ANTI-Aβ THERAPEUTIC VACCINES

Abstract

A liposomal vaccine composition comprising an amyloid β (Aβ)-derived B-cell peptide antigen presented on the liposome surface. The vaccine composition also comprises a peptide comprising a universal T-cell epitope encapsulated within the liposome. The vaccine composition further comprises an adjuvant, which may be part of the liposome and may be at least partially presented on its surface. These vaccine compositions are used to treat, prevent, induce a protective immune response, or alleviate the symptoms of an amyloid β-associated disease or condition, or a condition characterized by or associated with cognitive memory loss in a subject. The vaccine compositions may be supplied as kits. Related methods for producing liposomal vaccine compositions.

Description

ANTI-ABETA THERAPEUTIC VACCINES FIELD OF INVENTION The invention relates to therapeutic anti-Abeta vaccines and their use in the treatment and prevention of diseases. The vaccines incorporate peptide antigens for B cells derived from Aβ and epitopes for T cells. DESCRIPTION Alzheimer's disease (AD) is a progressive and devastating degenerative disorder characterized by the loss of cognitive functions, including memory, as well as the loss of the ability to perform regular daily activities. AD affects approximately 40 million patients worldwide, and this number is rapidly increasing as the population ages. The main neuropathological change in the brains of AD patients is neuronal death, primarily in regions related to memory and cognition (Soto, 1999). One of the most notable pathological features of AD is the abundant presence of beta-amyloid (Aβ) plaques in the brains of affected individuals (Soto, 1999). Aβ plaques are composed of Aβ peptides with a length of between 39 and 43 amino acids, which in their natural, non-pathological form adopt a random coil conformation.During the transition to the pathological state, they are mainly transformed into secondary structures of β-sheets, which spontaneously aggregate into insoluble deposits. The few treatments currently available for ankylosing spondylitis (AS) are considered to have primarily symptomatic effects. Despite significant efforts in treatment development over the years, no disease-modifying therapy has been approved to date. 1855117 of 55 disease for AD. Efforts have been made to develop immunotherapeutic treatments that neutralize the pathological Aβ plaques in the long-term diseased brain (Winblad, 2014). Vaccines have the advantage of stimulating the immune system to produce slightly different but highly specific antibody clusters, and if necessary, the response can be evoked again by additional vaccinations. However, an active immunization approach (vaccination) against Aβ has several significant complications. Beta amyloid is what is known as an autoantigen, to which the human body is constantly exposed. Therefore, it is difficult to overcome immune tolerance and induce an antibody-mediated response. Furthermore, it is difficult to induce a strong immune response to a vaccine in elderly and ill individuals, such as patients with Alzheimer's disease, due to their weakened immune systems and reduced number of immune cells. Despite these complications, in an initial study, a full-length Aβ142 vaccine (AN1792) induced an antibody-mediated response and showed promising efficacy, with a slower rate of cognitive decline in patients treated with it compared to those treated with a placebo (Gilman, 2005). However, 6% of treated patients developed meningoencephalitis, an inflammatory reaction attributed to a T-cell-mediated response to the full-length Aβ1-42 vaccine (Orgogozo, 2003). Another known anti-Aβ vaccine, ACI-24, contains a 15-amino-acid sequence that is completely identical to the human Aβ sequence 1-15 (WO2007 / 068411). This peptide antigen is bound to a liposomal carrier. 1855117 of 55 to stimulate antibodies against Aβ and prevent meningoencephalitis and hemorrhage (Muhs, 2007; Pihlgren, 2013). The selection of the Aβ1-15 peptide as an antigen was based on the logic that this sequence contains an epitope for B cells but lacks a strong reactive site for T cells to the full-length Aβ142 (Monsonego, 2003), the potential cause of undesirable inflammatory reactions. ACI-24 has been shown to act by simultaneously activating a B cell receptor specific for Aβ1-15 and the monophosphoryl lipid A (MPLA)-activated Toll-like receptor 4 (TLR4), an adjuvant present in the ACI-24 vaccine (Pihlgren, 2013). B cells are activated to proliferate and produce immunoglobulin (Ig) by cross-linking Ig receptors on their surface. To increase antibody production, a second signal can be provided by a helper T cell activated by a T cell epitope. T cell epitopes, presented by major histocompatibility complex (MHC) molecules (on the human leukocyte antigen (HLA)) on the surface of antigen-presenting cells (APCs), promote the differentiation of known helper T cells that can produce IFNγ and IL-4. Through the release of cytokines and costimulatory signals between activated T and B cells, antibody-mediated responses and class switching are enhanced. Following primary vaccination, naïve T cells proliferate and differentiate into effector cells.A small fraction of these cells form the pool of long-lived memory T cells, which can proliferate rapidly upon re-encountering the known peptide after a booster vaccination (Sallusto, 2010). So-called “universal” T cell epitopes are specific to the T cells present in the large T cells. 1855117 of 55 majority of human populations. In general, they originate from antigens to which humans are normally exposed during their lifetime (e.g., tetanus, influenza, etc.). The ability of a T cell epitope to activate T cells results from at least two complementary properties: (i) the affinity for binding to the HLA groove, i.e., the strength of the binding, and (ii) the ability to bind to diverse HLA haplotypes promiscuously, i.e., the ability to encompass very diverse human populations, with respect to differences in the expression of HLA molecules. There is a need to develop an anti-Aβ vaccine that is highly immunogenic and maintains a good safety profile. This need was met by incorporating a universal T-cell epitope into the liposomal vaccine ACI-24. Because the ACI-24 vaccine presents Aβ1-15 on the liposome surface, the inventors considered that including universal T-cell epitopes on the liposome surface would be the first approach selected to improve vaccine efficacy. However, surprisingly, including universal T-cell epitopes on the liposome surface did not increase (or substantially increase) vaccine efficacy. Therefore, as explained herein, an encapsulation approach was adopted, which resulted in superior efficacy.It was found that incorporating a universal T-cell epitope into a liposomal vaccine increases (or substantially increases) vaccine efficacy while maintaining a good safety profile through non-Aβ-directed T-cell activation. However, there were several challenges in developing this approach. First, the universal T-cell epitopes developed tended to be... 1855117 of 55 hydrophobic molecules, which hindered encapsulation in liposomes. Second, to improve immunogenicity, multiple epitopes for universal T cells tended to be combined. However, peptide synthesis yield and success rate decreased as peptide length increased. Third, the charge of the selected universal T cell epitopes influenced encapsulation efficiency and the experimental conditions required to ensure it, because the liposomal membrane is negatively charged. Accordingly, the invention provides a liposomal vaccine composition comprising (a) an amyloid β (Aβ)-derived B cell peptide antigen presented on the liposome surface; and (b) a peptide comprising a universal T cell epitope encapsulated in the liposome. A particularly preferred vaccine composition comprises an ACI-24 vaccine modified to include a peptide comprising a universal T-cell epitope encapsulated within a liposome. A liposome is an example of a carrier. Thus, the carrier is generally a liposome, but it can be any carrier suitable for presenting the Aβ-derived peptide antigen on its surface by a mechanism similar to that employed by liposomes (where the Aβ-derived peptide antigen adopts a predominantly β-sheet conformation) and also for encapsulating a peptide comprising a universal T-cell epitope. Examples include vesicles and particulate bodies. 1855117 of 55 A “universal T cell epitope” is an epitope that is specific to T cells present in most human populations. It commonly originates from antigens to which humans are normally exposed throughout their lives. Examples include antigens routinely incorporated into vaccines. Specific examples include T cell epitopes present in tetanus, influenza, and diphtheria, as well as California limpet hemocyanin (KLH) and Epstein-Barr virus (EBV). The “universal” ability of a T cell epitope to activate T cells results from at least two complementary properties: (i) its HLA groove binding affinity, i.e., the strength of the binding, and (ii) its ability to bind promiscuously to diverse HLA haplotypes, i.e., its ability to span highly diverse human populations with respect to differences in HLA molecule expression.Universal T cell epitopes can bind to most MHC class II alleles present in human populations. Consequently, universal T cell epitopes included in the vaccine compositions of the invention can stimulate a CD4 T cell-mediated response. Universal T cell epitopes included in the vaccine compositions of the invention can stimulate a helper T cell-mediated response that increases antibody production (with A3 specificity) by B cells. The universal T-cell epitopes included in the vaccine compositions of the invention are typically synthesized in solid phases. Therefore, in some embodiments, the universal T-cell epitopes are synthesized in solid phases. Due to these and other details related to encapsulation, in some non-limiting embodiments, the peptide that 1855117 of 55 comprises a universal T cell epitope having a length not exceeding 85, 80, 75, or 70 amino acids. The minimum length of a peptide that is a T cell epitope to ensure sufficient immunogenicity is typically approximately 10 amino acids. Therefore, to ensure that a sufficiently immunogenic T cell epitope is generated, the minimum peptide length is typically approximately 10 amino acids. In some embodiments, the peptide has a length of at least 20 amino acids. In other embodiments, the peptide has a length of between 30 and 60 amino acids: this is based on the preferred minimum length for universal T cell epitopes and the preference for a peptide comprising at least two, three, or four (linked) universal T cell epitopes. It was also determined that the universal T cell epitopes useful in the present invention are typically hydrophobic. This presents additional challenges for synthesis, purification, and encapsulation in liposomes due to interactions with lipids. The percentage of hydrophobicity is calculated by dividing the total amount of hydrophobic amino acids (Phe, Ile, Leu, Met, Val, Trp, Ala, and Pro) by the total amount of amino acids in either the general peptides comprising universal T cell epitopes (when considering the peptides as a whole) or the individual T cell epitopes (when considering each universal T cell epitope separately) and multiplying the result by 100. In the present invention, the hydrophobic amino acids include leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tryptophan (Trp), valine (Val), methionine (Met), proline (Pro), and alanine (Ala). Therefore, a peptide comprising a universal T-cell epitope typically comprises at least 30% hydrophobic amino acids. This 1855117 of 55 implies that at least 30% of the amino acids in peptides in general comprising universal T cell epitopes are hydrophobic amino acids. Most of the peptides with universal T cell epitopes evaluated comprised up to 50% hydrophobic amino acids. In some cases, a peptide may comprise at least 35%, 40%, 45%, or 50% hydrophobic amino acids. To enhance immunogenicity, it is preferred that a vaccine composition comprise at least two different universal T cell epitopes encapsulated in the liposome. Due to the capacity of liposomes, combined with the hydrophobicity of the peptides and limitations in synthesis, each universal T cell epitope ideally has a length of no more than 30 amino acids, preferably no more than 20 amino acids, and even more preferably approximately 10–20 amino acids. As explained in more detail herein, the inventors determined that longer universal T cell epitopes can be effectively trimmed to a length of 10–20 amino acids without altering their immunogenicity. The trimmed peptides were designed by selecting the shortest and most immunogenic subsequence, typically approximately 15 amino acids in length, within the sequence of each T cell epitope, based on the in silico predicted active regions.There are several software programs to help perform this analysis, including the EpiVax immunogenicity detection platform (http: / / www.epivax.com). Other examples include SYFPEITHI (Hans-Georg Rammensee, Jutta Bachmann, Niels Nikolaus Emmerich, Oskar Alexander Bachor, Stefan Stevanovic: SYFPEITHI: database for MHC ligands and peptide motifs, Immunogenetics (1999), 50:213-219, http: / / www.syfpeithi.com), SVMHC. 1855117 of 55 (https: / / www.ncbi.nlm.nih.gov / pubmed / 16844990) and the IEBD database (Vita, R., Overton, JA, Greenbaum, JA, Ponomarenko, J., Clark, JD, Cantrell, JR, Wheeler, DK, Gabbard, JL, Hix, D., Sette, A., Peters, B., The immune epitope database (IEDB) 3.0, Nucleic Acids Res., October 9, 2014, pii: gku938 (advance electronic publication), PubMed PMID: 25300482, http: / / www.iedb.org / ). In some embodiments, each universal T cell epitope comprises at least 30% hydrophobic amino acids. This means that at least 30% of the amino acids in the universal T cell epitope are hydrophobic amino acids. For certain epitopes, the proportion of hydrophobic amino acids can reach 80%. In some cases, there may be at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% hydrophobic amino acids. In some embodiments, the maximum proportion of hydrophobic amino acids can be 80%, meaning that the broadest range of hydrophobic amino acids spans from 30% to 80%. To achieve improved immunogenicity and overcome practical drawbacks related to encapsulation, a vaccine composition may comprise two, three, or four different universal T cell epitopes encapsulated in carriers. When encapsulating large quantities of different universal T cell epitopes (especially 3 or 4), it is preferable to trim them to a length of approximately 10–20 amino acids, such as approximately 15 amino acids. Including multiple different universal T cell epitopes within the same encapsulated peptides is preferred. Therefore, synthetic peptide constructs containing multiple epitopes for 1855117 of 55 different universal T cells represents a preferred implementation of the invention. In certain embodiments, the peptide comprises at least two different universal T cell epitopes. In more specific embodiments, the peptide comprises two, three, or four universal T cell epitopes. When there are at least two universal T cell epitopes in a synthetic peptide construct, they can be joined by linkers. The linkers are used to physically join universal T cell epitopes in such a way as not to impair their immunogenicity. Suitable linkers for joining amino acids are well known in the art. The preferred linkers are amino acid-based linkers, i.e., peptide linkers. In this way, universal T cell epitopes can be joined by peptide bonds. A linker enables the correct processing of the universal T cell epitopes.For antigen presentation by MHC class II molecules to occur, antigens must enter the endosomal-lysosomal compartment. Subsequently, these antigens are processed by proteolytic enzymes, of which lysosomal cysteine ​​proteases of the papain family may constitute an important subset. The generated peptides bind to MHC class II molecules, which are then presented on the surface of dedicated antigen-presenting cells (APCs), including macrophages, dendritic cells (DCs), and B cells (Lutzner and Kalbacher, 2008). Therefore, a connector preferably comprises a substrate for a lysosomal cysteine ​​protease of the papain family. The connector may also comprise a substrate for one or more enzymes such as cathepsin S, cathepsin B, or cathepsin L. In some embodiments, the connector... 1855117 of 55 comprises, consists essentially of, or consists of at least two or at least three amino acids. In some embodiments, the linker comprises, consists essentially of, or consists of the amino acids VVR, TVGLR, KVSVR, PMGAP, or PMGLP. Therefore, peptides comprising two epitopes for universal T cells can be linear peptides with the following format: [universal T cell epitope 1]-[connector]-[universal T cell epitope 2]. Peptides comprising three epitopes for universal T cells can be linear peptides with the following format: [universal T cell epitope 1]-[connector]-[universal T cell epitope 2]-[connector]-[universal T cell epitope 3]. Peptides comprising four epitopes for universal T cells can be linear peptides with the following format: [universal T cell epitope 1]-[connector]-[universal T cell epitope 2]-[connector]-[universal T cell epitope 3]-[connector]-[universal T cell epitope 4]. It is worth noting that the connectors between each pair of bound universal T cell epitopes do not need to be identical. For example, the connector between universal T cell epitope 1 and universal T cell epitope 2 can be different from the connector between universal T cell epitope 2 and universal T cell epitope 3. In the case of four universal T cell epitopes, each of the three connectors can be different, or two can be the same and the third different (in any order). In some 1855117 of 55 embodiments where there are multiple connectors in a peptide, all are identical. The inventors evaluated various sources of universal T cell epitopes when designing peptides suitable for encapsulation. In some embodiments, the universal T cell epitopes are derived from diphtheria toxin, tetanus toxin, Epstein-Barr virus, influenza hemagglutinin, and / or California limpet hemocyanin. Therefore, the preferred specific combinations of universal T cell epitopes are selected from the following: (a) a combination of universal T cell epitopes for diphtheria toxin and tetanus toxin; (b) a combination of universal T cell epitopes of the virus Epstein-Barr and tetanus toxin; (c) a combination of universal T cell epitopes of the virus Epstein-Barr virus, tetanus toxin, and California limpet hemocyanin; or (d) a combination of universal T-cell epitopes from influenza hemagglutinin, diphtheria toxin, tetanus toxin, and Epstein-Barr virus. These combinations are preferably provided in the connected formats described. To clarify, while the combinations are preferably included in a specific order, they may be included in an alternative order. For example, if there are three universal T-cell epitopes, A, B, and C, these may be included in any of the following orders: ABC, ACB, BAC, BCA, CAB, or CBA. Specific peptides comprising multiple epitopes for different universal T cells constitute another aspect of the invention. These peptides 1855117 of 55 are preferably included in vaccine compositions of the invention. Accordingly, the useful peptides of the invention comprise, consist essentially of, or consist of amino acid sequences selected from SEQ ID No. 1 (SAT42), SEQ ID No. 2 (SAT43), SEQ ID No. 3 (SAT44), or SEQ ID No. 4 (SAT47). The composition of these peptides is detailed in Table 2 below. Specific peptides comprising epitopes for individual universal T cells also constitute an aspect of the invention. These peptides are preferably included in vaccine compositions of the invention. Accordingly, the useful peptides in the invention comprise, essentially consist of, or consist of amino acid sequences selected from SEQ ID No. 5 (SAT6), SEQ ID No. 6 (SAT13), SEQ ID No. 7 (SAT15), or SEQ ID No. 8 (SAT17). The composition of these peptides is detailed in Table 1 below. Combinations of these peptides, trimmed to a length of 10–20 amino acids, may also be included in vaccine compositions of the invention. The combined peptides are preferably linked by one or more connectives, as defined herein. The Ae-derived antigenic peptide is presented on the surface of liposomes. Typically, this is based on its insertion into the outer surface of the liposomes. Insertion into the outer surface of liposomes can be facilitated by linking the Ae-derived antigenic peptides to units that are inserted into the outer surface of the liposomes. The liposomes can be any liposome suitable for presenting Ae-derived peptide antigens on their surface and encapsulating peptides that comprise epitopes for universal T cells. Typically, the unit comprises a hydrophobic portion for 1855117 of 55 to ensure insertion into the lipid bilayer of liposomes. The unit can be any appropriate unit, but preferably a fatty acid. The fatty acid may comprise a palmitoyl residue. A preferred construction, for example, ACI-24, comprises an Aβ-derived peptide antigen (Aβ(1-15) in ACI-24) linked to two palmitoyl residues at the N and C ends of the peptide. The peptide antigen is thus tetrapalmitolated. This can be facilitated by incorporating two lysine residues at the N and C ends of the Ae-derived peptide antigen. The lysine residues are palmitoylated. In some embodiments, a liposome has a negative surface charge, i.e., it is anionic. Preferably, a liposome comprises phospholipids, and even more preferably, the phospholipids comprise dimyrylsitoylphosphatidylcholine (DMPC) and dimyrylsitoylphosphatidylglycerol (DMPG). A liposome may also comprise cholesterol. In some embodiments, the molar ratio of these three components may be 9:1:7. Therefore, a more preferred construction comprises a peptide antigen derived from Aβ reconstituted in a liposome. Thus, the compositions of the invention may generally be referred to as “liposomal vaccine compositions of the invention.” The Aβ-derived peptide antigen induces a B cell-mediated response in a subject. It is a “B cell antigen.” As previously stated, Aβ plaques are composed of Aβ peptides with a length of between 39 and 43 amino acids, which in their natural, non-pathological form adopt a random coil conformation. During the transition to the pathological state, they are transformed primarily into secondary structures of β sheets, which 1855117 of 55 spontaneously aggregate into insoluble deposits. The Aβ-derived peptide antigen is therefore defined here as a peptide antigen derived from (a maximum of) 43 amino acids of Aβ but not full-length Aβ. More specifically, the Aβ-derived peptide antigen comprises the B-cell immunodominant epitope of Aβ(1-42) but lacks the T-cell epitope found in Aβ(1-42). Hence, in some embodiments, the Aβ-derived peptide antigen comprises, consists essentially of, or consists of between 13 and 15 contiguous amino acids from the 17 N-terminus amino acids of Aβ. It is noteworthy that the Aβ-derived peptide antigen may be provided in the context of a larger peptide molecule, the remainder of which is not derived from the amino acid sequence of Aβ. For example, the peptide may include additional residues, for example, lysine residues to facilitate palmitoylation.These residues are typically found at the N and C ends of the peptide. In this context, the term “consists essentially” denotes that the Aβ-derived peptide antigen comprises between 13 and 15 contiguous amino acids from the 17 N-terminus amino acids of Aβ but may include a limited number of additional residues, for example, four lysine residues to facilitate palmitoylation. A preferred Aβ-derived peptide antigen comprises, consists essentially, or consists of amino acids 1–15 of Aβ, which may be designated “Aβ(1–15)” (WO2007 / 068411, ACI-24). A peptide antigen derived from Aβ in a composition of the invention adopts a secondary structure that replicates a pathological form of Aβ. Preferably, the peptide antigen derived from Aβ adopts a secondary structure with a β-sheet conformation. Even more preferably, the 1855117 of 55 Aβ-derived peptide antigen adopts a predominantly β-sheet conformation when presented on the surface of a liposome. The compositions of the invention typically comprise at least one adjuvant. In some embodiments of the invention, the compositions comprise two adjuvants. The purpose of one or more adjuvants is to enhance or stimulate the immune response in the subject. Preferably, the at least one adjuvant is part of the carrier (rather than being encapsulated therein). Therefore, the at least one adjuvant may be part of a liposome and may be part of the lipid bilayer. The adjuvant may be a lipid-based adjuvant. The adjuvant may be at least partially presented on the surface of the liposome; this may be because the adjuvant is part of the lipid bilayer. In some embodiments, one or more adjuvants that are part of a liposome may be combined with an encapsulated adjuvant.In other embodiments, one or more adjuvants that are part of a liposome may be mixed with an additional adjuvant (such as Alum or CpG) during liposome formation. The carrier (liposome) may function as an adjuvant with the addition to the liposome of monophosphoryl lipid A (MPLA), a term that encompasses MPLA derivatives such as monophosphoryl hexaacyl lipid A, 3-deacyl (synthetic) (3D-(6-acyl) PHAD®), PHAD® (phosphorylated hexaacyl disaccharide), or MPL. Therefore, depending on the specific embodiment, the compositions also include MPLA. MPLA is typically added during liposome formation (as detailed later herein). Accordingly, preferred liposomes comprise dimyrisitoylphosphatidylcholine (DMPC), dimyrisitoylphosphatidylglycerol (DMPG), cholesterol, and MPLA. In some forms of. 1855117 of 55 realization, the molar ratio between these four components can be 9:1:7:0.05. Other adjuvants that can be used according to the invention include aluminum hydroxide (alumina) and CpG, among others. The vaccine compositions of the invention are administered to subjects to treat, prevent, induce protective immune responses, or alleviate the symptoms of a disease or condition associated with beta-amyloid or a condition characterized by or associated with loss of cognitive memory capacity. The vaccine compositions may have both prophylactic and therapeutic applications. The subjects are mammals, typically humans. A disease or condition associated with beta-amyloid can encompass neurological disorders such as Alzheimer's disease (AD). Other examples of diseases or conditions associated with beta-amyloid according to the invention include mild cognitive impairment (MCI), Down syndrome, cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, Lewy body dementia, ALS (amyotrophic lateral sclerosis), adult-onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, reticular dystrophy, and optic neuritis. Several of these conditions are characterized by or associated with a loss of cognitive memory capacity. The conditions characterized by or associated with a loss of cognitive memory capacity according to the invention include AD, mild cognitive impairment (MCI), Down syndrome, cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, 1855117 of 55 Lewy body dementia, ALS (amyotrophic lateral sclerosis) and inclusion body myositis (IBM). The invention provides a method for treating, preventing, inducing a protective immune response, or alleviating the symptoms of a disease or condition associated with beta amyloid or a condition characterized by or associated with loss of cognitive memory capacity in a subject, comprising administering a vaccine composition of the invention to the subject. The methods can also be expressed as medical uses of the vaccine compositions of the invention. Thus, the invention also provides a vaccine composition that can be used in the treatment, prevention, induction of a protective immune response, or relief of the symptoms of a disease or condition associated with beta-amyloid or a condition characterized by or associated with the loss of cognitive memory capacity in a subject. Furthermore, the invention provides for the use of vaccine compositions of the invention in the manufacture of a medicament useful in the treatment, prevention, induction of a protective immune response, or relief of the symptoms of a disease or condition associated with beta amyloid or a condition characterized by or associated with the loss of cognitive memory capacity in a subject. All embodiments of the present invention apply to the medical methods or uses described. Administration of a vaccine composition of the invention to a subject results in the production of typically polyclonal IgG antibodies that bind to pathological forms of Aβ. As indicated, these pathological forms of Aβ comprise multimers of 1855117 of 55 β sheets. Therefore, the antibodies produced can be called “Aβ-specific” antibodies. The ability of an antibody to bind to its target antigen is primarily regulated by two parameters: affinity and avidity. An antibody's affinity determines the strength of the monovalent interaction between the antibody and its antigen. An antibody's avidity encompasses the strengthening of the binding through more than one interaction site between the antigen and the antibody. The ability to detect polyclonal sera induced by vaccination relies on these two parameters (Siegrist, 2013). This is generally referred to as the avidity of the polyclonal response, as it is difficult to assess affinity and avidity independently. As explained in more detail in Example 4 herein (Section 4.2), the inventors developed an ELISA approach that evaluates the overall binding between sera containing polyclonal antibodies and antigens at higher or lower concentrations in parallel (Martineau, 2010).The ratio between low and high signals (the signal representing the concentration of bound antibody) is expressed as the avidity index. A higher index (closer to 1) represents greater overall binding strength compared to a lower index (closer to 0). An increase in the avidity index over time provides an indication of the overall maturation of vaccine-induced antibody avidity. In the present case (Example 4 and Figure 4), it is demonstrated that immunization with vaccine compositions of the invention, comprising an encapsulated peptide containing a universal T-cell epitope, produces a maturation effect greater than one. 1855117 of 55 immunization with ACI-24 (without peptides encapsulated with epitopes for universal T cells). The vaccine compositions of the invention can be administered to subjects by any appropriate route. Those skilled in the art will recognize that vaccine compositions can be administered topically, orally, rectally, nasally, or parenterally (e.g., intravenously, intradermally, subcutaneously, or intramuscularly). Furthermore, vaccine compositions can be incorporated into sustained-release matrices, such as biodegradable polymers, which are implanted in locations near or very near the site of administration. However, in preferred embodiments, a vaccine composition is administered intramuscularly or subcutaneously. To generate protective immune responses, the vaccine compositions of the invention can be administered once to subjects. However, in some embodiments, the vaccine compositions of the invention are administered multiple times to the same subject. Therefore, the invention encompasses what are known as priming-booster regimens. The vaccines are typically administered at intervals of at least one week, frequently approximately one to twelve months. Without wishing to limit the invention to a specific hypothesis, it is believed that by adding a universal T-cell epitope to ACI-24, the anti-Aβ antibody-mediated response is enhanced by providing a second, specific signal from T cells activated with specificity for known epitopes. The vaccine compositions of the invention represent a powerful new therapeutic option for the prevention and treatment of diseases or conditions associated with 1855117 of 55 beta-amyloid, such as EA. In some embodiments, the same vaccine composition is administered each time, in a homologous vaccination regimen. Homologous vaccination encompasses an immunization regimen where the same vaccine is used for both priming (first immunization) and booster (second immunization or any other additional immunization). On the other hand, in a heterologous priming-booster immunization, different vaccines are used for the primary immunization and at least some of the subsequent immunizations. In some embodiments, the vaccine compositions of the invention are administered multiple times to the same subject in a heterologous priming-booster combination, along with other “anti-Aβ” vaccines comprising peptide antigens derived from any portion of the Aβ protein, including peptide antigens derived from regions outside Aβ(1-15). In some embodiments, the vaccine compositions of the invention are administered multiple times to the same subject in a heterologous priming-booster combination, along with other “anti-Aβ” vaccines comprising the same peptide antigens, including Aβ(1-15) peptide antigens.In some embodiments, the vaccine compositions of the invention, preferably comprising Aβ(1-15) peptide antigens, are administered multiple times to the same subject in a heterologous priming-booster combination with other “anti-Aβ” vaccines comprising corresponding Aβ-derived peptide antigens, preferably Aβ(1-15) peptide antigens. Examples of “anti-Aβ” vaccines that can be administered in a priming-booster vaccination together with vaccine compositions of the invention are as follows. 1855117 of 55 comprise Aβ-derived antigens encompass, without limitation, the Ae(1-15)-PARENT vaccine (Agadjanyan et al., 2005; Ghochikyan et al., 2006), the Ae(1-15)-diphtheria toxoid (DT) vaccine or CRM vaccine (WO2010016912), the lysine-linked Aβ(1-15) tandem repeat (Maier et al., 2006), the Aβ(1-15) dendrimeric vaccine (Seabrook et al., 2006), the Aβ(1-15) DT conjugate (Liu et al., 2013), Aβ(1-6) linked to the bacteriophage Qe coating protein (Windblad et al., 2012), Ap(1-7)-CRM (Arai et al., 2015) and Nterm Αβ-KLH (Schneeberger et al., 2010). The invention also provides kits containing vaccine compositions according to the invention. Accordingly, a kit is provided for treating, preventing, inducing a protective immune response to, or alleviating the symptoms of a disease or condition associated with beta-amyloid or a condition characterized by or associated with cognitive memory loss in a subject, comprising a (liposomal) vaccine composition of the invention, as described herein. The kits may include appropriate instructions for use. The instructions for use may explain the administration schedule for the compositions. Accordingly, the kits may comprise multiple (separate) doses of vaccine compositions of the invention. The instructions for use may also explain the storage conditions for the compositions, particularly during the period between administrations of the vaccine composition doses.These kits can be applied to all relevant methods of the invention, as described herein. 1855117 of 55 The invention also provides methods for producing liposomal vaccine compositions of the invention. These methods may comprise the following steps: (a) generate a lipid film; (b) rehydrating the lipid film into a buffer comprising a peptide comprising a universal T cell epitope; (c) generating liposomes from the rehydrated lipid film to encapsulate the peptide comprising a universal T cell epitope and forming a solution containing liposomes comprising encapsulated universal T cell epitopes; (d) adding an amyloid β (Aβ) derived peptide antigen to the solution and maintaining it under appropriate conditions for it to be inserted into the lipid bilayer of the liposomes. These methods are described herein by way of example, and their details may be applied to any aspect of the invention. Generally speaking, the methods may comprise forming a thin lipid film, homogenizing it, and extruding it. Thus, in some embodiments, the lipid film is produced by dissolving a lipid in ethanol and evaporating the ethanol under vacuum. The preferred lipid components for the liposomal vaccine compositions of the invention include DMPC, DMPG, cholesterol, and MPLA (as an adjuvant). The molar ratio of these components may be 9:1:7:0.05. This molar ratio may also be applied to the liposomal vaccine compositions of the invention. The lipid components may be solubilized at elevated temperatures. An elevated temperature may be between 40°C and 80°C, for example, approximately 60°C. 1855117 of 55 In step (b), the buffer used for rehydration may depend on the peptide comprising the universal T-cell epitope employed. In general, any suitable buffer may be used. In some embodiments, the buffer comprises sodium acetate or PBS. If SAT42 is to be encapsulated, the buffer may be sodium acetate. If one or more of SAT43, SAT44, or SAT47 are to be encapsulated, the buffer may be PBS. In all cases, DMSO may be added to the buffer, for example, 5% DMSO. Rehydration may be carried out by shaking the sample. In step (c), liposomes can be generated by agitation in the presence of spheres. Any suitable sphere can be used; for example, glass spheres. In this step, multilamellar vesicles can be produced, which are subsequently converted into liposomes comprising lipid bilayers. This conversion can depend on several freeze-thaw cycles, for example, 5–15, preferably 10. The freeze-thaw cycles can be followed by homogenization. This can be followed by size-based extrusion. In some embodiments, the liposomes are extruded through pores with a diameter (or maximum dimension) of approximately 0.08–0.1 pm. This can occur through a membrane, such as a polycarbonate membrane. The extruded liposomes can be concentrated, for example, using a form of filtration such as ultrafiltration. Step (d) results in the insertion of the amyloid-β (Aβ)-derived peptide antigen into the lipid bilayer of liposomes. The necessary conditions may include agitation for 10–60 minutes, for example, 1855117 of 55 approximately 30 minutes, at a temperature of 25-35°C, such as approximately 30°C. The amyloid β-derived peptide antigen (Aβ) is a tetrapalmitoylated peptide comprising Aβ1-15. To produce the tetrapalmitoylated peptide, this peptide comprises two lysine residues at each end. The peptide can be pre-dissolved in disodium hydrogen phosphate, and then injected into the liposomal solution. As a final step, the method may also involve filtering the vaccine composition. This can be done under sterile conditions. Filtration can occur through a membrane with pores of 0.2 µm. Suitable membranes include polyethersulfone (PES) membranes, which can be supplied as syringe filters. The resulting vaccine composition can be stored under appropriate conditions until use, for example, refrigerated (e.g., at approximately 5°C). Other methods for producing liposomal vaccine compositions of the invention may be based on cross-flow injection, as described by way of example herein. Accordingly, the invention also provides methods for producing liposomal vaccine compositions of the invention by cross-flow injection. These methods may be particularly applicable to compositions in which SAT44 or SAT47 has been encapsulated. These methods may comprise the following steps: (a) Dissolving the lipids that form the liposomes (and the adjuvant, if lipid-based) in a solution; (b) dissolving the peptide comprising a universal T cell epitope in a solution; 1855117 of 55 (c) mixing the solutions from steps (a) and (b) using a cross-flow injection module, to form intermediate liposomes in which the peptide comprising a universal T cell epitope has been encapsulated; (d) extruding intermediate liposomes through a membrane to decrease their size and polydispersity; (e) mixing a solution comprising an amyloid β (Aβ) derived peptide antigen with the solution from step (d) using a cross-flow injection module, resulting in the insertion of the amyloid β (Aβ) derived peptide antigen into the lipid bilayer of liposomes. These methods are described herein by way of example, and their details may be applied to any aspect of the invention. Generally speaking, the methods use cross-flow injection to encapsulate a peptide comprising a universal T-cell epitope and insert an amyloid β (Aβ) peptide antigen into the lipid bilayer of liposomes. In step (a), the lipids (which may comprise an adjuvant, such as an MPLA adjuvant as described herein) are typically dissolved in ethanol. The ethanol may be 90%–100% ethanol, for example, 96% ethanol. Dissolution may be accelerated, for example, by heating to a temperature between 40°C and 80°C, for example, approximately 60°C. The preferred lipid components are those detailed for the liposomal vaccine compositions of the invention and include DMPC, DMPG, cholesterol, and MPLA (as an adjuvant). The molar ratio of these components may be 9:1:7:0.05. This molar ratio may also be applied to the liposomal vaccine compositions of the invention. 1855117 of 55 In step (b), the peptide comprising a universal T cell epitope is dissolved. The peptide may be dissolved in an appropriate buffer (e.g., a His-sucrose buffer), in some embodiments, under agitation, e.g., sonication. In step (c), the solutions from steps (a) and (b) are mixed using a cross-flow injection module to form intermediate liposomes in which a peptide comprising a universal T-cell epitope has been encapsulated. Prior to this step, the solutions from steps (a) and (b) may be filtered. An appropriate filter pore size is approximately 0.2 µm. The solutions may be used at any suitable concentration. Once filtered, the solutions may be heated to a temperature between 30°C and 60°C, for example, approximately 40°C. The liposomes are formed by injecting the two solutions (from steps (a) and (b)) through a cross-flow module (where the two solutions meet). This is generally performed at a specific flow rate and temperature, which should be understandable to those familiar with the technique (the appropriate temperatures are those mentioned previously).In some embodiments, a buffer may be added after liposome formation, typically to decrease the ethanol concentration. Any suitable buffer may be used, for example, a His-sucrose buffer. In step (d), intermediate liposomes are extruded through a membrane to decrease their size and polydispersity. The liposomes formed in solution contain an encapsulated peptide comprising a universal T-cell epitope. Any suitable membrane can be used. 1855117 of 55. An appropriate pore size can be approximately 100 nm. A suitable membrane type is a polycarbonate membrane. This step can be performed at any suitable temperature, preferably at room temperature (e.g., approximately 25°C). Following this step, a filtration step, e.g., ultrafiltration / diafiltration, can be implemented to remove the ethanol. Any suitable membrane can be used in this step, e.g., a hollow fiber membrane with a molecular weight threshold of approximately 500 kDa. A buffer exchange step can be implemented in a dispersion buffer. A preferred dispersion buffer is PBS. The PBS can have a suitable pH, e.g., between 6 and 8, particularly approximately 6.9. For this, between 5 and 15 volume exchanges may be required, e.g., approximately 10.Before step (e), the liposomes can be diluted in the dispersion buffer to the desired concentration. The desired concentration can be in the range of 0.1–10 mg / ml, for example, approximately 1 mg / ml. Before step (e), the solution containing the liposomes can be heated to an appropriate temperature, for example, between 30°C and 60°C, preferably approximately 35°C. Step (e) comprises mixing a solution comprising an amyloid β (Aβ)-derived peptide antigen with the solution from step (d) using a cross-flow injection module. As stated herein, the amyloid β (Aβ)-derived peptide antigen is preferably lipidized (e.g., tetrapalmitoylated), and the description provided applies mutatis mutandis. Prior to mixing, the amyloid β (Aβ)-derived peptide antigen is typically dissolved in a suitable buffer solution, e.g., a solution 1855117 of 55 of Beta-OG 10% w / v in a 10 mM Na2HPO4 buffer, pH 11.4. The solution is generally heated to an appropriate temperature, for example, between 30°C and 80°C, e.g., approximately 60°C. The solution may be further diluted, as needed, to ensure an appropriate concentration of the amyloid-derived peptide antigen β (Aβ). An appropriate concentration may be in the range of 0.1–10 mg / mL, e.g., approximately 1 mg / mL. The pH is typically maintained in the range of 11–12, e.g., approximately 11, preferably 11.4. Mixing the solution comprising an amyloid β (Aβ) derived peptide antigen with the solution from step (d) using a cross-flow injection module results in the insertion of the amyloid β (Aβ) derived peptide antigen into the outer lipid bilayer of liposomes.The mixture can be incubated for a fixed period of time at an appropriate temperature to facilitate the insertion of the amyloid-β (Aβ) peptide antigen into the liposome lipid bilayer. An appropriate time period can be between approximately 20 and approximately 120 minutes, for example, approximately 30 minutes. An appropriate temperature can be between 30°C and 60°C, preferably approximately 35°C. Incubation can be carried out under agitation, for example, centrifugation. After step (e), the product can be recovered for inclusion in the compositions of the invention. In this way, the product can be formulated into a liposomal vaccine composition of the invention. This may include an ultrafiltration / diafiltration step to remove Beta-OG from the buffer solution. Any suitable membrane can be used for this step, for example, a hollow fiber membrane with a molecular weight threshold of 1855117 of 55 approximately 500 kD. Ultrafiltration / diafiltration may include a buffer exchange step in a final buffer. A preferred final buffer is a His-sucrose buffer, which may be 10 mM histidine plus 250 mM sucrose. For this, between 5 and 15 volume exchanges may be required, for example, approximately 10. A concentration step may be implemented to obtain the preferred final volume. A final (sterile) filtration step may also be implemented. In this step, a filter cartridge may be used. The filtration step may be carried out through a sieve with pores of any appropriate size, for example, approximately 0.2 µm. Filtration may be carried out under sterile conditions. The resulting vaccine composition may then be stored under appropriate conditions until use, for example, under refrigeration (e.g., at approximately 5°C). DESCRIPTION OF THE FIGURES Figure 1. (A) Analysis of IgG antibodies specific for Aβ1-42 by ELISA in plasma from C57BL / 6 mice 21 (ACI-24.046) or 7 days (ACI-24, ACI-24.043, ACI-24.044) before (before exsanguination) or 7, 21, or 35 days after the first immunization with the indicated vaccines (arrows represent the time points where immunization was performed). Results are expressed as geometric mean ± 95% confidence interval (CI), in ng / ml, with n=5 mice per group. The X-axis represents the days on which treatments / exsanguinations were performed, while the Y-axis represents the antibody titer, expressed in ng / ml. (B) Analysis of IgG antibodies with specificity for Aβ1-42 by an ELISA in plasma of C57BL / 6 mice 21 (ACI-24.046) or 7 (ACI-24, ACI-24.043, ACI-24.044) days 1855117 of 55 days before (before exsanguination) or 21 days after the first immunization with the indicated vaccines. Results are expressed as geometric mean ± 95% CI, in ng / ml, with 5 mice per group. Statistical analysis between the different groups was performed on day 21: Kruskal-Wallis test with Dunn's multiple comparisons. *p<0.05; **p<0.01. The X-axis represents the individual plasma of the groups immunized with the indicated vaccines, while the Y-axis represents the antibody titer, expressed in ng / ml. Figure 2. (A) Analysis of Aβ1-42 self-association inhibition by an ELISA with IgG antibodies in plasma from C57BL / 6 mice 21 or 7 days before (dotted lines) or 21 days after the first immunization (bold lines) with the indicated vaccines. Results are expressed as mean ± standard deviation of the percentage of Aβ1-42 self-association inhibition, with 5 mice per group. The X-axis represents serial plasma dilutions, while the Y-axis represents the percentage of Aβ1-42 self-association inhibition. (B) Aβ1-42 self-association inhibition is expressed as the percentage (%) of inhibition on day 21 minus the percentage of inhibition on day -21 or -7 (background, prior to exsanguination), with a plasma dilution of 1 / 25. The X-axis represents the groups treated with the indicated vaccines, while the Y-axis represents the percentage of inhibition of Aβ1-42 self-association after background subtraction. Figure 3. Analysis of IgG antibodies specific for Aβ142 oligomers by ELISA in plasma from C57BL / 6 mice 21 (ACI-24.046) or 7 (ACI-24, ACI-24.043, ACI-24.044) days before or 21 days after the first immunization with the indicated vaccines. The results are expressed as 1855117 of 55 geometric mean ± 95% CI, in ng / ml, with 5 mice per group. Statistical analysis between the different groups performed on day 21: Kruskal-Wallis test with Dunn's multiple comparisons. *p<0.05; **p<0.01. The X-axis represents the groups immunized with the indicated vaccines, while the Y-axis represents the antibody titer, expressed in ng / ml. Figure 4. Analysis of Aβ1-42 avidity of IgG antibodies by ELISA in plasma from C57BL / 6 mice 7 or 21 days after the first immunization with the indicated vaccines. Results are expressed as geometric mean ± 95% CI of the avidity index, with 5 mice per group. Statistical analysis: Mann-Whitney U test between day 7 and day 21 for each group. *p<0.05; **p<0.01. The X-axis represents the groups immunized with the indicated vaccines, while the Y-axis represents the avidity index. Figure 5. Analysis of IgG antibodies with αβ oligomer specificity using an MSD approach in serum from Cynomolgus monkeys immunized with ACI-24.046 (SAT44, n=8), ACI-24.045 (SAT43, n=4), or ACI-24.043 (SAT47, n=4) before the first immunization (day 1) and 1 week after the third immunization (day 64). Results are expressed as geometric mean ± 95% CI, in AU / ml. The X-axis represents the individual plasma of the groups immunized with the indicated vaccines, while the Y-axis represents the antibody titer, expressed in AU / ml. Figure 6. Analysis of IgG antibodies specific for Aβ1-42 by ELISA in plasma from C57BL / 6 mice 7 days after 3a immunization (day 36) with the ACI-24 and ACI-24,046 (SAT44) vaccines (A) or the ACI-24 and ACI-24,043 (SAT47) vaccines (B). Results are expressed as the geometric mean ± 95% CI, in ng / ml, with n = 10 mice per group. The X-axis represents the 1855117 of 55 vaccines used for immunization of each particular group, while the Y-axis represents the antibody titer, expressed in ng / ml. Statistical test: Mann-Whitney test between ACI-24 and the indicated vaccine. *p<0.05; **p<0.01; ***p<0.001. Table of Abbreviations ABTS 2,2'-azino-bis(3-ethylbenzothiazolin-6-sulfonic acid) Aβ Beta amyloid (abeta) Ac2O Acetic anhydride EA Alzheimer's disease AP Alkaline phosphatase APC Antigen-presenting cells BSA Bovine calf serum AU / ml Arbitrary units per ml CI Confidence interval DMF Dimethylformamide DMPC 1,2-dimiristoyl-sn-glycero-3-phosphocholine DMPG 1,2-dimiristoyl-sn-glycero-3-phosphorylglycerol DMSO Dimethyl sulfoxide ELISA Enzyme-linked immunosorbent assay HLA Human leukocyte antigen HPLC High-performance liquid chromatography HRP Horseradish peroxidase Ig Immunoglobulin KLH California limpet hemocyanin MPLA Monophosphoryl lipid A 1855117 of 55 SRA Mass Spectrometry MSD Meso Scale Discovery Pal1-15 β1-15 Tetrapalmitoylated PBS Phosphate-buffered saline PES Polyethersulfone pNPP p-Nitrophenyl phosphate SC Subcutaneous TMB Tetramethylbenzidine AFT Trifluoroacetic acid TIS Triisopropylsilane TLR4 Toll-like receptor 4 Beta-OG n-octyl-ε-D-glucopyranoside The invention is best understood with reference to the following non-limiting examples. Example 1. Design of new epitopes for T cells The ability of a T cell epitope to activate T cells (immunogenicity score) results from two complementary properties: (i) HLA affinity and (ii) the ability to bind promiscuously to various HLA haplotypes. An in silico evaluation (Epivax) of various T cell epitopes from different origins was performed to select peptides with the highest immunogenicity scores. In a preliminary phase, 10 peptides from different origins (California limpet hemocyanin [KLH], diphtheria toxin, influenza virus, Epstein-Barr virus, and herpesvirus) were evaluated. Peptides with the highest immunogenicity scores (greater than 10) were selected due to their potential for high immunogenicity. 1855117 of 55 immunogenic in humans, based on the prediction of their affinity for HLA and their ability to react with various HLA haplotypes (the sequences of the selected peptides are provided in Table 1). Table 1 Name Sequence Origin of the peptide SAT6 STLEYFLYDPIFFLHHSNTDRLWAIWQALQKY RGKPYNTANCAIVRHDTY (SEQ ID NO 5) KLH SAT1 3 VHHNTEEIVAQSIALSSLMV (SEQ ID NO 6) Diphtheria toxin SAT1 5 IDGVKLESMGVYQILAIYSTVASSL (SEQ ID NO 7) Influenza hemagglutinin SAT1 7 VYGGSKTSLYNLRRGTALAI (SEQ ID NO: 8) Epstein Barr virus Once the individual peptides were selected, combined promiscuous peptides composed of two or three immunogenic T-cell epitopes from various sources (designated SAT42, SAT43, and SAT44) and promiscuous peptides composed of truncated peptides (e.g., SAT47 or SAT43) were designed (Table 2). The truncated peptides were designed by selecting, within the sequence of each T-cell epitope, the most immunogenic 15-unit peptide sequence, based on the T-cell epitope active regions predicted in silico. The aim was to increase the immunogenicity rating without increasing the size of the final promiscuous peptide, due to limitations in peptide synthesis and vaccine encapsulation processes. In summary, the yield rate and success of peptide synthesis The immunogenicity of peptides 1855117 out of 55 decreases with increasing peptide length, especially when the length exceeds 30 amino acids and when there are primarily hydrophobic residues, as is the case with the T cell epitope peptides described herein. Furthermore, the peptide encapsulation rate decreases with increasing length, since the probability of encapsulating them within the liposome lumen decreases with increasing peptide length. The in silico immunogenicity rating of these four promiscuous T cell epitopes was very high, particularly higher than that of each of the constituent peptides, thus confirming that combining peptides from diverse sources can improve HLA affinity and HLA haplotype coverage (the sequences of the promiscuous T cell epitopes are provided in Table 2). Table 2 No mb re Sequence Peptide design Origin of the peptide SA VHHNTEEIVAQSIALSSLMVPM SAT13+PMGAP+to T4 toxin GAPQYIKANSKFIGITEL (SEQ ID china of tetanus diphtheria+toxin 2 N° 1) of tetanus SA VHHNTEEIVAQSIALSSLMVPM SAT17+VVR+toxin Epstein T4 RQYICANSKFIGITELVVRPIFFL del Barr+tetanus+ 3 HHSNTDRLWAI (SEQ ID N° 2) tetanus+VVR+SAT6 KLH SA VYGGSKTSLYNLRGTALAIVV SAT17+VVR+toxin Epstein T4 RQYICANSKFIGITELVVRPIFFL Number of tetanus Barr+tetanus 4 3) 1855117 of 55 SA T4 7 SMGVYQILAIYSTVVRIVAQSIAL SSVVRYIKANSKFIGVVRLYNLR RGTAL (SEQ ID N° 4) SAT15+VVR+SAT1 3+VVR+tetanus+VV R+SAT17 Hemagglutinin a de influenza+diphtheria+tetanus+ Epstein Example 2. Vaccine Synthesis and Formulation General method for synthesizing and purifying peptides that are epitopes for universal T cells T-cell peptides were manufactured using a single-phase linear synthesis (SPPS) on a 2-chlorotrityl resin via a conventional reaction with Fmoc. The conventional joining procedure was performed with 3.0 equivalents of amino acids and a joining reagent in the presence of 3.0 equivalents of the base in DMF for 1 hour at room temperature. For difficult-to-join sequences, a double joining procedure with an extended reaction time was implemented. After amino acid joining was complete, an acetylation-limiting step was implemented using 5.0 equivalents of Ac₂O in pyridine to abort the elongation of unwanted peptide chains. The resin was washed with DMF, and the Fmoc group was removed using 20% ​​piperidine in DMF for 5 minutes.After SPPS was completed, the peptides were deprotected and cleaved from the resin using a conventional cleavage cocktail (TFA / TIS / water) for 2 hours at room temperature. The resin was separated by filtration and washed with TFA. Subsequently, the crude product was precipitated with a 10-volume excess of cold isopropyl ether / hexane, and the solid was filtered using a glass sieve and dried under vacuum. The crude peptide was... 1855117 of 55 was purified on a C18 reversed-phase column, using a gradient of solvent A (water, 0.1% TFA) and solvent B (acetonitrile, 0.1% TFA) in a preparative HPLC system. HPLC fractions containing the desired peptide with a purity greater than 90% were pooled, diluted in water, and subjected to ion exchange. The desired ion-exchange fractions were lyophilized. The identity and purity of the final peptide were determined and confirmed by HPLC-MS analysis. Preparation of vaccines ACI-24.043 / ACI-24.044 / ACI-24.045 / ACI-24.046 (thin lipid film) Vaccines containing encapsulated T-cell epitope peptides were produced using thin lipid film technology, followed by homogenization and extrusion. First, DMPC, DMPG (Lipoid, Germany), cholesterol, and monophosphoryl hexaacyl lipid A, synthetic 3-deacyl or 3D-(6-acyl) PHAD™ (Avanti Polar Lipids, USA) were solubilized in a molar ratio of 9:1:7:0.05 in ethanol at 60°C. The ethanol was evaporated by vacuum centrifugation to obtain a thin lipid film. The lipid film was rehydrated with one of these buffers (depending on the T cell epitope that was to be encapsulated): • 20 mM sodium acetate, pH 4 (Fluka), 5% DMSO (Sigma Aldrich) in MilliQ water with 0.8 mg / ml of the T cell epitope SAT42; or • 0.1x PBS, pH 7.4, 5% DMSO (all from Sigma-Aldrich) in MilliQ water with 0.3-0.4 mg / ml of the T cell epitope SAT43, SAT44 or SAT47. The solution was gently stirred for 15 minutes. The sample was vigorously shaken in the presence of glass beads. The resulting multilamellar vesicles were subjected to 10 freeze-thaw cycles (N2 The liposomes were homogenized in a 55-unit liquid bath (37°C) and extruded through polycarbonate membranes (Whatman, UK) with a pore size of 0.1 / 0.08 µm. The homogenization and extrusion steps were performed using EmulsiFlex-C5 (Avestin, Canada). The extruded liposomes were concentrated by ultrafiltration, and the buffer was exchanged for PBS, pH 7.4, by diafiltration (10 exchanges). The resulting liposomes were diluted in PBS, pH 7.4, and heated to 30°C before adding Pal1-15. A tetrapalmitoylated human peptide Pal1-15 (Bachem AG, Switzerland) was dissolved in 10 mM Na2HPO4, pH 11.4, in MilliQ water with 1% β-OG (Sigma-Aldrich, USA). The product was injected into the liposomal solution at 30°C, stirred for 30 minutes, and concentrated by ultrafiltration. The resulting liposomes were then diluted in PBS, pH 7.4, by diafiltration. The resulting liposomes were sterilized by filtering through syringe sieves with 0.2 µm polyethersulfone (PES) membranes and stored at 5°C. Preparation of the ACI-24.043 vaccine (cross-flow injection) The lipids (DMPG, DMPC, cholesterol, and 3D-(6-acyl) PHAD™ (Avanti Polar Lipids, USA)) were dissolved in 96% EtOH in a heating cabinet at 60°C. After complete lipid dissolution, the solution was filtered through a 0.2 µm pore size sieve into an injection system heated to 60°C. Specifically, the appropriate amount of ACI-24.043 (SAT47) was dispersed in EtOH at room temperature using sonication (the EtOH concentration was typically 2% v / v of the final SAT47 solution). After complete peptide dispersion, a histidine-sucrose buffer (10 mM histidine, 250 mM sucrose) was added until 1855117 of 55 to obtain a mass ratio between the drug and the lipids of 1 / 50. The SAT47 solution was filtered through a 0.2 µm pore size sieve (Sartoscale sieve) into the bottle containing the injection buffer, which was then heated to 40°C. Liposomes formed at the injection site when the lipid / EtOH solution and the injection buffer were mixed. Immediately after liposome formation, an online dilution step was implemented with 10 mM histidine and 250 mM sucrose to decrease the EtOH concentration. The intermediate liposomes were extruded through 100 nm pore size polycarbonate membranes (1 pass) at room temperature. To remove EtOH, ultra / diafiltration (UDF) was performed using a hollow fiber membrane (molecular weight threshold: 500 kD) and the buffer was exchanged for PBS, pH 6.9 (10 volume exchanges).The liposomes were then diluted with SAT47 using dispersion buffer (PBS, pH 6.9) to a total lipid concentration of 1 mg / ml and heated to 35°C. Pal1-15 was dissolved in a 10% w / v beta-OG solution in 10 mM Na2HPO4 buffer, pH 11.4, at 60°C, and further diluted in the same buffer to a final concentration of 1 mg / ml. The pH was adjusted to 11.4. After mixing these two solutions using a cross-flow injection module, the liposomal suspension was further incubated at 35°C for 30 minutes under shaking to allow complete incorporation of Pal1-15. A second UDF step was implemented using a hollow fiber membrane (molecular weight threshold: 500 kD) to remove beta-OG, and the buffer was exchanged for 10 mM histidine and 250 mM sucrose (10 volume exchanges). The product. 1855117 of 55 was concentrated to the final volume and filtered through 0.2 μm Acrodisc mPES syringe sieves. Preparation of the ACI-24.046 vaccine (cross-flow injection) Lipids (DMPG, DMPC, cholesterol, and 3D-(6-acyl)PHAD™ (Avanti Polar Lipids, USA)) were dissolved in 96% EtOH in a heating cabinet at 60°C. After complete lipid dissolution, the solution was filtered through a 0.2 μm pore sieve into an injection system heated to 60°C. In parallel, ACI-24.046 (SAT44) was dissolved in the injection buffer (10 mM histidine, 250 mM sucrose) at 40°C. After complete dissolution of SAT44, the solution was filtered through a 0.2 μm pore sieve (Sartoscale) into the injection buffer bottle, which was then heated to 40°C. Liposomes formed at the injection site when the lipid / EtOH solution and injection buffer were mixed. Immediately after liposome formation, an online dilution step was implemented using 10 mM histidine and 250 mM sucrose to decrease the EtOH concentration.Intermediate liposomes were extruded through polycarbonate membranes with 100 nm pores (1 pass) at room temperature. To remove EtOH, ultrafiltration / diafiltration (UDF) was performed using a hollow fiber membrane (molecular weight threshold: 500 kDa), and the buffer was exchanged for PBS, pH 6.9 (10 volume exchanges). The liposomes were then diluted with SAT44 using the dispersion buffer (PBS, pH 6.9) to a total lipid concentration of 1 mg / ml and heated to 35°C. Pal1-15 was dissolved in a 10% w / v beta-OG solution in 10 mM Na₂HPO₄ buffer, pH 11.4, at 60°C, and further dilution was performed in the same buffer. 1855117 of 55 to reach a final concentration of 1 mg / ml. The pH was checked and carefully adjusted once again to 11.4. After mixing these two solutions using a cross-flow injection module, the liposomal suspension was further incubated at 35°C for 30 minutes under shaking to allow complete insertion of Pal1-15. A second UDF step was implemented using a hollow fiber membrane (molecular weight threshold: 500 kD) to remove beta-OG, and the buffer was exchanged for 10 mM histidine and 250 mM sucrose (10 volume exchanges). The product was concentrated to the final volume and filtered through 0.2 µm Acrodisc mPES syringe sieves. Example 3. In vivo immunogenicity studies with vaccines containing encapsulated T-cell epitopes as proof of concept (PoC) Following successful encapsulation of various T-cell epitopes, the immunogenicity of vaccines containing the encapsulated T-cell epitopes with high immunogenicity ratings, SAT42, SAT44, and SAT47 (ACI-24.044, ACI-24.046, and ACI-24.043 vaccines, respectively), was evaluated in vivo compared to the ACI-24 vaccine. Wild-type C57BL / 6 mice received a total of three subcutaneous (SC) immunizations on days 0, 14, and 28, using ACI-24, ACI-24.044 (encapsulated SAT42), ACI-24.046 (encapsulated SAT44), and ACI-24.043 (encapsulated SAT47). Blood samples were collected on days -21 (ACI-24.046), -7 (ACI-24, ACI-24.043, ACI-24.044) (before exsanguination), 7, 21 or 35 to determine IgG titer with Aβ1-42 specificity by ELISA. Plates were coated with 10 pg / ml of a film containing the human Aβ1-42 peptide (Bachem, Switzerland) overnight at 4°C. After washing with Tween 1855117 of 55 0.05% / PBS and blocked with 1% BSA / 0.05% Tween / PBS, serial dilutions of plasma were added to the plates and incubated at 37°C for 2 hours. After washing, the plates were incubated with an alkaline phosphatase (AP)-conjugated mouse anti-IgG antibody (Jackson ImmunoResearch, PA, USA) for 2 hours at 37°C. After a final wash, the plates were incubated for 2.5 hours with the AP substrate (pNPP) and read at 405 nm using an ELISA plate reader. Results are expressed relative to serial dilutions made with a commercially available antibody (6E10, Biolegend, UK, Cat. 803002). Figure 1A shows the titration of IgG with specificity for Aβ1-42 induced by the ACI-24 vaccine, with or without epitopes for encapsulated T cells, over time.Although the ACI-24 vaccine resulted in the highest IgG titer with Aβ1-42 specificity on day 7, after the first immunization, an increase in antibody titer was observed after the second and third immunizations, when a T cell epitope was encapsulated in the ACI-24 vaccine. Based on the results in Figure 1B, it can be observed that immunization with ACI-24 vaccines comprising encapsulated T cell epitopes induced an increase in antibody titers specific to Aβ, compared to ACI-24, which reached statistical significance for the group immunized with the ACI-24.043 vaccine (encapsulated SAT47). Vaccines containing encapsulated SAT42, SAT43, SAT44, or SAT47 were evaluated in a study in Cynomolgus monkeys. Four monkeys per group received three monthly subcutaneous immunizations (on days 1, 29, and 57) with 1855117 of 55 the ACI-24.044 vaccine (SAT42 encapsulated - two groups with a total of 8 monkeys), the ACI-24.046 vaccine (SAT44 encapsulated - 2 groups with a total of 8 monkeys), the ACI-24.045 vaccine (SAT43 encapsulated - 4 monkeys) or the ACI-24.043 vaccine (SAT47 encapsulated - 4 monkeys). Blood was drawn before the first immunization (day 1) and 1 and 3 weeks after each immunization (days 8, 22, 36, 50, 64 and 78) to determine the IgG titer with specificity for Aβ1-42 by an ELISA. The plates were coated with 10 pg / ml of a human Aβ1-42 peptide film (Bachem, Switzerland) overnight at 4°C. After washing with 0.05% Tween 20 / PBS and blocking with 1% BSA / Tween 20 / 0.05% PBS, eight serial dilutions of serum medium were applied to the plates and incubated at 37°C for 2 hours. After washing, the plates were incubated with horseradish peroxidase-conjugated (HRP) anti-monkey IgG antibody (KPL, Cat. No. 074 11 021) for 2 hours at 37°C. After washing, the plates were incubated with 50 µL of ABTS / H₂O₂ (2,2'-azino-bis(3-ethylbenzothiazolin-6-sulfonic acid) (substrate for HRP)) and read at 405 nm after one hour using an ELISA plate reader. The results were expressed relative to serial dilutions from a group of positive monkeys used as a reference. The immunogenicity of vaccines with various T-cell epitopes was compared to that of the ACI-24 vaccine. Table 3 shows the increase in antibody titers specific for Aβ compared to the ACI-24 vaccine 1 week after the third immunization. All the vaccines evaluated, ACI-24.046 (SAT44), ACI-24.043 (SAT47), ACI-24.045 (SAT43), and ACI-24.044 (SAT42), induced an increase in antibody titers of 1855117 of 55 at least 7 times (ACI-24.044 with encapsulated SAT42), compared to the titer induced by the ACI-24 vaccine. The ACI-24.043 (encapsulated SAT47) and ACI-24.046 (encapsulated SAT44) vaccines induced significantly higher Aβ-specific antibody titers than ACI-24 1 week after the third immunization (Table 3). The ACI-24.043 (encapsulated SAT47) and ACI-24.046 (encapsulated SAT44) vaccines had high Epivax scores (142.89 and 57.2, respectively). Table 3. Increase in antibody titer specific for Aβ compared to ACI-24 (1 week after the third immunization, day 64) ACI-24.046 vaccine (SAT44 encapsulated) ACI-24.043 (SAT47 encapsulated) ACI-24.045 (SAT43 encapsulated) ACI-24.044 (SAT42 encapsulated) Increase, expressed in times, in the titer of IgG with specificity for Aβ, in relation to ACI-24 40, p=0.002 7 (**) 144, p=0.0003 (***) 17, p=0.1408 (ns) 7, p=0.6003 (ns) Statistical analysis: Kruskal-Wallis test with Dunn's multiple comparisons; *p<0.05; **p<0.01; ***p<0.001; ns: not significant Based on the in vivo results obtained (Figure 1) with the ACI-24.046 (SAT44 encapsulated) and ACI-24.043 (SAT47 encapsulated) vaccines manufactured with thin lipid film technology, the in vivo immunogenicity of the same vaccines manufactured with a method was evaluated 1855117 of 55 cross-flow injection. Wild-type C57BL / 6 mice were subjected to a total of three subcutaneous (sc) immunizations on days 0, 14, and 28 with the vaccines ACI-24, ACI-24.046 (encapsulated SAT44), or ACI-24.043 (encapsulated SAT47). Blood samples were taken on days 7, 7, 21, and 35 to determine IgG titers specific for Aβ1-42 using an ELISA. Based on the results in Figure 6, it can be concluded that immunization with ACI-24 vaccines comprising encapsulated T cell epitopes induced a significant increase in the titer of antibodies with Aβ specificity, compared to ACI-24. Example 4. Quality of antibodies with specificity for induced Aβ 4.1. Inhibition of human Aβ1-42 self-association in vitro The quality of the induced Aβ-specific antibodies was assessed in vitro by measuring the inhibition of Aβ1-42 self-association / aggregation. This study is based on the ability of mouse plasma before and after immunization to alter the natural predisposition of human Aβ1-42 to self-associate. Conventional ELISA plates were coated with 1 pg / ml of Aβ1-42 overnight at 4°C. The plates were washed four times with 300 ml of 0.05% Tween 20 / PBS. Saturation was achieved by adding 0.5% BSA / PBS and incubating for 1 hour at 37°C. After washing, four plasma dilutions were serially added to the plates for 20 minutes at room temperature with shaking. Biotinylated Aβ1-42 was added to each well to a final concentration of 0.1 pg / ml and incubated at room temperature for 2 hours with shaking. Biotinylated Aβ1-42 without plasma was used as a positive control for Aβ1-42 self-association (considered as 1855117 of 55 (100% self-association, 0% inhibition). After a washing step, the plates were incubated with streptavidin-conjugated horseradish peroxidase (HRP) (R&D Systems, Canada, Ref. 890803), at a 1 / 200 dilution in 0.5% BSA / 0.05% Tween 20 / PBS, for 1 hour at room temperature with shaking. After washing, the plates were incubated with Sure Blue Reserve TMB substrate (Seracare, Cat. 5120-0081) for 10 minutes. The reaction was stopped with Bethyl termination solution (Bethyl Laboratories, Inc., Cat. E115), and the plates were read at 450 nm using an ELISA plate reader. The percentage of self-association inhibition was calculated in relation to biotinylated Aβ1-42 without plasma as a positive control (0% inhibition). Based on the results, it was concluded that Aβ-specific antibodies generated after two immunizations with all vaccines containing T-cell epitopes affected Aβ1-42 self-association more efficiently than ACI-24-induced antibodies (Figure 2A). Because pre-exsanguination plasma induces background inhibition of self-association, the percentage on day 21 was normalized by subtracting the pre-exsanguination background. Anti-Aei-42 specific antibodies generated by immunization with all ACI-24 vaccines containing T-cell epitopes induced greater inhibition of Aβ1-42 self-association than ACI-24: this inhibition reached statistical significance in the group immunized with ACI-24.046 (encapsulated SAT44) (Figure 2B). 4.2. Generation of antibodies that recognize Aβ oligomers To evaluate the specificity of the induced antibodies in binding to pathological Aβ oligomers in C57BL / 6 mice, the responses were determined 1855117 of 55 IgG with specificity for Aβ1-42 oligomers by ELISA. Plates were coated with 10 μg / ml of oligomers prepared as previously described (Adolfsson, 2012) overnight at 4°C. After washing with 0.05% Tween 20 / PBS and blocking with 1% BSA / 0.05% Tween 20 / PBS, serial plasma dilutions were added to the plates and incubated at 37°C for 2 hours. After washing, the plates were incubated with an alkaline phosphatase-conjugated mouse anti-IgG antibody (Jackson ImmunoResearch, Cat. 115055-164, PA, USA) for 2 hours at 37°C. After the final wash, the plates were incubated for 2.5 hours with the AP substrate (pNPP) and read at 405 nm using an ELISA plate reader. The results were expressed relative to serial dilutions of a commercially available antibody (6E10, Biolegend, UK, Cat. 803002). Each sample was analyzed in eight or four serial half dilutions, starting with a 1 / 100, 1 / 400, 1 / 800, or 1 / 1600 dilution, depending on the Aβ1-42 antibody titer. Based on the results in Figure 3, it was concluded that immunization with all ACI-24 vaccines containing T-cell epitopes induced an increase in antibody titers specific for Aβ1-42 oligomers, compared to ACI-24, which reached statistical significance for the group immunized with the ACI24.043 (encapsulated SAT47) vaccine. The avidity index of antibodies induced in C57BL / 6 mice was determined 7 and 21 days after immunization using an ELISA. Half of a conventional ELISA plate was coated with 10 μg / ml of an Aβ1-42 peptide film, while the other half was coated with 1 μg / ml of an Aβ1-42 peptide film, overnight at 4°C. After washing Eight serial dilutions were applied to plasma medium under both coating conditions and incubated at 37°C for two hours. After a wash step, the plates were incubated with an alkaline phosphatase (AP)-conjugated mouse anti-IgG antibody (Jackson ImmunoResearch, Cat. 115-055-164, PA, USA) for two hours at 37°C. After the final wash, the plates were incubated for 2.5 hours with the AP substrate (pNPP) and read at 405 nm using an ELISA plate reader. The results were expressed relative to serial dilutions of a commercially available antibody (6E10, Biolegend, UK, Cat. 803002). To determine the avidity index, AU / ml were calculated for each sample with both coatings using a reference curve obtained with 10 pg / ml of the Aβ1-42 peptide. OD values ​​between 0.6 and 2.8 were used for subsequent concentration calculations. The avidity index was calculated as the ratio of antibody concentration at the lowest coating concentration (1 pg / ml of the Aβ1-42 peptide) to the saturated coating concentration (10 pg / ml of the Aβ1-42 peptide). Based on the results in Figure 4, it was concluded that immunization with all ACI-24 vaccines containing epitopes for T cells induced the maturation of antibody avidity with specificity for Aβ1 42 between the first and second immunization (day 7 and day 21 respectively), which reached statistical significance in the groups immunized with ACI24.044 (SAT42 encapsulated) and ACI-24.043 (SAT47 encapsulated). To evaluate the binding specificity of the antibodies induced in Cynomolgus monkeys, IgG titers with specificity were determined 1855117 of 55 by pathological Aβ1-42 oligomers using Meso Scale Discovery (MSD) technology on day 64 (1 week after the third immunization) in serum immunized with the ACI-24.046 vaccine (SAT44 encapsulated - 2 groups with a total of 8 monkeys), the ACI-24.045 vaccine (SAT43 encapsulated - 4 monkeys) or the ACI-24.043 vaccine (SAT47 encapsulated - 4 monkeys). MSD plates were saturated with streptavidin overnight with 5% of the A-blocker (MSD, Ref. R93BA-4) at 4°C. The next day, the plates were washed 4 times with Tween 20 at 0.05% / PBS and coated with 25 pl of the biotinylated capture antibody 6E10 (Biolegend, Ref. 803008) in PBS, at a rate of 0.5 pg / ml, for 1 hour on a shaker at 37°C. After washing, the plates were incubated with 25 pl of Aβ1-42 oligomers (Adolfsson, 2012), at a rate of 10 pg / ml in PBS, for 1 hour at 37°C on a shaker.The plates were washed and incubated with eight dilutions to monkey serum medium (initial dilution: 1 / 50 in 1% skim milk / 0.05% Tween / PBS). The samples were incubated for 2 hours at 37°C on a shaker. The plates were washed four times, and a SULFO-TAG-labeled anti-human IgG detection antibody (Jackson, Ref. 109-005098) was added and diluted in 1% skim milk / Tween 20 / 0.05% PBS for 1 hour at 37°C on a shaker. After four washes, MSD T 2X reading buffer (MSD, Ref. R92TC-2) was added, and the plates were read for 5 minutes. The results are expressed relative to serial dilutions of the reference monkey group. Based on the results, it was concluded that all the vaccines evaluated, ACI-24.046 (encapsulated SAT44), ACI-24.043 (encapsulated SAT47) and ACI-24.045 (encapsulated SAT43), induced an increase in the amount of antibodies capable of recognizing Aβ oligomers on day 64 (1 week 1855117 of 55 days after the third immunization compared with day 1 (before the first immunization); see figure 5. REFERENCES Adolfsson, O., Pihlgren, M., Toni, N., Varisco, Y., Buccarello, AL, Antoniello, K., Lohmann, S., Piorkowska, K., Gafner, V., Atwal, JK, Maloney, J., Chen, M., Gogineni, A., Weimer, RM, Mortensen, DL, Friesenhahn, M., Ho, C., Paul, R., Pfeifer, A., Muhs, A., Watts, R.J., An effector-reduced anti-e-amyloid (AP) antibody with unique aP binding properties promotes neuroprotection and glial engulfment of Λβ, J. Neurosci, 11 de Julio, 32(28):9677-89 (2012). Agadjanyan, M.G., Ghochikyan, A., Petrushina, I., Vasilevko, V., Movsesyan, N., Mkrtichyan, M., Saing, T, y Cribbs, D.H., Prototype Alzheimer's Disease Vaccine Using the Immunodominant B Cell Epitope from β-Amyloid and Promiscuous T Cell Epitope Pan HLA DR-Binding Peptide, J. Immunol., 174 (3), 1580-1586 (2005). Arai, H., Suzuki, H., Yoshiyama, T., Vanutide cridificar and the QS-21 adjuvant in Japanese subjects with mild to moderate Alzheimer's disease: results from two phase 2 studies, Curr. Alzheimer Res., 12(3):242-54 (2015). Ghochikyan, A., Mkrtichyan, M., Petrushina, I., Movsesyan, N., Karapetyan, A., Cribbs, D. H., Agadjanyan, M. G., Prototype Alzheimer's disease epitope vaccine induced strong Th2-type anti-Abeta antibody response with Alum to Quil A adjuvant switch, Vaccine, 20, 24(13):2275-82 (2006). Gilman, S., Koller, M., Black, R. S., Jenkins, L., Griffith, S. G., Fox, N. C., Eisner, L., Kirby, L., Boada Rovira, M., Forette, F., Orgogozo, J. M., Clinical effect of AP immunization (AN1792) in patients with AD in an interrupted trial, Neurology, 64, 1553-1562 (2005). 1855117 de 55 Liu, B., Frost, J. L., Sun, J., Fu, H., Grimes, S., Blackburn, P., Lemere, C. A., MER5101, a novel Ae1-15:DT conjugate vaccine, generates a robust anti-Ae antibody response and attenuates Ae pathology and cognitive deficits in APPswe / PS1ΔE9 transgenic mice, J. Neurosci., 33(16):7027-37 (2013). Lutzner, N., Kalbacher, H., Quantifying Cathepsin S Activity in Antigen Presenting Cells Using a Novel Specific Substrate, J. Biol. Chem., vol. 283, N° 52, p. 36185 (2008). Maier, M., Seabrook, T. J., Lazo, N. D., Jiang, L., Das, P., Janus, C., Lemere, C. A., Short amyloid-beta (Abeta) immunogens reduce cerebral Abeta load and learning deficits in an Alzheimer's disease mouse model in the absence of an Abeta-specific cellular immune response, J. Neurosci., 3, 26(18):4717-28 (2006). Martineau, P., capítulo 41: Affinity Measurements by Competition ELISA, Pages 657-665, de Antibody engineering, vol. 1, R. Kontermann y S. Dübel (2010) Monsonego, A., Weiner, H. L., Immunotherapeutic approaches to Alzheimer's disease, Science, 31, 302(5646):834-8 (2003). Muhs, A., Hickman, D.T., Pihlgren, M., Chuard, N., Giriens, V., Meerschman, C., van der Auwera, I., van Leuven, F., Sugawara, M., Weingertner, M.-C., Bechinger, B., Greferath, R., Kolonko, N., Nagel-Steger, L., Riesner, D., Brady, RO, Pfeifer, A., Nicolau, C., Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice, PNAS, 104, 23:9810-9815 (2007). Orgogozo, JM, Gilman, S., Dartigues, JF, Laurent, B., Puel, M., Kirby, LC, Jouanny, P., Dubois, B., Eisner, L., Flitman, S., Michel, BF, Boada, M., Frank, A., Hock, C., Subacute meningoencephalitis in a subset of patients with AD after Abet42 immunization, Neurology, 61:46-54 (2003). 1855117 of 55 Pihlgren, M., Silva, A. B., Madani, R., Giriens, V., Waeckerle-Men, Y., Fettelschoss, A., Hickman, D. T., López-Deber, M. P., Ndao, D. M., Vukicevic, M., Buccarello, A. L., Gafner, V., Chuard, N., Reis, P., Piorkowska, K., Pfeifer, A., Kündig, T. M., Muhs, A., Johansen, P., TLR4- and TRIF-dependent stimulation of B lymphocytes by peptide liposomes enables T cell-independent isotype switch in mice, Blood, 3 de Enero, 121(1):85-94 (2013). Sallusto, F., Lanzavecchia, A., Araki, K., Ahmed, R., From vaccines to memory and back, Immunity, 29 de Octubre, 33(4):451-63 (2010). Schneeberger, A., Mandler, M., Mattner, F., Schmidt, W., AFFITOME® technology in neurodegenerative diseases: the doubling advantage, Hum. Vaccin., 11:948-52 (2010) Seabrook, T. J., Thomas, K., Jiang, L., Bloom, J., Spooner, E., Maier, M., Bitan, G., Lemere, C. A., Dendrimeric Abeta1-15 is an effective immunogen in wildtype and APP-tg mice, Neurobiol. Aging, 28(6):813-23 (2006). Siegrist, C. A., capítulo 2: Vaccine Immunology, páginas 14-32, de Vaccine (6aedición 2013), Walter A. Orenstein y Paul. Soto, C., Plaque busters: strategies to inhibit amyloid formation in Alzheimer’s disease, Molecular Medicine Today (vol. 5), Agosto de 1999. Winblad, B., Graf, A., Riviere, M. E., Andreasen, N., Ryan, J. M., Active immunotherapy options for Alzheimer's disease, Alzheimers Res. Ther., 30 de Enero de 2014, 6(1):7. Winblad, B., Andreasen, N., Minthon, L., Floesser, A., Imbert, G., Dumortier, T., Maguire, R. P., Blennow, K., Lundmark, J., Staufenbiel, M., Orgogozo, J. M., Graf, A., Safety, tolerability, and antibody response of active Ap immunotherapy 1855117 de 55 with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study, Lancet. Neurol., 11(7):597-604 (2012). Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those commonly given to them by those skilled in the art to which this invention pertains. All publications and patents specifically mentioned herein are incorporated by reference in their entirety for all purposes related to the invention. The scope of the present invention is not limited by the specific embodiments described. In fact, those skilled in the art should be able to conceive of various modifications based on the preceding description and accompanying figures. These modifications should fall within the scope of the appended claims. Furthermore, it is considered that all aspects and embodiments of the invention described herein can be broadly applied and combined with any other consistent embodiment, including those taken from other aspects of the invention (even individually), as appropriate. 1855117 of 55 MIGUEL NORBERTO ARMANDO - 20109002225 Digitally signed by PORTALTRAM ITES - INPI Date: 2022.07.06 10:08:42 -03:00 Reason: Digitally Signed by the INPI Location: Buenos Aires, Argentina 1855117

Claims

1. A liposomal vaccine composition characterized in that it comprises: (a) an amyloid β (Aβ)-derived peptide antigen presented on the liposome surface, wherein the Aβ-derived peptide antigen comprises amino acids 1-15 of Aβ; (b) a peptide comprising a universal T-cell epitope, wherein the peptide comprises: i. the amino acid sequence of SEQ ID NO: 6 and the tetanus toxin domain of SEQ ID NO: 1; ii. the amino acid sequence of SEQ ID NO: 8, the tetanus toxin domain of SEQ ID NO: 2, and an immunogenic domain of California limpet hemocyanin (KLH); iii. the amino acid sequence of SEQ ID NO: 8 and the tetanus toxin domain of SEQ ID NO: 3; or v.an immunogenic domain of influenza hemagglutinin, the diphtheria toxin domain of SEQ ID NO: 4, the tetanus toxin domain of SEQ ID NO: 4, and the Epstein-Barr virus domain of SEQ ID NO: 4; and wherein the universal T-cell epitope is encapsulated in the liposome, stimulating a helper T-cell-mediated response that enhances antibody production by B cells; (c) an adjuvant, wherein the adjuvant comprises monophosphoryl lipid A (MPLA), CpG, or both MPLA and CpG. 15 Claims follow.