2 to 5 days. In some embodiments, the Type III interferon agent and / or the agent that stimulates the production of Type III interferon is administered once every two days for 2 to 5 days.

[1372] In some embodiments, the Type III interferon agent and / or the agent that stimulates Type III interferon production is administered every two days for 8 to 15 days.

[1373] In some embodiments, the anti-IFNα agent is administered once or twice within a period of 8 to 15 days.

[1374] In some embodiments, the agent, combination, composition, medicament, or kit described above is administered one, two, three, four, five, six, seven, eight, nine, ten, or more times.

[1375] In some embodiments, an agent, combination, composition, medicament, or kit as described above is administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more days.

[1376] In some embodiments, the agent, combination, composition, medicament, or kit described above is administered once a month for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more months.

[1377] In some embodiments, an agent, combination, composition, medicament, or kit as described above is administered annually for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years.

[1378] In some embodiments, an agent, combination, composition, medicament, or kit as described above will be administered at least twice (eg, on day 0 and day 14).

[1379] In some embodiments, an agent, combination, composition, medicament, or kit as described above will be administered at least 7 times (eg, on days 0, 1, 3, 7, 28, and 29).

[1380] Sequential application

[1381] The agents, combinations, compositions, medicaments or kits described above may be administered simultaneously, separately or sequentially.

[1382] Therefore, the agents, combinations, compositions, medicaments or kits described above may be administered simultaneously or at different times.

[1383] For simultaneous administration, the agents can be administered as one composition or as different compositions according to circumstances.

[1384] Start / Strengthen

[1385] In one embodiment, the administration of each agent or each part of the combination, composition, medicament or kit as described above can be carried out in a prime / boost mode. Therefore, the present invention also includes a variety of prime-boost regimens.

[1386] In one embodiment, the priming / boosting protocol comprises administering the following steps:

[1387] - one or more priming vaccinations, and

[1388] - One or more booster vaccinations.

[1389] In the startup / boosting scheme, the composition of every kind of medicament or each part in the above-mentioned combination, composition, medicine or test kit can be identical or different in each immunization, and the composition type, route of administration and the preparation of every kind of medicament or each part in the above-mentioned combination, composition, medicine or test kit can also change.For example, if use expression vector in startup and boosting step, its type can be identical or different (for example, DNA, bacteria or viral expression vector).For example, a useful startup-boosting scheme comprises starting immunization at least twice, at intervals of two weeks, then carries out at least one booster immunization (for example, at 4-5 week and / or 8-9 week) after starting immunization for the last time.It will also be understood by those skilled in the art that using DNA, bacteria and viral expression vector or bacterium of the present disclosure to provide startup and boosting scheme can comprise multiple permutations and combinations.For example, CMV vector can be reused, and expression is derived from the different antigens of identical or different pathogens.

[1390] In some embodiments, the prime / boost regimen is a heterologous prime / boost regimen. In this case, the booster is administered with a different agent than the priming agent.

[1391] For example, when a DNA-based vaccine, particularly one comprising a vector (eg, a viral vector), is used for priming, it is preferred to use a different vector for boosting.

[1392] In one embodiment, the boosting step comprises administering a non-infectious dose of SIV or HIV, or an attenuated SIV or HIV (eg, HIV or SIV with a nef protein deleted). In one embodiment, the boosting step is in a form suitable for oral, rectal, or vaginal administration.

[1393] Attenuated SIV or HIV viruses are well known in the art. A non-limiting example of such attenuated viruses is protein-depleted HIV or SIV.

[1394] In some embodiments, the type III interferon and / or the agent that stimulates the production of type III interferon and the agent that blocks interferon-α are administered at different times and routes than the tolerogenic vaccine and / or the effector vaccine.

[1395] In one embodiment, the tolerizing vaccine and / or the effector vaccine are administered at least 2 times (e.g., on day 0 and day 14). In another embodiment, type III interferon and / or an agent that stimulates the production of type III interferon and an agent that blocks interferon-α are administered at least 2 times (e.g., on day -7 and day -3) before administration of the tolerizing vaccine and / or the effector vaccine and at least 9 times (e.g., on days 3, 11, 38, 45, 52, 59, 66, 73, and 80) after administration of the tolerizing vaccine and / or the effector vaccine.

[1396] In one embodiment, the tolerogenic vaccine and / or the effector vaccine are administered at least 7 times (e.g., on days 0, 1, 3, 7, 28, and 29). In another embodiment, type III interferon and / or an agent that stimulates the production of type III interferon and an agent that blocks interferon alpha are administered prior to the first portion of administration (e.g., on days -3, 0, 28, and 29) and are administered at least once more (e.g., on day 57).

[1397] In one embodiment, the tolerogenic vaccine and / or the effector vaccine is administered at least 7 times in the priming and boosting steps (e.g., priming on days 0, 1, 2, 3, and 5, and the first boost on days 28 and 29). Type III interferon and / or an agent that stimulates the production of type III interferon and an agent that blocks interferon alpha are administered at least once in the priming and first boosting steps (e.g., from day 0 to day 40), and at least once after the last administration of the tolerogenic vaccine and / or the effector vaccine. Type III interferon and / or an agent that stimulates the production of type III interferon and an agent that blocks interferon alpha are administered 0, 1, 2, or 3 days before each administration of the tolerogenic vaccine and / or the effector vaccine.

[1398] In some embodiments, at least one broadly neutralizing antibody (bnAb) or antiretroviral (ART) agent is administered daily for the entire duration of the methods of the invention.

[1399] In some embodiments, a priming dose of the tolerizing vaccine and / or the effector vaccine is administered between day 1 and day 5, eg, on day 1, 2, 3, 4, and / or 5.

[1400] In some embodiments, a booster dose of the tolerizing and / or effector vaccine is administered between day 21 and day 28, for example, on days 21, 22, 23, 24, 25, 26, 27 and / or 28.

[1401] Generally, the methods of the present invention may comprise administering to a subject in need thereof:

[1402] - During a first period, administering at least one broadly neutralizing antibody (bnAb) or antiretroviral (ART) agent, for example once daily, and

[1403] -During the second time period:

[1404] ix. administering the at least one broadly neutralizing antibody (bnAb) or antiretroviral (ART) agent, for example daily,

[1405] x. On day -2: administering type III interferon or an agent that stimulates the production of type III interferon,

[1406] xi. on day 0: administration of a priming tolerogenic vaccine specific for at least one HIV antigen, xii. on days 5, 15, and 26: administration of a type III interferon or an agent that stimulates the production of type III interferon and an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[1407] xiii. On Day 28: administer a boost of a tolerogenic vaccine specific for at least one HIV antigen, and

[1408] -During the third time period:

[1409] xiv. administering the at least one broadly neutralizing antibody (bnAb) or antiretroviral (ART) agent, for example daily,

[1410] xv. On day 54: administering a type III interferon or an agent that stimulates the production of type III interferon and an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[1411] xvi. on day 56: administration of a priming effector vaccine comprising at least one HIV immunogen, xvii. on days 61, 71, and 82: administration of a type III interferon or an agent that stimulates the production of type III interferon and an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling,

[1412] xviii. On Day 84: Administer a boost of an effector vaccine comprising at least one HIV immunogen.

[1413] Also generally, the methods of the invention may comprise administering to a subject in need thereof:

[1414] 1) administering at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) throughout the vaccination course, e.g., once daily, and

[1415] 2) During the startup phase:

[1416] a) on day -2: administration of type III interferon or an agent that stimulates the production of type III interferon,

[1417] b) on day 0: administration of a tolerizing vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen,

[1418] c) on days 5, 15, and 26: administering a type III interferon or an agent that stimulates the production of type III interferon and an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling, and

[1419] 3) During the boost phase following the initiation phase:

[1420] a) on day 28: administering a tolerizing vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and

[1421] b) On days 33 and 43: administer a type III interferon or an agent that stimulates the production of type III interferon and an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling.

[1422] In some embodiments, the boost phase is repeated until HIV neutralizing antibodies are detected in the subject's serum.

[1423] Subjects in need

[1424] The term "subject" refers to humans or other mammals in need of therapeutic treatment or prophylactic treatment for HIV infection, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-domesticated animals such as non-human primates, mammalian wildlife, etc.

[1425] In some embodiments, the subject is a mammal, a primate, preferably a human.

[1426] In some embodiments, the HIV is HIV-1. In some embodiments, the HIV is HIV-2. In some embodiments, the HIV is HIV-1 and HIV-2.

[1427] In some embodiments, the subject is HIV negative.

[1428] In some embodiments, the subject has a relatively high CD4 + T cell count (e.g. more than 500 CD4 +T cells / μL, more than 600 CD4 + T cells / μL, more than 700 CD4 + T cells / μL).

[1429] In some embodiments, the subject has not received antiviral treatment prior to initiating the method of the present invention, ie, prior to being administered the above-described combination vaccine.

[1430] In some embodiments, the subject is receiving ART or combined ART (cART) treatment prior to initiating the method of the present invention, ie, prior to being administered the above-mentioned combination vaccine.

[1431] In some embodiments, the subject may already be infected with HIV or be at risk of becoming infected with HIV.

[1432] In some embodiments, the subject has been identified as an individual at risk for sexual transmission of HIV. In some embodiments, the individual has been identified as:

[1433] - Anal intercourse with at least two different sexual partners in the past 6 months without consistent condom use;

[1434] - History of sexually transmitted disease (STD) in the past 12 months (e.g., syphilis, gonorrhea, chlamydia, HBV, or HCV infection);

[1435] - Use of psychoactive drugs during sexual intercourse (e.g., cocaine, gamma-hydroxybutyrate (GHB), methylenedioxymethamphetamine (MDMA), mephedrone);

[1436] - Having sex with one or more partners from regions with high HIV infection rates (>1%) (e.g., South America, sub-Saharan Africa, Southeast Asia, Eastern Europe, French Guiana) and not using condoms consistently;

[1437] -Sex workers;

[1438] - Their sexual partner is an intravenous drug user and they share injecting materials; and / or

[1439] -Has an HIV-infected sex partner with a detectable plasma viral load (eg, >50 copies (cp) / mL).

[1440] Prophylactic and event-driven administration

[1441] In some embodiments, the methods disclosed herein include event-driven administration. As used herein, the term "event-driven" or "event-driven administration" refers to administering a pharmaceutical agent: (1) before an event that may expose a subject to HIV (or otherwise increase the risk of HIV infection in a subject) occurs (e.g., 2 hours, 1 day, 2 days, 5 days, 7 days, 10 days, 14 days, 28 days (i.e., one month) or more days before the event); and / or (2) during an event (or multiple repeated events) that may expose a subject to HIV (or otherwise increase the risk of HIV infection in a subject); and / or (3) after an event (or after the last event in a series of repeated events) that may expose a subject to HIV (or otherwise increase the risk of HIV infection in a subject).

[1442] In some embodiments, event-driven administration is performed before the subject is exposed to HIV. In some embodiments, event-driven administration is performed after the subject is exposed to HIV.

[1443] As used herein, the term "period of exposure" refers to a period of time during which a subject is exposed to HIV, ranging from a single event to multiple events over an extended period of time.

[1444] Also provided herein is a method for reducing the risk of HIV infection in a subject, comprising administering the composite vaccine of the present invention to the subject.

[1445] In some embodiments, the method for reducing the risk of HIV infection comprises administering a combination vaccine to a subject. In certain embodiments, the method for reducing the risk of HIV infection comprises administering a combination vaccine to a subject at risk of HIV infection. Examples of subjects at high risk of HIV infection include, but are not limited to, subjects at risk of sexual transmission of HIV.

[1446] In some embodiments, the risk of HIV infection is reduced by at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95% (compared to a subject not administered an agent according to any of the methods provided herein).

[1447] dose

[1448] It should be understood that the total daily dosage of the first part, the total daily dosage of the second part, and the total daily dosage of the third part in the combination, drug combination, medicament or kit of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific dosage of any particular subject will depend on a variety of factors, such as the infectious disease to be treated; the age, weight, general health, sex and diet of the subject, and similar factors well known in the medical field. Therefore, the combination, drug combination, medicament or kit of the present invention can be applied to the subject once or multiple times. Preferably, there is a set time interval between the separate applications of the combination, drug combination, medicament or kit of the present invention. Although this interval varies from subject to subject, it is generally 1 day to several weeks, generally 1, 2, 4, 6 or 8 days, or 1, 2, 4, 6 or 8 weeks. In one embodiment of the invention, the interval is generally 1 to 6 weeks. In one embodiment of the invention, the intervals are longer, advantageously about 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, or 80 weeks. In one embodiment, the administration regimen typically comprises 1 to 20 administrations of the three different parts described herein, but may be as few as 1, 2, 4, 8, or 10. In another embodiment, the administration regimen is annual, biennial, or other long interval (5-10 years).

[1449] In some embodiments, the administration regimen typically has 1 to 15 administrations, but can be as few as one or two or four or eight or ten.

[1450] For example, when the tolerogenic vaccine comprises a CMV vector as described above, and the subject to be treated is a mammal, a primate, or a human, the therapeutically effective dose of the CMV vector may range from a few micrograms to several hundred micrograms (e.g., 5 to 500 μg per administration). The CMV vector may be administered in any suitable amount to achieve expression at these dose levels. In a non-limiting example, the CMV vector may be administered in an amount of at least 10 μg per administration. 1 , 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 or 10 8 Therefore, the amount of CMV vector administered per administration may be at least 10 1 pfu, or about 10 1 pfu to about 10 8The CMV vector may be lyophilized for resuspension at the time of administration, or may be present in solution.

[1451] In one embodiment, the amount of a CMV vector as described above administered to a subject is at least 10 1 , 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 or 10 8 In one embodiment, the amount of CMV vector as described above administered per time ranges from about 10 1 to about 10 8 , preferably about 10 2 to about 10 7 , more preferably about 10 3 to about 10 6 , even more preferably about 10 4 to about 10 5 In one embodiment, the daily amount of the CMV vector as described above administered to a subject is at least 10 1 pfu / day, 10 2 pfu / day, 10 3 pfu / day, 10 4 pfu / day, 10 5 pfu / day, 10 6 pfu / day, 10 7 pfu / day or 10 8 In one embodiment, the daily amount of the CMV vector as described above administered daily ranges from about 10 1 pfu / day to about 10 8 pfu / day, preferably about 10 2 pfu / day to about 10 7 pfu / day, more preferably about 10 3 pfu / day to about 10 6 pfu / day, even more preferably about 10 4 pfu / day to about 10 5 pfu / day, including all integer values ​​within these ranges. In one embodiment, the amount of CMV vector as described above administered to a subject is at least 10 1 , 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 or 108 viruses / kg body weight.

[1452] For example, when the tolerogenic vaccine comprises a non-pathogenic bacterium as described above, and when the subject to be treated is a human, the therapeutically effective dose of the non-pathogenic bacterium (i.e., Lactobacillus, Lactobacillus plantarum, or Mycobacterium) may range from about 10 mg / dL per administration. 1 to about 10 18 The therapeutically effective dose of the HIV antigen may range from about 10 cfu per administration. 1 to about 10 14 A virus.

[1453] In one embodiment, the amount of the non-pathogenic bacteria as described above administered to a subject is at least 10 1 , 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 or 10 14 In one embodiment, the amount of non-pathogenic bacteria as described above administered per administration ranges from about 10 1 to about 10 18 , preferably about 10 2 to about 10 16 , more preferably about 10 4 to about 10 14 , even more preferably about 10 6 to about 10 12 In one embodiment, the daily amount of the non-pathogenic bacteria as described above administered to a subject is at least 10 1 10 per day 2 10 per day 3 10 per day 4 10 per day 5 10 per day 6 10 per day 7 10 per day 8 10 per day 9 10 per day 10 10 per day 11 10 per day 12 10 per day 13 10 per day 14 10 per day15 10 per day 16 10 per day 17 or 10 per day 18 In one embodiment, the daily amount of the non-pathogenic bacteria as described above administered daily ranges from about 10<1> to about 10<1> cfu per day. 18 , preferably about 10 per day 2 to about 10 16 , more preferably about 10 per day 4 to about 10 14 , even more preferably about 10 6 to about 10 12 In one embodiment, the amount of the non-pathogenic bacteria as described above administered to a subject is at least 10 1 , 10 2 , 10 3 , 10 4、 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 or 10 14 bacteria / kg body weight.

[1454] In one embodiment, the amount of the inactivated SIV or HIV virus described above administered to the subject is at least 10 1 , 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 or 10 14 In one embodiment, the amount of inactivated SIV or HIV virus administered each time is in the range of about 10 1 to about 10 18 , preferably about 10 2 to about 10 16 , more preferably about 10 4 to about 10 14 , even more preferably about 10 6 to about 10 12In one embodiment, the daily amount of inactivated SIV or HIV virus as described above administered to a subject is at least 10 1 10 per day 2 10 per day 3 10 per day 4 10 per day 5 10 per day 6 10 per day 7 10 per day 8 10 per day 9 10 per day 10 10 per day 11 10 per day 12 10 per day 13 10 per day 14 10 per day 15 10 per day 16 , 10 per day 17 or 10 per day 18 In one embodiment, the daily amount of inactivated SIV or HIV virus as described above administered daily ranges from about 10 1 to about 10 18 , preferably about 10 per day 2 to about 10 16 , more preferably about 10 per day 4 to about 10 14 , even more preferably about 10 6 to about 10 12 In one embodiment, the amount of inactivated SIV or HIV virus as described above administered to a subject is at least 10 1 , 10 2 , 10 ...

Claims

1. A composite vaccine comprising: a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) For use in the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seropositive patient who has no AIDS symptoms or has AIDS symptoms, and wherein: 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject throughout the vaccination process, and 2) Among them: a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon, b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and c) Effector vaccines comprising at least one HIV immunogen is administered to the subject during the priming phase, and 3) Among them: a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon, b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and c) Effector vaccines Administered to subjects during a boost phase following a priming phase.

2. A composite vaccine comprising: a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) For use in preventing acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is a human immunodeficiency virus (HIV) seronegative patient, and wherein: 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject during the priming phase and the boosting phase throughout the vaccination process, and 2) Among them: a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon, b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and c) Effector vaccines comprising at least one HIV immunogen is administered to the subject during the priming phase, and 3) Among them: a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon, b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and c) Effector vaccines Administered to subjects during a boost phase following a priming phase.

3. A composite vaccine comprising: a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, c) optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) For use in the prophylactic or therapeutic treatment of acquired immunodeficiency syndrome (AIDS) in a subject in need thereof, wherein the subject is an elite controller patient who is seropositive for human immunodeficiency virus (HIV), and wherein: 1) the at least one antiretroviral (ART) agent or the at least one broadly neutralizing antibody (bnAb) is administered to the subject during the priming phase and the boosting phase throughout the vaccination process, and 2) Among them: a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon, b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and c) Effector vaccines comprising at least one HIV immunogen is administered to the subject during the priming phase, and 3) Among them: a) optionally, a type III interferon or an agent that stimulates the production of a type III interferon, b) agents that neutralize circulating interferon alpha or agents that block interferon alpha signaling, and c) Effector vaccines Administered to subjects during a boost phase following a priming phase.

4. A composite vaccine comprising: a) an agent that neutralizes circulating interferon alpha or an agent that blocks interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, and c) Optionally, a Type III interferon or an agent that stimulates the production of a Type III interferon.

5. The combination vaccine for use according to any one of claims 1 to 3 or the combination vaccine according to claim 4, wherein the type III interferon is IFN-λ1, IFN-λ2, IFN-λ3 and / or IFN-λ4, and wherein the agent that stimulates the production of type III interferon comprises a TLR ligand, a RIG-I ligand and / or an MDA5 ligand.

6. The combination vaccine for use according to any one of claims 1 to 3 or the combination vaccine according to claim 4, wherein the type III interferon is at least one IFN-λ1, IFN-λ2, IFN-λ3 and / or IFN-λ4 protein, at least one plasmid comprising a DNA sequence encoding IFN-λ1, IFN-λ2, IFN-λ3 and / or IFN-λ4, or at least one RNA molecule or mRNA-LNP encoding IFN-λ1, IFN-λ2, IFN-λ3 and / or IFN-λ4.

7. A combination vaccine for use according to any one of claims 1-3, 5-6 or a combination vaccine according to any one of claims 4-6, wherein the agent that neutralizes circulating interferon alpha is an anti-interferon, an anti-IFN-alpha antibody or an anti-IFN-alpha hyperimmune serum; and wherein the agent that blocks interferon alpha signaling is an anti-type I interferon R1 or R2 antibody, or an endogenous regulator of interferon alpha including SOSC1 or the aryl hydrocarbon receptor.

8. The combination vaccine for use according to any one of claims 1 to 3, 5 to 7, or the combination vaccine according to any one of claims 4 to 7, wherein the agent that neutralizes circulating interferon alpha or blocks interferon alpha signaling is an agent that neutralizes circulating interferon beta or blocks interferon beta signaling, or is combined with an agent that neutralizes circulating interferon beta or blocks interferon beta signaling.

9. The combination vaccine for use according to any one of claims 1 to 3, 5 to 8 or the combination vaccine according to any one of claims 4 to 8, wherein the effector vaccine comprising at least one HIV immunogen comprises: - a protein-based vaccine comprising at least one HIV-derived trimeric protein, peptide or epitope, - A DNA-based vaccine comprising: a) non-replicating viral vectors or live attenuated viral vectors, and b) at least one DNA sequence encoding at least one HIV-derived protein, peptide or epitope, or at least one DNA sequence encoding at least one antigen-binding fragment of a broadly neutralizing anti-HIV antibody, or at least one DNA sequence encoding a chimeric immunogen, - RNA-based vaccines comprising at least one RNA sequence encoding at least one HIV-derived trimeric peptide or protein, and / or - A passive vaccine comprising at least one broadly neutralizing anti-HIV antibody.

10. The combination vaccine for use according to any one of claims 1 to 3, 5 to 9 or the combination vaccine according to any one of claims 4 to 9, wherein the at least one HIV immunogen is derived from gag, pol, env, nef, tat, vif and rev.

11. The composite vaccine for use according to any one of claims 1-3, 5-10 or the composite vaccine according to any one of claims 4-10, wherein the at least one HIV immunogen is a natural Env gp160 trimer, a stabilized Envgp160 trimer, a stabilized Env gp140 trimer (SOS gp140 or SOSIP gp140), a stabilized Env single-chain gp140 trimer, or a stabilized native flexible link (NFL) Env gp140 trimer.

12. The composite vaccine for use according to any one of claims 1 to 3, 5 to 11 or the composite vaccine according to any one of claims 4 to 11, wherein the at least one HIV immunogen is in a soluble form or is displayed on the surface of nanoparticles.

13. The combination vaccine for use according to any one of claims 1-3, 5-12, wherein the at least one antiretroviral (ART) agent is selected from nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), integrase inhibitors (INSTI), fusion inhibitors (FI), chemokine receptor antagonists (CCR5 antagonists) and entry inhibitors (CD4-directed post-attachment inhibitors).

14. The composite vaccine for use according to any one of claims 1-3, 5-13, wherein the composite vaccine produces anti-HIV specific neutralizing antibodies and / or anti-HIV specific cytotoxic cells in the subject.

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