Composite aids vaccine generating Anti-hiv specific neutralizing antibodies and / or Anti-hiv cytotoxic t cells

Abstract

In the present invention, the Applicant provides a novel method for prophylactically or curatively treating acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)-seropositive patient. The Applicant also provides a novel method for preventing acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)-seronegative patient. The Applicant further provides a novel method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)-seropositive Elite Controller patient.

Description

COMPOSITE AIDS VACCINE GENERATING ANTI-HIV SPECIFIC NEUTRALIZING ANTIBODIES AND / OR ANTI-HIV CYTOTOXIC T CELLSFIELD OF INVENTION

[0001] In the present invention, the Applicant provides a novel method for prophylactically or curatively treating acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive patient. The Applicant also provides a novel method for preventing acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seronegative patient. The Applicant further provides a novel method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive Elite Controller patient.BACKGROUND OF INVENTION

[0002] Soon after the initial discovery of human immunodeficiency virus (HIV) as the cause of acquired immune deficiency syndrome (AIDS), a very small group of HIV-infected patients has been identified to remain AIDS-free for several decades. These so-called HIV elite controllers (EC) usually have relatively high CD4+T cell counts and are able to maintain clinically undetectable plasma HIV-1 RNA level (HIV RNA <50 copies / mL) during a prolonged period of time in the absence of any antiretroviral treatment (ART). During recent years, extensive research has been made to define mechanisms by which these rare individuals control HIV.

[0003] Interestingly, the EC status suggests a low activation profile of T cells and the existence of a unique MHC-lb / E-restricted CD8+T cell population able to suppress the early activation of pathogenic HIV antigen-presenting CD4+T cells. Furthermore,recent advances in the field of SIV vaccinology also have highlighted the role of MHC- Ib / E-restricted CD8+T cell responses in controlling SIV infection in rhesus macaques. These observations have suggested alternative strategies for developing an HIV vaccine.

[0004] Indeed, since an activated state of the CD4+T cell is a prerequisite for productive HIV infection also in vivo, and thus replication in quiescent CD4+T cells is essentially nonproductive and generally abortive, it has been hypothesized that it might be possible to suppress viral replication by interfering with the CD4+T cell activation. Therefore, several groups have tempted to suppress virus-specific CD4+T cell activation with vaccines that induce MHC-lb / E-restricted CD8+cells.

[0005] For example, Andrieu et al. have developed a vaccine able to induce MHC- lb / E-restricted CD8+T cells in macaques. This vaccine consisted of inactivated simian immunodeficiency virus (SIV) particles associated with a tolerogenic adjuvant, such as, for example, Lactobacillus plantarum. Although this vaccine strategy effectively immunized and induced suppressive MHC-lb / E-restricted CD8+T cells in Chinese macaques, macaques of Indian origin that were immunized with the same adjuvanted vaccine were not protected.

[0006] Hansen et al., by modifying cytomegalovirus (CMV) vectors determinants that control unconventional T cell priming, have shown that it was possible to uniquely tailor the CD8+T cell response in order to maximize prophylactic or therapeutic protection. Specifically, it was found that the use of such rhesus cytomegalovirus vectors expressing SIV protein in rhesus macaques (RMs) induces post-challenge sterile protection against SIV. However, this protection was effective in only 50% of vaccinated RMs.

[0007] Globally, these results have expanded the current paradigm from one focused on a preventive HIV vaccine to one in which an immunotherapy for HIV / AIDS can be an essential part of the fight against this pandemic. Thus, in addition to a preventive vaccine, there remains a need for an effective therapy to treat individuals living with

[0008] The applicant has recently shown that elevated IFN-a is the key pathogenic mediator of HIV pathogenesis blocking initiation of anti-HIV adaptive immune reaction.

[0009] Moreover, they have shown that the receptor of type III interferon (IFNXR) are not constitutively expressed by CD4+ T cells and do not harm anti-viral responses. Therefore, type III interferon (IFNk) may be used as a substitute to elevated IFN- a during anti-HIV immune reaction.

[0010] Based on the discovery of pathogenic effects of type I interferons (in particular, IFN-a) and on beneficial effects of type III interferon (IFN-III), the Applicant proposes to improve existing vaccine strategies for preventing or treating HIV.

[0011] In the present invention, the Applicant thus provides a novel method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) in a subject in need thereof, comprising administering to the subject a composite vaccine including a broadly neutralizing antibody (bnAb) or an antiretroviral (ART) agent, optionally a type III interferon or an agent stimulating the production of type III interferon, an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, a tolerogenic vaccine specific for at least one HIV antigen and / or an effector vaccine comprising at least one HIV immunogen. The present invention thus relates to a composite AIDS vaccine or immunotherapy generating anti-HIV specific neutralizing antibodies and / or anti-HIV specific cytotoxic T cells.SUMMARY

[0012] This invention relates to a composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of typeIII interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prophylactic treatment or curative treatment of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive patient with no AIDS symptoms or with AIDS symptoms, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during a priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccineare to be administered to the subject during a boosting phase following the priming phase.

[0013] This invention further relates to a composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of typeIII interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prevention of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)- seronegative patient, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure during a priming phase and a boosting phase, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during the priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccineare to be administered to the subject during the boosting phase following the priming phase.

[0014] This invention further relates to a composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of typeIII interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prophylactic treatment or curative treatment of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive Elite Controller patient, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure during a priming phase and a boosting phase, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during the priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, andc) the effector vaccine are to be administered to the subject during the boosting phase following the priming phase.

[0015] The invention further relates to composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, and c) optionally a type III interferon or an agent stimulating the production of typeIII interferon.

[0016] In some embodiments, the at least one antiretroviral (ART) agent is selected from the group consisting of Nucleoside reverse transcriptase inhibitors (NRTIs), Nonnucleoside reverse transcriptase inhibitors (NNRTIs), Protease inhibitors (Pls), Integrase inhibitors (INSTIs), Fusion inhibitors (FIs), Chemokine receptor antagonists (CCR5 antagonists) and Entry inhibitors (CD4-directed post-attachment inhibitors).

[0017] In some embodiments, the type III interferon is IFN-kl , IFN-X2, IFN-X3 and / or IFN-X4, and wherein the agent stimulating the production of type III interferon comprises a TLR ligand, a RIG-I ligand, and / or a MDA5 ligand.

[0018] In some embodiments, the type III interferon is at least one IFN-kl , IFN-X2, IFN-Z3 and / or IFN-Z4 protein, at least one plasmid comprising a DNA sequence encoding IFN-kl, IFN-X2, IFN-X3 and / or IFN-X4, or at least one RNA molecule or mRNA-LNP encoding IFN- 1, IFN-Z2, IFN-Z3 and / or IFN-X4.

[0019] In some embodiments, the agent neutralizing circulating interferon alpha is an antiferon, an anti-IFN-a antibody, or an anti-IFN-a hyper-immune serum; and wherein the blocking agent of interferon alpha signaling is an anti-type I interferon R1 or R2 antibody, or an interferon alpha endogenous regulator including SOSC1 or an aryl hydrocarbon receptor.

[0020] In some embodiments, the agent neutralizing circulating interferon alpha or blocking interferon alpha signaling is, or is combined with, an agent neutralizing circulating interferon beta or blocking interferon beta signaling.

[0021] In some embodiments, the tolerogenic vaccine elicits suppressor MHC-lb / E- restricted CD8+T cells.

[0022] In some embodiments, the tolerogenic vaccine is a live viral vector selected from the group consisting of cytomegalovirus (CMV), lentivirus, vaccinia virus, adenovirus and plasmid, and wherein the tolerogenic vaccine comprises at least one HIV immunogen, said HIV immunogen being an HIV antigen.

[0023] In some embodiments, the tolerogenic vaccine is a cytomegalovirus (CMV) vector comprising: a. a first nucleic acid sequence encoding at least one HIV antigen, b. optionally a second nucleic acid sequence comprising a first microRNA recognition element (MRE) operably linked to a CMV gene that is essential or augmenting for CMV growth, wherein the MRE silences expression in the presence of a microRNA that is expressed by a cell of endothelial lineage; andwherein the CMV vector does not express an active ULI 28 protein or ortholog thereof; does not express an active ULI 30 protein or ortholog thereof; does not express an active ULI 46 or ortholog thereof; does not express an active ULI 47 protein or ortholog thereof, and wherein the CMV vector expresses at least one active UL40 protein or an ortholog thereof; expresses at least one active US27 protein or an ortholog thereof and / or expresses at least one active US28 protein or an ortholog thereof.

[0024] In some embodiments, the tolerogenic vaccine comprises at least one HIV immunogen, said HIV immunogen being an HIV antigen, and a non-pathogenic bacterium.

[0025] In some embodiments, the HIV antigen is an inactivated virus, an inactivated virus particle, a virus-like particle, an inactivated recombinant virus particle, a conjugate viral protein or a concatemer viral protein.

[0026] In some embodiments, the non-pathogenic bacterium is a living attenuated or inactivated pathogenic bacterium.

[0027] In some embodiments, the non-pathogenic bacterium is Lactobacillus bacterium, Lactobacillus plantarum, or Mycobacterium bovis.

[0028] In some embodiments, the tolerogenic vaccine comprises at least one lipid nanoparticle (LNP) containing, or conjugated to, at least one nucleic acid molecule comprising a single chain trimer of HLA-E with a pathogen-specific antigen.

[0029] In some embodiments, the tolerogenic vaccine comprises at least one HIV immunogen, said HIV immunogen being an HLA-E-binding peptide derived from an HIV antigen selected from the group consisting of gag, pol, env, nef, tat, vif and rev.

[0030] In some embodiments, the HIV-derived HLA-E-binding peptide is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 4, SEQ ID NO: 56 to SEQ ID NO:58, and SEQ ID NO: 63.

[0031] In some embodiments, said 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) a non-replicating viral vector or a live attenuated viral vector, and b) at least one DNA sequence encoding at least one HIV-derived protein, peptide or epitope, or at least one DNA sequence encoding an antigenbinding fragment of at least one broadly neutralizing anti-HIV antibody, or at least one DNA sequence encoding a mosaic immunogen,an RNA-based vaccine 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.

[0032] In some embodiments, said at least one HIV immunogen is derived from gag, pol, env, nef, tat, vif and rev.

[0033] In some embodiments, said at least one HIV immunogen is a native Env gpl60 trimer, a stabilized Env gpl60 trimer, a stabilized Env gpl40 trimer (SOS gpl40 or SOSIP gpl40), a stabilized Env single-chain gpl40 trimer, a stabilized native flexibly linked (NFL) Env gpl40 trimer.

[0034] In some embodiments, said at least one HIV immunogen is a Tat toxoid as described in patent applications W003013593, incorporated herein by reference.

[0035] In some embodiments, said at least one HIV immunogen is in a soluble form, or is displayed at the surface of a nanoparticle.

[0036] In some embodiments, the infectious disease to be prevented or treated is preferably acquired immune deficiency syndrome (AIDS), a human immunodeficiency virus (HIV) infection or a simian immunodeficiency virus (SIV) infection.

[0037] In some embodiments, the composite vaccine generates anti-HIV specific neutralizing antibodies and / or anti-HIV specific cytotoxic cells in the subject.DEFINITIONS

[0038] In the present invention, the following terms have the following meanings:

[0039] "About" preceding a figure encompasses plus or minus 10%, or less, of the value of said figure. It is to be understood that the value to which the term "about” refers is itself also specifically, and preferably, disclosed.

[0040] As used herein, the term "adjuvant" refers to a compound or combination of compounds that helps and enhances the pharmacological effect of a drug or a vaccine, or increases an immunogenic response, including a CD8+immune response (e.g., an immune response characterized by a high percentage of the CD8+T cell response being restricted by MHC-Ib / E used in an infectious disease treatment).

[0041] The term "administering" means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body. For example, according to some embodiments, the fact to administer a subject with an agent, by any effective route. Exemplary routes of administration include, but are not limited to, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, and intravenous), oral, sublingual, rectal, transdermal, intranasal, vaginal and inhalation routes.

[0042] The term "antigen" refers to a compound, composition, or substance that can stimulate the production of antibodies or a T cell response in an animal, including compositions that are injected or absorbed into an animal. An antigen reacts with the 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 and / or T cells respond. In some embodiments, T cells respond to the epitope, when the epitope is presented in conjunction with an MHC molecule. Epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5, about 9, or about 8-10 amino acids in a unique spatial conformation. Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography and 2-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 is an antigen that elicitsan immune response against the pathogen and / or is unique to a pathogen (such as a virus, bacterium, fungus or protozoan).

[0043] The term "attenuated", in the context of a live virus or bacterium, refers to a virus or bacterium with reduced (for example, eliminated) ability to infect a cell or subject and / or reduced (for example, eliminated) ability to induce or cause disease compared to a wild-type virus or wild-type bacterium. Typically, an attenuated virus or bacterium retains at least some capacity to elicit an immune response following administration to an immunocompetent subject. In some cases, an attenuated virus or bacterium 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 bacterium to cause disease in a subject is reduced at least about 10%, at least about 25%, at least about 50%, at least about 75% or at least about 90% relative to wild-type virus or wild-type bacterium.

[0044] The term "CMV" (cytomegalovirus) refers to a member of the beta subclass of the family of herpesviruses. CMV is a large (~230 kB genome), double stranded DNA virus, with host-range specific variants such as MCMV (murine CMV), RhCMV (rhesus CMV) and HCMV (human CMV). In the context of the present invention, "RhCMV" refers to any strain, isolate or variant of rhesus CMV. In the context of the present invention, "HCMV" refers to any strain, isolate or variant of human CMV.

[0045] The term "decrease" refers to reducing the quality, amount, or strength of something. For example, a therapy (such as the methods provided herein) decreases the infectious load or titer of a pathogen, or one or more symptoms associated with infection.

[0046] The term "deletion" refers to the removal of a sequence of DNA, the regions on either side of the removed sequence being joined together.

[0047] The term "expression" refers to the translation of a nucleic acid into a protein, for example the translation of an mRNA encoding a tumor-specific or pathogenspecific antigen into a protein.

[0048] The term "expression control sequences" refers to nucleic acid sequences that regulate the expression of a heterologous nucleic acid sequence to which it is operatively linked, for example the expression of a heterologous polynucleotide spliced in a CMV genome and encoding an antigenic protein operably linked to expression control sequences. Expression control sequences are operatively linked to a nucleic acid sequence when the expression control sequences control and regulate the transcription and, as appropriate, translation of the nucleic acid sequence. Thus, expression control sequences can include appropriate promoters, enhancers, transcription terminators, a start codon (ATG) in front of a protein-encoding gene, splicing signal for introns, and maintenance of the correct reading frame of that gene to permit proper translation of mRNA, and stop codons. The term "control sequences" is intended to include, at a minimum, components whose presence can influence expression, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences. Expression control sequences can include a promoter. A promoter is a minimal sequence sufficient to direct transcription. Also included are those promoter elements which are sufficient to render promoter-dependent gene expression controllable for cell-type specific, tissue-specific, or inducible by external signals or agents; such elements may be located in the 5' or 3' regions of the gene. Both constitutive and inducible promoters are included (see for example, Bitter et al., Methods in Enzymology 153:516-544, 1987). For example, when cloning in bacterial systems, inducible promoters such as pL of bacteriophage lambda, plac, ptrp, ptac (ptrp-lac hybrid promoter) and the like may be used. In one embodiment, when cloning in mammalian cell systems, promoters derived from the genome of mammalian cells (such as metallothionein promoter) or from mammalian viruses (such as the retrovirus long terminal repeat; the adenovirus late promoter; the vaccinia virus 7.5K promoter) can be used. Promoters produced by recombinant DNA or synthetic techniques may also be used to provide for transcription of the nucleic acid sequences. A polynucleotide can be inserted into an expression vector, including a viral vector, containing a promoter sequence, which facilitates the efficient transcription of the inserted genetic sequence of the host. The expression vector typically contains an origin of replication, a promoter, as well asspecific nucleic acid sequences that allow phenotypic selection of the transformed cells.

[0049] The term "fragment" refers to a portion of a polypeptide that exhibits at least one useful epitope. The phrase "functional fragment(s) of a polypeptide" refers to all fragments of a polypeptide that retain an activity, or a measurable portion of an activity, of the polypeptide from which the fragment is derived. Fragments, for example, can vary in size from a polypeptide fragment as small as an epitope capable of binding an antibody molecule to a large polypeptide capable of participating in the characteristic induction or programming of phenotypic changes within a cell. An epitope is a region of a polypeptide capable of binding an immunoglobulin generated in response to contact with an antigen.

[0050] As used herein, the term "heterologous" refers to a heterologous polypeptide or polynucleotide (such as, for example antigen or a protein) derived from a different source or species. In some embodiments of the invention, the heterologous sequence is from a different genetic source, such as a virus or other organism, than the second sequence.

[0051] The term "immunogenic peptide" (or "antigenic peptide") refers to a peptide which comprises an allele-specific motif or other sequence, such as an N-terminal repeat, such that the peptide will bind an MHC molecule and induce a cytotoxic T lymphocyte ("CTL") response, or a B cell response (for example 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, such as neural net or polynomial determinations known in the art. Typically, algorithms are used to determine the "binding threshold" of peptides to select those with scores that give them a high probability of binding at a certain affinity and will be immunogenic. The algorithms are based either on the effects on MHC binding of a particular amino acid at a particular position, the effects on antibody binding of a particular amino acid at a particular position, or the effects on binding of a particular substitution in a motif-containing peptide. Within the context of an immunogenic peptide, a "conserved residue" is one which appears in a significantly higherfrequency than would be expected by random distribution at a particular position in a peptide. In some embodiments, a conserved residue is one where the MHC structure may provide a contact point with the immunogenic peptide.

[0052] The term "immunity" refers to the state of being able to mount a protective response upon exposure to an immunogenic agent. Protective responses can be antibody-mediated or immune cell-mediated, and can be directed toward a particular pathogen or tumor antigen. Immunity can be acquired actively (such as by exposure to an immunogenic agent, either naturally or in a pharmaceutical composition) or passively (such as by administration of antibodies or in vitro stimulated and expanded T cells).

[0053] The term "isolated" or "non-naturally occurring" with reference to a biological component (such as a nucleic acid molecule, protein organelle or cells), refers to a biological component altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not "isolated," but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated”. An isolated nucleic acid or peptide can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell. Typically, a preparation of isolated nucleic acid or peptide contains the nucleic acid or peptide 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. Nucleic acids and proteins that are "non-naturally occurring" or have been "isolated" include nucleic acids and proteins purified by standard purification methods. The term also embraces nucleic acids and proteins prepared by recombinant expression in a host cell as well as 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.

[0054] The terms "individual," and "patient" are used interchangeably herein, and refer to an animal, for example a human, to whom treatment, including prophylactic treatment, with the agent according to the present invention, is provided.

[0055] The term "subject" as used herein refers to mammals, primates and / or humans and include all mammals, e.g., mammals, such as non -human primates, (particularly higher primates), sheep, dog, rodent, (e.g. , mouse or rat), guinea pig, goat, pig, cat, rabbits, cows, horses.

[0056] The term "mutation" refers to any difference in a nucleic acid or polypeptide sequence from a normal, consensus or "wild type" sequence. A mutant is any protein or nucleic acid sequence comprising a mutation. In addition, a cell or an organism with a mutation may also be referred to as a mutant. Some types of coding sequence mutations include point mutations (differences in individual nucleotides or amino acids); silent mutations (differences in nucleotides that do not result in an amino acid changes); deletions (differences in which one or more nucleotides or amino acids are missing, up to and including a deletion of the entire coding sequence of a gene); frameshift mutations (differences in which deletion of a number of nucleotides indivisible by 3 results in an alteration of the amino acid sequence. A mutation that results in a difference in an amino acid may also be called an amino acid substitution mutation. Amino acid substitution mutations may be described by the amino acid change relative to wild type at a particular position in the amino acid sequence.

[0057] As used herein, an "inactivating mutation" is any mutation in a viral gene which finally leads to a reduced function or to a complete loss of function of the viral protein.

[0058] The term "operably linked" refers to a first nucleic acid sequence that is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences are contiguous and, where necessary to join two protein-coding regions, in the same reading frame.

[0059] The term "open reading frame" (ORF) refers to a series of nucleotide triplets (codons) coding for amino acids without any internal termination codons. These sequences are usually translatable into a peptide.

[0060] As used herein, the terms "prevent", "preventing" and "prevention" refer to preventative measures, wherein the object is to reduce the chances that a subject will develop the pathologic condition or disorder over a given period of time. Such a reduction may be reflected, e.g., in a delayed onset of at least one symptom of the pathologic condition or disorder in the subject.

[0061] The term "prophylactic" refers to a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing pathology. In particular, a prophylactic treatment of a HIV or SIV infection in a subject refers to a treatment that allows the subject to become an elite controller (EC) i.e., to have a relatively high CD4+T cell count (such as e.g., superior to 500 CD4+T cells per microliter) and / or to maintain clinically undetectable plasma HIV-1 RNA level (such as e.g., HIV RNA <50 copies / mL) during a prolonged period of time in the absence of any antiretroviral treatment (ART).

[0062] The term "therapeutic" refers to a treatment administered to a subject who exhibit early or established signs of a disease.

[0063] The term "curative" refers to a treatment administered to a subject suffering from a disease for the purpose of curing the disease, i.e., of making any sign of the disease disappear or becoming undetectable.

[0064] The term "polynucleotide" refers to a polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA). A polynucleotide is made up of four bases; adenine, cytosine, guanine, and thymine / uracil (uracil is used in RNA). A coding sequence from a nucleic acid is indicative of the sequence of the protein encoded by the nucleic acid.

[0065] The terms "protein", "peptide", "polypeptide", and "amino acid sequence" are used interchangeably herein to refer to polymers of amino acid residues of any length. The polymer can be linear or branched, it may comprise modified amino acidsor amino acid analogs, and it may be interrupted by chemical moieties other than amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling or bioactive component.

[0066] The term "purified" does not require absolute purity; rather, it is intended as a relative term. Thus, for example, a purified protein preparation is one in which the protein referred to is purer than the protein in its natural environment within a cell or within a production reaction chamber (as appropriate).

[0067] The term "recombinant" refers to a nucleic acid that has a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two otherwise separated segments of sequence. This artificial combination can be accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques.

[0068] The term "sample" or "biological sample" refers to a biological specimen obtained from a subject, such as a cell, fluid of tissue sample. In some cases, biological samples contain genomic DNA, RNA (including mRNA and microRNA), protein, or combinations thereof. Examples of samples include, but are not limited to, saliva, blood, serum, urine, spinal fluid, tissue biopsy, surgical specimen, cells (such as PBMCs, white blood cells, lymphocytes, or other cells of the immune system) and autopsy material.

[0069] The term "sequence identity" refers to the similarity between two nucleic acid sequences, or two amino acid sequences, is expressed in terms of the similarity between the sequences, and otherwise referred to as sequence identity. Sequence identity is frequently measured in terms of percentage identity (or similarity or homology); the higher the percentage, the more similar the two sequences are.

[0070] Methods of alignment of sequences 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. (Meth. Mol. Biol. 24: 307-31, 1994). Altschul et al. (Nature Genet., 6: 119-129, 1994) presents a detailed consideration of sequence alignment methods and homology calculations. The alignment tools ALIGN (Myers and Miller, CABIOS 4: 11-17, 1989) or LFASTA (Pearson and Lipman, 1988) may be used to perform sequence comparisons (Internet Program© 1996, W. R. Pearson and the University of Virginia, fasta20u63 version 2.0u63, release date December 1996). ALIGN compares entire sequences against one another, while LFASTA compares regions of local similarity. These alignment tools and their respective tutorials are available on the Internet at the NCSA Website. Alternatively, for comparisons of amino acid sequences of greater than about 30 amino acids, the Blast 2 sequences function can be employed using the default BLOSUM62 matrix set to default parameters, (gap existence cost of 11, and a per residue gap cost of 1).

[0071] When aligning short peptides (fewer than around 30 amino acids), the alignment should be performed using the Blast 2 sequences function, employing the PAM30 matrix set to default parameters (open gap 9, extension gap 1 penalties). The BLAST sequence comparison system is available, for instance, from the NCBI web site; see also 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.

[0072] Orthologs of proteins are typically characterized by possession of greater than 75% sequence identity counted over the full-length alignment with the amino acid sequence of specific protein using ALIGN set to default parameters. Proteins with even greater similarity to a reference sequence will show 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. In addition, sequence identity can be compared over the full length of particular domains of the disclosed peptides.

[0073] When significantly less than the entire sequence is being compared for sequence identity, homologous sequences will typically possess at least 80% sequence identity over short windows of 10-20 amino acids, and may possess sequence identities of at least 85%, at least 90%, at least 95%, or at least 99% depending on their similarity to the reference sequence. Sequence identity over such short windows can be determined using LFASTA; methods are described at the NCSA Website. One of skill in the art will appreciate that these sequence identity ranges are provided for guidance only; it is entirely possible that strongly significant homologs could be obtained that fall outside of the ranges provided.

[0074] Nucleic acid sequences that do not show a high degree of identity may nevertheless encode similar amino acid sequences, due to the degeneracy of the genetic code.

[0075] It is understood that changes in nucleic acid sequence can be made using this degeneracy to produce multiple nucleic acid sequences that each encode substantially the same protein.

[0076] As used herein, the term "treatment" refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition. For example, in case of HIV infection, HIV RNA (viral load) and CD4 T lymphocyte (CD4) cell count are the two surrogate markers of antiretroviral treatment (ART) responses and HIV disease progression that have been used for decades to manage and monitor HIV infection. Thus, the efficacy of the treatment may be evaluated by the plasma viral RNA load of a "treated" human before and after the treatment, if it is reduced by at least about 10%, 20%, 30%, 40%, 50%, more preferably by at least about 70%, yet more preferably by 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%) the treatment is considered as effective, and / or by the monitoring of CD4 cell count before and after the treatment, if the absolute count of CD4 cell is increased by at least about 5%, 10%, 15%, 20%, 25% , more preferably by at least about 30%, yet more preferably by at least about 35% or 40% or 45% or 50% or 55% or 60% or 65%, or even more the treatment is considered as effective. As used herein, the terms "treatment", "treat" and "treating," with reference to a disease,pathological condition or symptom, also refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed. A prophylactic treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs, for the purpose of decreasing the risk of developing pathology. In particular, a prophylactic treatment of a HIV or SIV infection in a subject refers to a treatment that allows the subject to become an elite controller (EC) i.e., to have a relatively high CD4+T cell count (such as e.g., superior to 500 CD4+T cells per microliter) and / or to maintain clinically undetectable plasma HIV-1 RNA level (such as e.g., HIV RNA <50 copies / mL) during a prolonged period of time in the absence of any antiretroviral treatment (ART). A prophylactic treatment is a treatment administered to a subject suffering from a disease for the purpose of curing the disease, i.e., of making any sign of the disease disappear or becoming undetectable.

[0077] The term "vector" may include nucleic acid sequences that permit it to replicate in a host cell, such as an origin of replication. A vector may also include one or more selectable marker genes and other genetic elements known in the art, including promoter elements that direct nucleic acid expression. Vectors can be viral vectors, such as CMV vectors. Viral vectors may be constructed from wild type or attenuated virus, including replication deficient virus. Vectors can also be non-viral vectors, including any plasmid known to the art.

[0078] The term "virus" refers to microscopic infectious organism that reproduces inside living cells. A virus consists essentially of a core of nucleic acid (the viral genome) surrounded by a protein coat (capsid), and has the ability to replicate only inside a living cell. "Viral replication" is the production of additional virus particles by the occurrence of at least one viral life cycle. A virus may subvert the host cells'normal functions, causing the cell to behave in a manner determined by the virus. For example, a viral infection may result in a cell producing a cytokine, or responding to a cytokine, when the uninfected cell does not normally do so. The term "lytic" or "acute" viral infection refers to a viral infection wherein the viral genome is replicated and expressed, producing the polypeptides necessary for production of the viral capsid. Mature viral particles exit the host cell, resulting in cell lysis. Particular viral species can alternatively enter into a "lysogenic" or "latent" infection. In the establishment of latency, the viral genome is replicated, but capsid proteins are not produced and assembled into viral particles.

[0079] As used herein, the term "microRNA" or "miRNA" refers to a major class of biomolecules involved in control of gene expression. For example, in human heart, liver or brain, miRNAs play a role in tissue specification or cell lineage decisions. In addition, miRNAs influence a variety of processes, including early development, cell proliferation and cell death, and apoptosis and fat metabolism. The large number of miRNA genes, the diverse expression patterns, and the abundance of potential miRNA targets suggest that miRNAs may be a significant source of genetic diversity.

[0080] A mature miRNA is typically an 18-25 nucleotide non-coding RNA that regulates expression of an mRNA including 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 suppress translation. MiRNAs may also bind to target mRNAs and mediate gene silencing through the RNAi pathway. MiRNAs may also regulate gene expression by causing chromatin condensation.

[0081] A miRNA silences translation of one or more specific mRNA molecules by binding to a miRNA recognition element (MRE), which is defined as any sequence that directly base pairs with and interacts with the miRNA somewhere on the mRNA transcript. Often, the MRE is present in the 3' untranslated region (UTR) of the mRNA, but it may also be present in the coding sequence or in the 5' UTR. MREs are not necessarily perfect complements to miRNAs, usually having only a few bases of complementarity to the miRNA and often containing one or more mismatches withinthose bases of complementarity. The MRE may be any sequence capable of being bound by a miRNA sufficiently that the translation of a gene to which the MRE is operably linked (such as a CMV gene that is essential or augmenting for growth in vivo) is repressed by a miRNA silencing mechanism such as the RISC.DETAILED DESCRIPTIONSecond medical use

[0082] This invention relates to a composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of typeIII interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prophylactic treatment or curative treatment of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive patient with no AIDS symptoms or with AIDS symptoms, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine comprising at least one HIV immunogenare to be administered to the subject during a priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine are to be administered to the subject during a boosting phase following the priming phase.

[0083] This invention further relates to a composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of typeIII interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prevention of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)- seronegative patient, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure during a priming phase and a boosting phase, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during the priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine are to be administered to the subject during the boosting phase following the priming phase.

[0084] This invention further relates to a composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of typeIII interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prophylactic treatment or curative treatment of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive Elite Controller patient, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure during a priming phase and a boosting phase, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine comprising at least one HIV immunogenare to be administered to the subject during the priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine are to be administered to the subject during the boosting phase following the priming phase.

[0085] This invention relates to a composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of typeIII interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prophylactic treatment or curative treatment of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive patient with no AIDS symptoms or with AIDS symptoms, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, andc) the tolerogenic vaccine specific for at least one HIV immunogen and / or the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during a priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine are to be administered to the subject during a boosting phase following the priming phase.

[0086] This invention further relates to a composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of typeIII interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prevention of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)- seronegative patient, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure during a priming phase and a boosting phase, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of type III interferon,b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the tolerogenic vaccine specific for at least one HIV immunogen and / or the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during the priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine are to be administered to the subject during the boosting phase following the priming phase.

[0087] This invention further relates to a composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of typeIII interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prophylactic treatment or curative treatment of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive Elite Controller patient, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure during a priming phase and a boosting phase, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the tolerogenic vaccine specific for at least one HIV immunogen and / or the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during the priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine are to be administered to the subject during the boosting phase following the priming phase.

[0088] This invention relates to a composite vaccine comprising: a) an agent neutralizing at least one circulating type I interferon or an agent blocking the signaling of at least one type I interferon, b) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of typeIII interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb)for use in the prophylactic treatment or curative treatment of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive patient with no AIDS symptoms or with AIDS symptoms, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing at least one circulating type I interferon or the agent blocking the signaling of at least one type I interferon, and c) the tolerogenic vaccine specific for at least one HIV immunogen and / or the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during a priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing at least one circulating type I interferon or the agent blocking the signaling of at least one type I interferon, and c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine are to be administered to the subject during a boosting phase following the priming phase.

[0089] This invention further relates to a composite vaccine comprising: a) an agent neutralizing at least one circulating type I interferon or an agent blocking the signaling of at least one type I interferon, b) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen,c) optionally a type III interferon or an agent stimulating the production of typeIII interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prevention of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)- seronegative patient, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure during a priming phase and a boosting phase, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing at least one circulating type I interferon or the agent blocking the signaling of at least one type I interferon, and c) the tolerogenic vaccine specific for at least one HIV immunogen and / or the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during the priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing at least one circulating type I interferon or the agent blocking the signaling of at least one type I interferon, and c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine are to be administered to the subject during the boosting phase following the priming phase.

[0090] This invention further relates to a composite vaccine comprising:a) an agent neutralizing at least one circulating type I interferon or an agent blocking the signaling of at least one type I interferon, b) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of typeIII interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prophylactic treatment or curative treatment of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive Elite Controller patient, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure during a priming phase and a boosting phase, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing at least one circulating type I interferon or the agent blocking the signaling of at least one type I interferon, and c) the tolerogenic vaccine specific for at least one HIV immunogen and / or the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during the priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of typeIII interferon, b) the agent neutralizing at least one circulating type I interferon or the agent blocking the signaling of at least one type I interferon, and c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccineare to be administered to the subject during the boosting phase following the priming phase.

[0091] The invention also relates to a composite vaccine comprising: i. optionally a type III interferon or an agent stimulating the production of type III interferon, ii. an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, iii. at least one broadly neutralizing antibody (bnAb), and iv. optionally at least one antiretroviral (ART) agent for use in the prophylactic treatment or curative treatment of acquired immune deficiency syndrome (AIDS) in a subject in need thereof.Methods

[0092] This invention relates to method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)- seropositive patient with no AIDS symptoms or with AIDS symptoms, said composite vaccine method comprising:1) all along the vaccination procedure, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) an effector vaccine comprising at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject:a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the effector vaccine depending on the priming vaccine.

[0093] This invention further relates to method for preventing acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seronegative patient, said method comprising:1) all along the vaccination procedure during a priming phase and a boosting phase, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) an effector vaccine comprising at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject: a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the effector vaccine depending on the priming vaccine.

[0094] This invention further relates to method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive Elite Controller patient, said method comprising:1) all along the vaccination during a priming phase and a boosting phase, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) an effector vaccine comprising at least one HIV immunogen,3) following the priming phase, the boosting phase comprising administering to the subject: a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the effector vaccine.

[0095] This invention relates to method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)- seropositive patient with no AIDS symptoms or with AIDS symptoms, said composite vaccine method comprising:1) all along the vaccination procedure, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) an effector vaccine comprising at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject:a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the effector vaccine depending on the priming vaccine.

[0096] This invention further relates to method for preventing acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seronegative patient, said method comprising:1) all along the vaccination procedure during a priming phase and a boosting phase, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) an effector vaccine comprising at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the effector vaccine depending on the priming vaccine.

[0097] This invention further relates to method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive Elite Controller patient, said method comprising:1) all along the vaccination during a priming phase and a boosting phase, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject:a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) an effector vaccine comprising at least one HIV immunogen,3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the effector vaccine.

[0098] This invention relates to method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)- seropositive patient with no AIDS symptoms or with AIDS symptoms, said composite vaccine method comprising:1) all along the vaccination procedure, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject: a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling,c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine.

[0099] This invention further relates to method for preventing acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seronegative patient, said method comprising:1) all along the vaccination procedure during a priming phase and a boosting phase, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject: a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine.

[0100] This invention further relates to method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive Elite Controller patient, said method comprising:1) all along the vaccination during a priming phase and a boosting phase, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) an effector vaccine comprising at least one HIV immunogen,3) following the priming phase, the boosting phase comprising administering to the subject: a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the effector vaccine.

[0101] The invention also relates to a composite vaccine / composition / pharmaceutical composition / medicament comprising: a) optionally a type III interferon or an agent stimulating the production of typeIII interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) an effector vaccine comprising at least one HIV immunogen.

[0102] The invention also relates to a composite vaccine / composition / pharmaceutical composition / medicament comprising a) optionally a type III interferon or an agent stimulating the production of type III interferon,b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen.

[0103] This invention relates to method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)- seropositive patient with no AIDS symptoms or with AIDS symptoms, said composite vaccine method comprising:1) all along the vaccination procedure, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) a tolerogenic vaccine specific for at least one HIV immunogen lysing infected CD4+ cells expressing HIV peptide in an HLA-E restriction and / or an effector vaccine comprising at least one HIV immunogen lysing infected CD4+ cells expressing HIV peptide in an HLA-Ia (A, B, C) restriction, and3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine.

[0104] This invention further relates to method for preventing acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seronegative patient, said method comprising:1) all along the vaccination procedure during a priming phase and a boosting phase, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) a tolerogenic vaccine specific for at least one HIV immunogen lysing infected CD4+ cells expressing HIV peptide in an HLA-E restriction and / or an effector vaccine comprising at least one HIV immunogen lysing infected CD4+ cells expressing HIV peptide in an HLA-Ia (A, B, C) restriction, and3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine.

[0105] This invention further relates to method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive Elite Controller patient, said method comprising:1) all along the vaccination during a priming phase and a boosting phase, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) an effector vaccine comprising at least one HIV immunogen lysing infected CD4+ cells expressing HIV peptide in an HLA-Ia (A, B, C) restriction,3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the effector vaccine.

[0106] This invention relates to method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)- seropositive patient with no AIDS symptoms or with AIDS symptoms, said composite vaccine method comprising:1) all along the vaccination procedure, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing at least one circulating type I interferon or an agent blocking the signaling of at least one type I interferon, c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject:a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing at least one circulating type I interferon or an agent blocking the signaling of at least one type I interferon, c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine.

[0107] This invention further relates to method for preventing acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seronegative patient, said method comprising:1) all along the vaccination procedure during a priming phase and a boosting phase, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing at least one circulating type I interferon or an agent blocking the signaling of at least one type I interferon, c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing at least one circulating type I interferon or an agent blocking the signaling of at least one type I interferon, c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine.

[0108] This invention further relates to method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating asubject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive Elite Controller patient, said method comprising:1) all along the vaccination during a priming phase and a boosting phase, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing at least one circulating type I interferon or an agent blocking the signaling of at least one type I interferon, c) an effector vaccine comprising at least one HIV immunogen,3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing at least one circulating type I interferon or an agent blocking the signaling of at least one type I interferon, c) the effector vaccine.

[0109] This invention relates to method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HIV)- seropositive patient with no AIDS symptoms or with AIDS symptoms, said composite vaccine method comprising:1) all along the vaccination procedure, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling,c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine.

[0110] This invention further relates to method for preventing acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seronegative patient, said method comprising:1) all along the vaccination procedure during a priming phase and a boosting phase, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling,c) the tolerogenic vaccine and / or the effector vaccine depending on the priming vaccine.

[0111] This invention further relates to method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive Elite Controller patient, said method comprising:1) all along the vaccination during a priming phase and a boosting phase, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) an effector vaccine comprising at least one HIV immunogen,3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the effector vaccine.

[0112] Optionally, the method of the invention comprises a preliminary step (before 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.

[0113] In some embodiments, the invention relates to a method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive patient with no AIDS symptoms or withAIDS symptoms; or to a method for preventing acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seronegative patient; said composite vaccine method comprising:1) all along the vaccination procedure, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) a tolerogenic vaccine specific for at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the tolerogenic vaccine.

[0114] In some embodiments, the invention relates to a method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive patient with no AIDS symptoms or with AIDS symptoms; or to a method for preventing acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seronegative patient; said composite vaccine method comprising:1) all along the vaccination procedure, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) an effector vaccine comprising at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the effector vaccine.

[0115] In some embodiments, the invention relates to a method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive patient with no AIDS symptoms or with AIDS symptoms; or to a method for preventing acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seronegative patient; said composite vaccine method comprising:1) all along the vaccination procedure, administering to the subject at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), and2) the priming phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) a tolerogenic vaccine specific for at least one HIV immunogen and an effector vaccine comprising at least one HIV immunogen, and3) following the priming phase, the boosting phase comprising administering to the subject: a) a type III interferon or an agent stimulating the production of type III interferon, b) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, c) the tolerogenic vaccine and the effector vaccine.

[0116] The invention also relates to a method for prophylactically treating or curatively treating acquired immune deficiency syndrome (AIDS) by vaccinating a subject in need thereof, said method comprising administering to the subject: v. a type III interferon or an agent stimulating the production of type III interferon, vi. an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, vii. at least one broadly neutralizing antibody (bnAb), and viii. optionally at least one antiretroviral (ART) agent.

[0117] In some embodiments, the method is a method of prophylactic treatment or a method of curative treatment.

[0118] Due to the great variability in the HIV genome, which results from mutation, recombination, insertion and / or deletion, HIV has been classified in groups, subgroups, types, subtypes and genotypes. There are two major HIV groups (HIV-1 and HIV-2) and many subgroups because the HIV genome mutates constantly. The major difference between the groups and subgroups is associated with the viral envelope. HIV-1 is classified into a main group (M), said group M being divided into least nine genetically distinct subtypes. These are subtypes A, B, C, D, F, G, H, J and K. Many other subtypes resulting from in vivo recombination of the previous ones also exist (e.g., CRF).

[0119] In some embodiments, the HIV antigen is related to a specific HIV group, subgroup, type, subtype or to a combination of several subtypes.

[0120] In some embodiments, the HIV virus is HIV-1 or HIV-2, preferably, HIV-1. In some embodiments, the HIV-1 virus is from group M and subtype B (HXB2).Technical effects of the composite vaccine of the invention

[0121] While not 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:- they allow to control of the pathogenic effect of elevated IFN-a on activated CD4+ T cells initiating the adaptive immune reaction (which is notably done by the agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling), they allow to preserve the antiviral activity of interferon (which is notably done by the type III interferon or an agent stimulating the production of type III interferon, which may partially replace interferon alpha)- they allow to control the viral replication (which is notably done by the broadly neutralizing antibody (bnAb) or antiretroviral (ART) agent administered all along the vaccine method),- they allow to induce anti-HIV specific adaptative immune response (which is notably done by the effector vaccine and / or by the tolerogenic vaccine).

[0122] While not wishing to be bound by any particular theory or mechanism of action, the tolerogenic vaccine may lead to the induction of HIV-specific CD8+ regulatory (or suppressor) T cells. In this case, the methods and composite vaccines provide a functional cure.

[0123] A “functional cure” herein designates a cure or a treatment that allows an HIV-infected patient to become, or reach the status of, an elite controller (EC). For instance, a “functional cure” allows an HIV-infected patient to have a relatively high CD4+T cell count (such as e.g. superior to 500 CD4+T cells per microliter) and / or to maintain clinically undetectable plasma HIV-1 RNA level (such as e.g. HIV RNA <50copies / mL) during a prolonged period of time in the absence of any antiretroviral treatment (ART).

[0124] While not wishing to be bound by any particular theory or mechanism of action, the effector vaccine may lead to the induction of broad HIV-specific cytotoxic T lymphocytes (CTLs) and / or broadly neutralizing antibody (bnAb). In this case, the methods and composite vaccines provide a sterilizing cure.

[0125] A “sterilizing cure” herein designates a cure or a treatment that allows an uninfected patient or an HIV-infected patient to reach a status where no HIV replication is detected in a blood sample from the patient. In some embodiments, a sterilizing cure” designates a cure or a treatment that allows an uninfected patient or an HIV-infected patient to reach a status where no cell containing replication- competent proviral HIV DNA is detected in a blood sample from the subject.ART agent

[0126] As used herein, the term "antiretroviral therapy" or "ART" or "highly active antiretroviral therapy" or "HAART" refers to any combination of antiretroviral (ARV) drugs to maximally suppress the HIV virus (e.g., reduce viral load reduce HIV multiplication...), and stop the progression of HIV disease. There are several classes of HIV drug, such as, for example, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), postattachment inhibitors (or entry inhibitors), protease inhibitors (Pls), CCR5 antagonists, integrase strand transfer inhibitors (INSTIs), fusion inhibitors (FIs).

[0127] In one embodiment, the antiretroviral (ART) agent is selected from the group consisting of Nucleoside reverse transcriptase inhibitors (NRTIs), Non-nucleoside reverse transcriptase inhibitors (NNRTIs), Protease inhibitors (Pls), Integrase inhibitors (INSTIs), Fusion inhibitors (FIs), Chemokine receptor antagonists (CCR5 antagonists) and Entry inhibitors (CD4-directed post-attachment inhibitors).

[0128] Non-limiting examples of antiretroviral (ART) agents include:- Nucleoside reverse transcriptase inhibitors (NRTIs) such as e.g. :o Abacavir (Ziagen®) o Didanosine (Videx®, Videx® EC) o Emtricitabine (Emtriva) o Lamivudine (Epivir®) o Stavudine (Zerit®) o Tenofovir disoproxil fumarate DF (Viread®) o Tenofovir alafenamide AF o Zidovudine (Retrovir®)- Non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as e.g. : o Delavirdine (Rescriptor®) o Efavirenz (Sustiva®) o Etravirine (Intelence®) o Nevirapine (Viramune®, Viramune® XR) o Rilpivirine (Edurant®) o Doravirine (Pifeltro®)Protease inhibitors (Pls) such as e.g. : o Atazanavir (Reyataz®) o Darunavir (Prezista®) o Fosamprenavir (Lexiva®) o Indinavir (Crixivan®) o Lopinavir / ritonavir (Kaletra®) o Nelfinavir (Viracept®) o Ritonavir (Norvir®) o Saquinavir (Invirase®) o Tipranavir (Aptivus®)Integrase inhibitors (INSTIs) such as e.g.: o Raltegravir (Isentress®, Isentress® HD) o Dolutegravir (Tivicay®) o Elvitegravir (Vitekta®)Chemokine receptor antagonist (CCR5 antagonist) such as e.g. o Maraviroc (Selzentry®)Fusion inhibitor (FI) such as e.g.o Enfuvirtide (Fuzeon®)Entry inhibitor such as e.g. o Ibalizumab (Trogarzo®) and any combination thereof.

[0129] In one embodiment, the ART agent according to the invention comprises several ART agents, or is a combination of several ART agents. These several ART agents are for instance chosen among the ART agents listed hereabove.

[0130] Generally, initial treatment regimens usually include two NTRIs combined with a third active antiretroviral drug, which may be in the INSTI, NNRTI, or PI class. They may sometimes include a booster, which may be cobicistat (Tybost®) or ritonavir (Norvir®).

[0131] In one embodiment, the ART agent according to the invention comprises a combination of at least two ART agents, preferably chosen among the ART agents listed hereabove.

[0132] In one embodiment, the ART agent according to the invention comprises a combination of two, three, four, five or six ART agents, preferably chosen among the ART agents listed hereabove.

[0133] ART combination products are known in the art and some of them are approved as complete daily regimens.

[0134] Non-limiting examples of antiretroviral (ART) agents which are combination ARTs or combined ARTs (cARTs) include the following ART combinations:- Elvitegravir + cobicistat + emtricitabine + tenofovir DF (Stribild®) Elvitegravir + cobicistat + emtricitabine + tenofovir AF (Genvoya®) Darunavir + cobicistat + emtricitabine + tenofovir AF (Symtuza®) Rilpivirine + emtricitabine + tenofovir AF (Odefsey®) Rilpivirine + emtricitabine + tenofovir DF (Complera®) Bictegravir + emtricitabine + tenofovir AF (Biktarvy®) Dolutegravir + abacavir + lamivudine (Triumeq®)Dolutegravir + rilpivirine (Juluca®)Dolutegravir + lamivudine (Dovato®)Efavirenz + emtricitabine + tenofovir DF (Atripla®)Efavirenz + lamivudine + tenofovir DF (Symfi®)Doravirine + lamivudine + tenofovir DF (Delstrigo®)Emtricitabine + tenofovir AF (Descovy®)Emtricitabine + tenofovir DF (Truvada®)Abacavir + lamivudine (Epzicom®)Lamivudine + tenofovir DF (Cimduo®)Abacavir + lamivudine + zidovudine (Trizivir®)Zidovudine + lamivudine (Combivir®)Atazanavir + cobicistat (Evotaz®)Darunavir ethanolate + cobicistat (Prezcobix®).

[0135] 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).

[0136] Preferably, the antiretroviral (ART) agent is an ART combination or combined ART (cART) selected from: emtricitabine (NRTI) + tenofovir alafenamide (NRTI) + rilpivirine (NNRTI), or emtricitabine (NRTI) + tenofovir alafenamide (NRTI) + bictegravir (INSTI), or emtricitabine (NRTI) + tenofovir disoproxil fumarate (NRTI) + efavirenz (NNRTI).

[0137] In some embodiments, the subject has already received at least one dose of at least one antiretroviral (ART) agent, or is under antiretroviral therapy or under combined antiretroviral therapy (cART) comprising at least one antiretroviral (ART) agent, before the first period of time according to the invention. Said at least one antiretroviral (ART) agent may be the same antiretroviral (ART) agent as the one administered in the method of the invention, or it may be different from the antiretroviral (ART) agent administered in the method of the invention.

[0138] In some embodiments, said at least one antiretroviral (ART) agent already received is the same antiretroviral (ART) agent as the one administered in the method of the invention. In this case, when being treated according to the method of the invention, the subject may go on receiving the at least one antiretroviral (ART) agent he / she has already been given before.

[0139] In some embodiments, said at least one antiretroviral (ART) agent already received is not the same antiretroviral (ART) agent as the one administered in the method of the invention.

[0140] In some embodiments, the subject has already received at least one dose of a combined antiretroviral therapy (cART) before being administered the at least one antiretroviral (ART) agent of the invention, and said cART comprises Nucleoside reverse transcriptase inhibitors (NRTIs), Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and Protease inhibitors (Pls).

[0141] Preferably, if the subject has already received at least one dose of at least one antiretroviral (ART) agent, or is under antiretroviral therapy or under combined antiretroviral therapy (cART) comprising at least one antiretroviral (ART) agent, before the first period of time according to the invention, then said subject is administered at least one antiretroviral (ART) agent in the first period of time according to the invention, preferably the same at least one antiretroviral (ART) agent as the one he has already received before.Broadly neutralizing antibody (bnAb)

[0142] As used herein, the term “broadly neutralizing antibodies” (bnAb) designated antibodies that have the potential to provide complete protection from HIV infection. In particular, broadly neutralizing antibodies broadly protect against heterologous HIV- 1 strains.

[0143] Broadly neutralizing antibodies (bnAb) may be isolated from an HIV- seropositive subject.

[0144] In some embodiments, the methods of the invention comprise administration of at least one broadly neutralizing anti-HIV antibody.

[0145] Broadly neutralizing anti-HIV antibodies may for instance bind to one or more epitope(s) comprised in the CDR2 domain of the viral CD4 receptor, in the CD4 binding site, in the gp41, in the gpl20, in the V1V2 region of the HIV-1 envelope, or in the V3 glycan.

[0146] 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.

[0147] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the CDR2 domain of the viral CD4 receptor include UB-421 (semzuvolimab).

[0148] 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.

[0149] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the gp41 include 10E8.4 / iMab.

[0150] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the gpl20 include VH3810109 (also known as GSK3810109 or N6-LS).

[0151] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the V1V2 region of the HIV-1 envelope include CAP256V2LS, PGDM1400LS, PGDM1400, SAR441236.

[0152] 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, Elipovimab.

[0153] When the method of the invention comprises administration of at least one broadly neutralizing anti-HIV antibody, preferably two or more different broadly neutralizing anti-HIV antibodies are administered.

[0154] 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.

[0155] When a combination of several broadly neutralizing anti-HIV antibodies are used, the at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 broadly neutralizing anti-HIV antibodies preferably bind to different epitopes, and more preferably to different targets chosen among the group comprising the CDR2 domain of the viral CD4 receptor, the CD4 binding site, the gp41, the gpl20, the V1V2 region of the HIV-1 envelope, and the V3 glycan.

[0156] In some embodiments, the at least one broadly neutralizing anti-HIV antibody targets the CD4 binding site and the VI V2 region of the HIV-1 envelope. For instance, the at least one broadly neutralizing anti-HIV antibody may be SAR441236.

[0157] In some embodiments, the at least one broadly neutralizing anti-HIV antibody targets the CD4 binding site, the V1V2 region of the HIV-1 envelope, and the V3 glycan. For instance, the at least one broadly neutralizing anti-HIV antibody may be PGDM1400LS or PGDM1400.

[0158] In some embodiments, the at least one broadly neutralizing anti-HIV antibody is a combination of antibodies selected from the group consisting of:- 3BNC117-LS and 10-1074-LS;- 3BNC117-LS-J and 10-1074-LS-J;- PGT121.414.LS and VRC07-523LS;- PGDM1400LS, VRC07-523LS and PGT121.414.LS; and- CAP256V2LS, VRC07-523LS and PGT121.

[0159] In some embodiments, the methods of the invention comprise administration of nucleic acid sequences encoding at least one broadly neutralizing anti-HIV antibody.Type III interferon

[0160] As used herein, the term "type III interferon", also called interferon-lambda (IFN-X), refers to naturally occurring and / or recombinant cytokines of the type III interferon-lambda family. There are four IFN-X members in humans, IFN-X1 / IL-29, IFN-X2 / IL-28A, IFN-X3 / IL-28B, IFN-X4.

[0161] In some embodiments, the type III interferon is IFN-X.

[0162] In some embodiments, the IFN-X comprises at least one IFN-X subtype (e.g., IFN-X1, IFN-X2 IFN-X3, IFN-X4).

[0163] In some embodiments, the IFN-X is selected from the group consisting of IFN- I, IFN-X2 IFN-X3, IFN-X4 or a combination thereof.

[0164] In some embodiments, the human IFN-X 1 has the following accession number NP_742152.1. In some embodiments, the human IFN-X2 has the following accession number NP 742150.1. In some embodiments, the human IFN-X3 has the following accession numbers NP_001333866.1 (isoform 1) or NP_742151.2 (isoform 2). In some embodiments, the human IFN-X4 has the following accession number NP_001263183.2.

[0165] In some embodiments, the interferon-lambda is IFN-X1. In some embodiments, the interferon-lambda is IFN-X2. In some embodiments, the interferon- lambda is IFN-X3. In some embodiments, the interferon-lambda is IFN-X4.

[0166] In some embodiments, the interferon-lambda is chemically modified to improve certain properties such as serum half-life. In one embodiment the interferon- lambda of the invention is pegylated (i.e., the interferon-lambda is covalently attached to poly(ethyleneglycol), and the like). Methods for producing pegylated proteins are well known in the art, see for example Chapman A et al., 2002, Advanced Drug Delivery Reviews 54: 531 -545.

[0167] In some embodiments, the type III interferon is a pegylated interferon IFN-X. In some embodiments, the type III interferon is a pegylated interferon IFN-X-la.

[0168] In some embodiments, the type III interferon is Eiger BioPharmaceuticals Inc.’s pegylated interferon lambda (also named “Peginterferon lambda” or “lambda PEG-rIL-29”). This pegylated interferon lambda is well-known in the art and is described e.g. in US 8,454,947 and WO 2013 / 028233, which content is herein incorporated by reference.

[0169] In other embodiments, the type III interferon or an agent stimulating the production of type III interferon is a nucleic sequence, e.g. an RNA, a mRNA, a DNA or a plasmid encoding a type III interferon.

[0170] The type III interferon or the agent stimulating the production of type III interferon may be at least one RNA molecule, such as e.g. at least one mRNA molecule, encoding IFN-kl, IFN-X2, IFN-X3 and / or IFN-X4.

[0171] In some embodiments, the type III interferon or the agent stimulating the production of type III interferon is at least one RNA molecule, such as e.g. at least one mRNA molecule, carried by a lipid nanoparticle (LNP). The type III interferon or the agent stimulating the production of type III interferon may be at least one RNA molecule within, or conjugated to, a lipid nanoparticle (LNP).

[0172] In some embodiments, the type III interferon or the agent stimulating the production of type III interferon is an RNA-LNP encoding IFN-kl, IFN-X2, IFN-X3 and / or IFN-X4.

[0173] In some embodiments, the lipid nanoparticle (LNP) comprising the RNA molecule encoding the type III interferon further comprises molecules that target it to dendritic cells (DCs). For instance, the lipid nanoparticle may comprise or express molecules that are recognized by, or bound to, receptors expressed by dendritic cells (DCs). Thus, the lipid nanoparticle may deliver the RNA molecules encoding the type III interferon to dendritic cells (DCs), leading to increased production of type III interferon by the dendritic cells (DCs).

[0174] In some embodiments, the interferon-lambda is a functional mimetic of IFN- I. In some embodiments, the interferon-lambda is a functional mimetic of IFN-X2. Insome embodiments, the interferon-lambda is a functional mimetic of IFN-X3. In some embodiments, the interferon-lambda is a functional mimetic of IFN-X4.

[0175] As used herein, the term "functional mimetic" means a molecule which has the same or similar biological effects as the naturally occurring protein. For example, an interferon-lambda functional mimetic may activate the interferon-lambda receptor and drive the transcription of IFN-stimulated genes.

[0176] In some embodiments, the interferon-lambda functional mimetic is a fragment of IFN-X1. In some embodiments, the interferon-lambda functional mimetic is a fragment of IFN-X2. In some embodiments, the interferon-lambda functional mimetic is a fragment of IFN-X3. In some embodiments, the interferon-lambda functional mimetic is a fragment of IFN-X4.

[0177] In some embodiments, the interferon-lambda functional mimetic is an antibody. Such interferon-lambda functional mimetic antibody can elicit the same or similar biological effects as the naturally occurring protein. For example, the antibody may bind to an epitope on the interferon-lambda receptor, activating receptor signaling and driving the transcription of IFN-stimulated genes. The heterodimeric receptor complex of interferon-lambda (IFNLR) comprises IFNLR1 (IFNLRA, IL-28RA), and IL10R2 (IL-10RB). IFNLR1 confers ligand specificity and enables receptor assembly, while IL10R2 is shared with IL- 10 family members and is required for signaling.

[0178] In some embodiments, the interferon-lambda derivative is a small molecule chemical entity (such as, for example, a chemical entity with a molecular weight less than 900 Daltons). Methods of screening chemical libraries to identify small molecule chemical entities which may be potential drug candidates are known in the art. For example, a chemical library may be tested in a ligand-receptor binding assay.

[0179] In some embodiments, the agent stimulating the production of type III interferon is an agent that stimulates pattern-recognition receptors (PRRs).

[0180] "Pattern-recognition receptor" includes mainly Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG- 1 -like receptors (RLRs), and C-type lectin receptors(CLRs). They recognize different microbial signatures or host-derived danger signals and trigger an immune response, such as interferon production.

[0181] In some embodiments, the agent stimulating the production of type III interferon comprises toll-like receptor (TLR) ligands (e.g., TLR3, TLR5, TLR7 / 8 and TLR9), RIG-I ligands and MDA-5 ligands.

[0182] In some embodiments, the agent stimulating the production of type III interferon comprises poly I:C, CpG and / or Tat protein.

[0183] In some embodiments, the agent stimulating the production of type III interferon does not induce production of type I interferon.

[0184] In some embodiments, the agent stimulating 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 a MDA5 ligand.Anti-IFN-alpha agent

[0185] As used herein, the term "alpha interferon" (IFN-a) or “interferon-alpha” refers to a family of more than 20 related but distinct members or subtypes, including IFN-al / 13, IFN-a2, IFN-a4, IFN-a5, IFN-a6, IFN-a7, IFN-a8, IFN-alO, IFN-al4, IFN-al6, IFN-al7, IFN-a21. These members are encoded by a cluster on chromosome 9 and all bind to the same IFN receptor. Among these, the IFN-a2 have 3 recombinant variants (a2a, a2b, a2c) depending upon the cells of origin and the IFN-a2b is the predominant variant in human genome. There is evidence though that each subtype has a different binding capacity to the IFNAR, modulating the signaling transduction events and the biological effects in the target cells.

[0186] In the context of the invention, the term “interferon-alpha” or “IFN-a” may designate any subtype of IFN-a, such as e.g. IFN-al / 13, IFN-a2, IFN-a4, IFN-a5, IFN-a6, IFN-a7, IFN-a8, IFN-alO, IFN-al4, IFN-al6, IFN-al7, IFN-a21.

[0187] In one embodiment, the interferon-alpha blocking agent, or anti-IFN-a agent, described herein is an agent neutralizing circulating IFN-a and / or an agent blockingIFN-a signaling, and / or an agent depleting IFN-a producing cells, and / or an agent blocking IFN-a production.

[0188] In one embodiment, the interferon-alpha blocking agent described herein comprises at least one agent selected from: an agent neutralizing circulating IFN- a and / or an agent blocking IFN-a signaling, and / or an agent depleting IFN- a producing cells, and / or an agent blocking IFN-a production.

[0189] In one embodiment, the agent neutralizing circulating IFN-a and / or the agent blocking IFN-a signaling, and / or the agent depleting IFN-a producing cells, and / or the agent blocking IFN-a production is / are an IFN-a antagonist.

[0190] In some embodiments, the interferon-alpha blocking agent is selected from the group consisting of : an agent neutralizing circulating interferon alpha, an agent blocking interferon-alpha signaling, an agent depleting IFN-a producing cells, and / or an agent blocking IFN-a production, wherein the agent neutralizing circulating interferon alpha is selected from the group comprising active anti-IFN-a vaccine including IFN-a-kinoid, IFN-a DNA-based or IFN-a RNA-based vaccine, or passive anti-IFN-a vaccine including anti-IFN-a antibodies or anti-IFN-a hyper-immune serum, wherein the blocking agent of interferon-alpha signaling is selected from the group consisting of an active anti-IFNARl or anti-IFNAR2 vaccine, such as an IFNAR1 or IFNAR2 DNA-based or an IFNAR1 or IFNAR2 RNA-based vaccine, a passive anti-IFNARl or anti-IFNAR2 vaccine, such as an anti-type I interferon R1 or R2 antibody, and an IFN-a endogenous regulator, such as SOSC1 or an aryl hydrocarbon receptor, wherein the agent depleting IFN-a producing cells is an agent depleting plasmacytoid dendritic cells (pDCs), and wherein the agent blocking IFN-a production is an agent blocking the production of IFN-a by pDCs.

[0191] In some embodiments, the interferon-alpha blocking agent is an agent neutralizing circulating interferon alpha selected from the group consisting of active anti-IFN-a vaccine including IFN-a-kinoid, IFN-a DNA-based or IFN-a RNA-based vaccine, or passive anti-IFN-a vaccine including anti-IFN-a antibodies or anti-IFN-ahyper-immune serum, and the blocking agent of interferon-alpha signaling is selected from the group consisting of an active anti-IFNARl or anti-IFNAR2 vaccine, such as an IFNAR1 or IFNAR2 DNA-based or an IFNAR1 or IFNAR2 RNA-based vaccine, a passive anti-IFNARl or anti-IFNAR2 vaccine, such as an anti-type I interferon R1 or R2 antibody, and an IFN-a endogenous regulator, such as SOSC1 or an aryl hydrocarbon receptor.

[0192] As used herein, the term "interferon alpha antagonist" refers to a substance which interferes with or inhibits the IFN-a biological activity. "IFN-a biological activity" as used herein refers to any activity occurring as a result of IFN-a binding to its receptor IFNAR (IFNAR1 / IFNAR2 heterodimer). Such binding can, for example, activate the JAK-STAT signaling cascade, and trigger tyrosine phosphorylation of a number of proteins including JAKs, TYK2, STAT proteins. Thus, the blocking agent of interferon-alpha signaling can neutralize the fixation of the INF-a to its receptor and / or block the signaling cascade induced by the binding of IFN-a to its receptor. In some embodiments, the IFN-a antagonist is selected from the group of active anti- IFN-a vaccine (e.g., IFN-a-kinoid, IFN-a DNA-based or IFN-a RNA-based vaccine) or passive anti-IFN-a vaccine (e.g., anti-IFN-a antibody or anti-IFN-a hyper-immune serum). See for example Noel et al. (2018). Cytokine Growth Factor Rev 40:99-112.

[0193] In some embodiments, the methods of the invention comprise administering to a subject an agent neutralizing at least one circulating type I interferon or an agent blocking the signaling of at least one type I interferon.

[0194] In some embodiments, the agent neutralizing circulating interferon alpha or blocking interferon alpha signaling is an agent neutralizing at least one circulating type I interferon or blocking the signaling of at least one type I interferon.

[0195] In humans, type I interferons include IFN-a, IFN-P, IFN-co, IFN-e, IFN-K, and any subtype thereof. In the context of the invention, the type I interferon may be any type I interferon selected from the group consisting of IFN-a, IFN-P, IFN-co, IFN-e, IFN-K and any subtype thereof.

[0196] In some embodiments, the agent neutralizing circulating interferon alpha or blocking interferon alpha signaling is an agent neutralizing any circulating type I interferon or blocking any type I interferon signaling.

[0197] In some embodiments, the agent neutralizing circulating interferon alpha or blocking interferon alpha signaling is at least one agent neutralizing circulating IFN-a and at least one other type I interferon or blocking IFN-a signaling and at least one other type I interferon signaling.

[0198] In some embodiments, the agent neutralizing circulating interferon alpha or blocking interferon alpha signaling is at least one agent neutralizing circulating IFN-a and at least one interferon selected from IFN-P, IFN-co, IFN-e and IFN-K, or blocking IFN-a signaling and signaling of at least one interferon selected from IFN-P, IFN-co, IFN-e and IFN-K.

[0199] In some embodiments, the agent neutralizing circulating interferon alpha or blocking interferon alpha signaling is an agent neutralizing both circulating IFN-a and IFN-P or blocking both IFN-a and IFN-P signaling.

[0200] The at least one agent neutralizing circulating IFN-a and at least one other type I interferon, or blocking IFN-a signaling and at least one other type I interferon signaling, may be a single agent, compound or molecule or a combination of several agents, compounds or molecules.

[0201] In some embodiments, the agent neutralizing circulating interferon alpha or blocking interferon alpha signaling is combined, or used in combination with, an agent neutralizing circulating interferon beta or blocking interferon beta signaling.Agent neutralizing circulating IFNa

[0202] In one embodiment, the agent neutralizing circulating IFN-a is a passive anti- IFN-a vaccine, such as an anti-IFN-a antibody or an anti-IFN-a hyper-immune serum.

[0203] In one embodiment, the agent neutralizing circulating IFN-a is an anti-IFN-a antibody, preferably a neutralizing antibody preferably a chimeric, humanized orhuman antibody. The anti-IFN-a antibody may be a monoclonal or a polyclonal antibody, and is preferably a monoclonal antibody. The anti-IFN-a antibody may be a single domain antibody (sdAb) or a nanobody, obtained for example in camelids such as dromedaries, camels, llamas, or alpacas.

[0204] Examples of anti-IFN-a antibodies include, without limitation, Sifalimumab, Rontalizumab, S95021 (as described in Duguet et al. Journal of Translational Autoimmunity 4(2021)100093, which is herein incorporated 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.

[0205] In one embodiment, the agent neutralizing circulating IFN-a is an anti-IFN-a hyper-immune serum.

[0206] In one embodiment, the agent neutralizing circulating IFN-a described herein is an IFN-a ligand inhibitor.

[0207] In one embodiment, the agent neutralizing circulating IFN-a is a soluble receptor that binds IFN-a.

[0208] In another embodiment, the agent neutralizing circulating IFN-a is an active anti-IFN-a vaccine.

[0209] An “active anti-IFN-a vaccine” designates a compound or composition that is capable of inducing the production of anti-IFN-a antibodies. For instance, an “active anti-IFN-a vaccine” designates a compound or composition which, upon administration to a subject, is capable of inducing the production of anti-IFN-a autoantibodies by said subject.

[0210] The active ingredient of the active anti-IFN-a vaccine may be a polypeptide, a protein, a DNA or an RNA molecule.

[0211] For instance, the active ingredient of the active anti-IFN-a vaccine is an IFN- a-kinoid. A kinoid is an inactivated and / or non-toxic IFN derivative withimmunogenic properties. Usually, it is in the form of a heterocomplex obtained by chemical binding of the IFN derivative to a carrier.

[0212] The kinoid may be used as an immunogen capable of inducing high affinity auto-antibodies against a given IFN. Immunization with kinoids thus induce high titers of neutralizing antibodies directed against the corresponding IFN.

[0213] In one embodiment, the agent neutralizing circulating IFN-a described herein is an IFN-a-kinoid, such as, for example, Antiferon®.

[0214] The active ingredient of the active anti-IFN-a vaccine may also be a DNA molecule, for instance part(s) of or full-length IFN-a DNA, or an RNA molecule, for instance part(s) of or full-length IFN-a RNA.

[0215] The active anti-IFN-a vaccine may induce the production of antibodies that binds to one IFN-a subtype or to several IFN-a subtypes. For instance, the RNA molecule used in the IFN-a RNA-based vaccine may be specific of one IFN-a subtype. Alternatively, the active anti-IFN-a vaccine may comprise at least two RNA molecules corresponding to at least two IFN-a subtypes.Agent blocking IFNa signaling

[0216] In another embodiment, the interferon-alpha blocking agent is an agent blocking IFN-a signaling.

[0217] In one embodiment, the agent blocking IFN-a signaling is an agent that antagonizes the type I IFN signaling pathway.

[0218] In one embodiment, the agent blocking IFN-a signaling described herein is an IFNAR antagonist.

[0219] In one embodiment, the agent blocking IFN-a signaling is an IFNAR1 antagonist. In another embodiment, the agent blocking IFN-a signaling is an IFNAR2 antagonist.

[0220] In one embodiment, the agent blocking IFN-a signaling is a passive anti- IFNAR1 or anti-IFNAR2 vaccine, such as an anti -type I interferon R1 or R2 antibody.

[0221] In one embodiment, the agent blocking IFN-a signaling is an antibody that binds to IFNAR1 or IFNAR2.

[0222] In another embodiment, the agent blocking IFN-a 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.

[0223] An “active anti-IFNARl or anti-IFNAR2 vaccine” designates a compound or composition that is capable of inducing the production of anti-IFNARl or anti- IFNAR2 antibodies. For instance, an “active anti-IFNARl or anti-IFNAR2 vaccine” designates a compound or composition which, upon administration to a subject, is capable of inducing the production of anti-IFNARl or anti-IFNAR2 auto-antibodies by said subject.

[0224] The active ingredient of the active anti-IFNARl or anti-IFNAR2 vaccine may be a DNA molecule, for instance part(s) of or full-length IFNAR1 or IFNAR2 DNA, or an RNA molecule, for instance part(s) of or full-length IFNAR1 or IFNAR2 RNA.

[0225] In one embodiment, the agent blocking IFN-a signaling can be an inhibitor of type I IFN signaling pathway. Type I IFN signaling pathway inhibitors are well known in the art and include, without limitation, JAK1 / 2 / 3 inhibitors and STAT inhibitors. Accordingly, in one embodiment, the agent blocking IFN-a signaling is selected from JAK1 / 2 / 3 inhibitors, STAT inhibitors, and Tyrosine Kinase 2 (TYK2) inhibitors. Nonlimiting examples of JAK1 / 2 / 3 inhibitors include Ruxolitinib, Tofacitinib and Baricitinib. Non-limiting examples of TYK2 inhibitors include the BMS-986165 inhibitor.

[0226] In one embodiment, the agent blocking IFN-a signaling can be an endogenous negative regulator of type I IFN signaling pathway. Endogenous negative regulators are well known in the art and include, without limitation, SOCS1 / 3, FOXO3, Arylhydrocarbon Receptor (AhR) or other negative regulators. Accordingly, in one embodiment, the agent blocking interferon signaling is selected from SOCS1 / 3, FOXO3 or Aryl hydrocarbon Receptor (AhR).

[0227] In one embodiment, the agent blocking IFN-a signaling is a PASylated antagonist. PASylated antagonist of type I IFN are known in the art, see for example Nganou-Makamdop et al. (2018). PLoS Pathog 14(8): el007246.Agent depleting IFNa producing cells

[0228] In one embodiment, the IFN-a antagonist described herein is an agent depleting IFN-a producing cells.

[0229] As used herein, the term “IFN-a producing cells” refers to any cell that produce IFN-a. In particular, it is well known in the art that the plasmacytoid dendritic cells (pDCs) are the main producer of IFN-a. Thus, in one embodiment, the agent depleting IFN-a producing cells depletes pDCs.

[0230] In one embodiment, the agent depleting IFN-a producing cells is an antibody. In one embodiment, the antibody depletes pDCs, such as, for example, an anti-CD123 antibody (i.e., anti-IL-3RA).Agent blocking IFNa production

[0231] In one embodiment, the IFN-a antagonist described herein is an agent that blocks the production of IFN-a.

[0232] In one embodiment, the agent that blocks the production of the IFN-a is an antibody. In one embodiment, the antibody blocks the production of IFN-a by pDCs. Said antibody can be, for example, an anti-BDCA2 (Blood DC Antigen 2) antibody.Concrete examples of interferon-alpha blocking agents

[0233] In some embodiments, the interferon-alpha blocking agent is selected from the group consisting of an anti-IFN-a antibody, preferably Sifalimumab, Rontalizumab, 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, an anti-IFN-a hyper-immune serum, an IFN-a-kinoid, such as e.g. Antiferon®, an IFN-a DNA-based or an IFN-a RNA-based vaccine, a soluble receptor that binds IFN-a, an IFNAR1 or IFNAR2 antagonist, preferably an antibody that binds to IFNAR1 or IFNAR2, such as the anti-IFNARl MAb Anifrolumab (Saphnelo®, AstraZeneca), or the anti-IFNAR antibody described in WO 2022 / 087274 (which content is herein incorporated by reference). an IFNAR1 or IFNAR2 DNA-based or an IFNAR1 or IFNAR2 RNA-based vaccine, a type I IFN signaling pathway inhibitors selected from a STAT inhibitor, a JAK 1 / 2 / 3 inhibitor, such as e.g. Ruxolitinib, Tofacitinib or Baricitinib, and a TYK2 inhibitor, such as e.g. BMS-986165, an endogenous negative regulator of type I IFN signaling pathway selected from SOCS1 / 3, FOXO3, Aryl hydrocarbon Receptor (AhR) or another negative regulator, a PASylated antagonist, an antibody depleting pDCs, preferably an anti-CD123 (i.e. anti-IL-3RA) antibody, an antibody blocking the production of IFN-a by pDCs, preferably an anti-BDCA2 (Blood DC Antigen 2) antibody.

[0234] In some embodiments, the interferon-alpha blocking agent is an antibody, preferably a monoclonal antibody, preferably a neutralizing antibody, preferably a chimeric, humanized or human antibody.

[0235] In some embodiments, the interferon-alpha blocking agent is an antigenbinding polypeptide, such as e.g. an antigen-binding fragment of an antibody.

[0236] In one embodiment, the interferon-alpha blocking agent is an anti-IFN-a antibody, preferably a monoclonal antibody, preferably a neutralizing antibody, preferably a chimeric, humanized or human antibody. In some embodiments, the interferon-alpha blocking agent is Sifalimumab, Rontalizumab or S95021.

[0237] In one embodiment, the interferon-alpha blocking agent is a human monoclonal antibody that binds the type I interferon receptor subunit 1. In one embodiment, the interferon-alpha blocking agent is Anifrolumab (Saphnelo®, AstraZeneca).Anti-IFN-beta agent

[0238] In some embodiments, the agent neutralizing circulating interferon alpha or blocking interferon alpha signaling also neutralizes circulating IFN-P or also blocks IFN-P signaling.

[0239] In some embodiments, the agent neutralizing circulating interferon alpha or blocking interferon alpha signaling is combined, or used in combination with, an agent neutralizing circulating interferon beta or blocking interferon beta signaling.

[0240] The term "beta interferon" (IFN-P) or “interferon-beta” refers to a family of two related but distinct members IFN-P 1 and IFN-P3. They both bind to the same IFN receptor, the IFN-a receptor (IFNAR), which is a cell surface receptor complex consisting of 2 chains: IFNAR1 and IFNAR2 (IFNAR1 / IFNAR2 heterodimer). Binding of IFN-P to the IFNAR receptor triggers signaling transduction events and biological effects in the target cell.

[0241] As used herein, the term "beta interferon" (IFN-P) or “interferon-beta” refers to a family of two related but distinct members IFN-P 1 and IFN-P3. They both bind to the same IFN receptor, the IFN-a receptor (IFNAR), which is a cell surface receptorcomplex consisting of 2 chains: IFNAR1 and IFNAR2 (IFNAR1 / IFNAR2 heterodimer).

[0242] Binding of IFN-P to the IFNAR receptor triggers signaling transduction events and biological effects in the target cell.

[0243] In one embodiment, the interferon-beta blocking agent described herein is an agent neutralizing circulating IFN-P and / or an agent blocking IFN-P signaling.

[0244] In one embodiment, the interferon-beta blocking agent described herein comprises at least one agent selected from an agent neutralizing circulating IFN-P and an agent blocking IFN-P signaling.

[0245] In one embodiment, the agent neutralizing circulating IFN-P and / or the agent blocking IFN-P signaling is / are an IFN-P antagonist.

[0246] As used herein, the term "beta interferon antagonist" refers to a substance which interferes with or inhibits the IFN-P biological activity. " IFN-P biological activity" as used herein refers to any activity occurring as a result of IFN-P binding to its receptor IFNAR (IFNAR1 / IFNAR2 heterodimer). Such binding can, for example, activate the JAK-STAT signaling cascade, and trigger tyrosine phosphorylation of a number of proteins including JAKs, TYK2, STAT proteins. Thus, the signaling blocking agent of interferon can neutralize the fixation of the IFN-P to its receptor and / or block the signaling cascade induced by the binding of IFN-P to its receptor. In some embodiments, the IFN-P antagonist is selected from the group of active anti- IFN-P vaccine (e.g., IFN-P-kinoid, IFN-P DNA-based or IFN-P RNA-based vaccine) or passive anti-IFN-P vaccine (e.g., anti-IFN-P antibody or anti-IFN-P hyper-immune serum).

[0247] In one embodiment, the agent neutralizing circulating IFN-P is a passive anti- IFN-P vaccine, such as an anti-IFN-P antibody or an anti-IFN-P hyper-immune serum.

[0248] In one embodiment, the interferon-beta blocking agent is an agent neutralizing circulating IFN-P, wherein the agent neutralizing circulating IFN-P is an anti-IFN-P antibody or anti-IFN-P hyper-immune serum.

[0249] In one embodiment, the agent neutralizing circulating IFN-P is an anti-IFN-P antibody, preferably a neutralizing antibody, preferably a chimeric, humanized or human antibody. The anti-IFN-P antibody may be a monoclonal or a polyclonal antibody, and is preferably a monoclonal antibody.

[0250] Non-limiting examples of anti-IFN-P antibodies include:- the neutralizing monoclonal antibody against human IFN-beta, clone 10B10 (Invivogen),- the polyclonal anti-human IFN-beta antibodies (R&D systems), the monoclonal anti-human IFN-beta antibodies clone #76703, clone #MMHB-3 and clone #937912 (R&D systems),- the neutralizing polyclonal anti-human IFN-beta goat IgG (PBL assay sciences).

[0251] In one embodiment, the agent neutralizing circulating IFN-P is an anti-IFN-P hyper-immune serum.

[0252] In one embodiment, the agent neutralizing circulating IFN-P described herein is an IFN-P ligand inhibitor.

[0253] In one embodiment, the agent neutralizing circulating IFN-P is a soluble receptor that binds IFN-p.

[0254] In another embodiment, the interferon-beta blocking agent is an active anti- IFN-P vaccine.

[0255] An “active anti-IFN-P vaccine” designates a compound or composition that is capable of inducing the production of anti-IFN-P antibodies. For instance, an “active anti-IFN-P vaccine” designates a compound or composition which, upon administration to a subject, is capable of inducing the production of anti-IFN-P autoantibodies by said subject.

[0256] The active ingredient of the active anti-IFN-P vaccine may be a polypeptide, a protein, a DNA or an RNA molecule.

[0257] For instance, the active ingredient of the active anti-IFN-P vaccine is an IFN- P-kinoid. A kinoid is an inactivated and / or non-toxic IFN derivative with immunogenic properties. Usually, it is in the form of a heterocomplex obtained by chemical binding of the IFN derivative to a carrier.

[0258] The kinoid may be used as an immunogen capable of inducing high affinity auto-antibodies against a given IFN. Immunization with kinoids thus induce high titers of neutralizing antibodies directed against the corresponding IFN.

[0259] The active ingredient of the active anti-IFN-P vaccine may also be a DNA molecule, for instance part(s) of or full-length IFN-P DNA, or an RNA molecule, for instance part(s) of or full-length IFN-P RNA.

[0260] In one embodiment, the interferon-beta blocking agent is an agent blocking IFN-P signaling, wherein the blocking agent of IFN-P signaling is selected from the group consisting of anti -type I interferon R1 or R2 antibodies, SOSC1 and aryl hydrocarbon receptors.

[0261] In one embodiment, the agent blocking IFN-P signaling described herein is an IFNAR antagonist. In one embodiment, the agent blocking IFN-P signaling is an IFNAR1 antagonist. In another embodiment, the agent blocking IFN-P signaling is an IFNAR2 antagonist.

[0262] In one embodiment, the agent blocking IFN-P signaling is an antibody that binds to IFNAR 1 or IFNAR2.

[0263] In one embodiment, the agent blocking IFN-P signaling is an agent that antagonizes the type I IFN signaling pathway.

[0264] In one embodiment, the agent blocking IFN-P signaling can be an inhibitor of type I IFN signaling pathway. Type I IFN signaling pathway inhibitors are well known in the art and include, without limitation, JAK1 / 2 / 3 inhibitors and STAT inhibitors. Accordingly, in one embodiment, the agent blocking IFN-P 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.

[0265] Non-limiting examples of TYK2 inhibitors include the BMS-986165 inhibitor.

[0266] In one embodiment, the agent blocking IFN-P signaling can be an endogenous negative regulator of type I IFN signaling pathway. Endogenous negative regulators are well known in the art and include, without limitation, SOCS1 / 3, FOXO3, Aryl hydrocarbon Receptor (AhR) or other negative regulators. Accordingly, in one embodiment, the agent blocking interferon signaling is selected from SOCS1 / 3, FOXO3 or Aryl hydrocarbon Receptor (AhR).

[0267] In one embodiment, the agent blocking IFN-P signaling is a PASylated antagonist. PASylated antagonist of type I IFN are known in the art, see for example Nganou-Makamdop et al. (2018). PLoS Pathog 14(8): el007246.Tolerogenic / CD8 vaccine

[0268] As used herein, the term "vaccine" refers to an immunogenic product or composition that can be administered to a mammal, such as a human, to confer immunity, such as passive or active immunity, to a disease or other pathological condition. Vaccines can be used preventively or therapeutically, either prophylactically or curatively. Thus, vaccines can be used to reduce the likelihood of developing a disease (such as infection) or to reduce the severity of symptoms of a disease or condition, limit the progression of the disease or condition (such as infection), or limit the recurrence of a disease or condition.

[0269] The terms “tolerogenic vaccine” and “CD8 vaccine” may herein be used indifferently.

[0270] In one embodiment, the tolerogenic vaccine is a preventive vaccine. In another embodiment, the tolerogenic vaccine is a therapeutic vaccine. As used herein, a therapeutic vaccine may be a prophylactic vaccine or a curative vaccine. In someembodiments, the tolerogenic vaccine is a prophylactic vaccine. In other embodiments, the tolerogenic vaccine is a curative vaccine.

[0271] In one embodiment, the tolerogenic vaccine induces immunotolerance to at least one HIV-related antigen. In one embodiment, the tolerogenic vaccine is thus specific for at least one HIV immunogen, said HIV immunogen being an HIV antigen.

[0272] As used herein, the terms "immunotolerance" and "Ts" are synonymous. Immunotolerance is the physiological capacity of the immune system to recognize antigens and to develop anergy generally associated with other immunological modifications to a subsequent encounter with the same antigens. In the present invention, immunotolerance is principally characterized by the activity of CD8+T cells which suppress the activation CD4+T cells that present at least one HIV-related antigen. Globally, each time where one or several HIV-related antigen(s) is / are involved in the specific activation of CD4+T cells (which present epitopes derived from the HIV-related antigen), the specific suppression / prevention of activation of CD4+T cell can be raised by MHC-lb / E-restricted CD8+T cells generated by the tolerogenic vaccines as described in the present invention.

[0273] In some embodiments, the tolerogenic vaccine specific for at least one HIV immunogen lyses infected CD4+ cells expressing at least one HIV peptide in an HLA- E restriction.

[0274] In one embodiment, the tolerogenic vaccine of the invention elicits suppressor MHC-lb / E-restricted CD8+T cells. In another embodiment, the tolerogenic vaccine of the invention comprises or consist essentially of suppressor MHC-lb / E-restricted CD8+T cells.

[0275] As used herein, "consisting essentially of", with reference to a cell population, means that the suppressor MHC-lb / E-restricted CD8+T cell population is the only one therapeutic agent or agent with a biologic activity within said composition.

[0276] In one embodiment, the suppressor MHC-lb / E-restricted CD8+T cells are generated by ex vivo or in vivo induction of HLA- la-deprived dendritic, natural killer or B cells.

[0277] In one embodiment, the suppressor MHC-lb / E-restricted CD8+T cells are cytolytic CD8+T cells. In one embodiment, the suppressor MHC-lb / E-restricted CD8+T cells are non-cytolytic CD8+T cells.

[0278] In one embodiment, the tolerogenic vaccine is an active vaccine. In another embodiment, the tolerogenic vaccine is a passive vaccine.

[0279] As used herein, the term "active vaccine" refers to a vaccine that induces an active immunity and refers to the process of exposing the body to an antigen to generate an adaptive immune response: the response takes days / weeks to develop but may be long lasting, even lifelong. A "passive vaccine" induces a passive immunity and refers to the process of providing, for example, antibodies or cells to protect against infection; it gives immediate, but short-lived protection — several weeks to months.

[0280] In some embodiments, the tolerogenic vaccine is a vaccine eliciting suppressor MHC-lb / E-restricted CD8+T cells, said vaccine being selected from the group consisting of: an active vaccine which is a live viral vector comprising at least one pathogenspecific antigen, wherein the live viral vector is selected from the group consisting of cytomegalovirus, lentivirus, vaccinia virus, adenovirus and plasmid; an active vaccine comprising at least one pathogen-specific antigen and at least one non-pathogenic bacterium, preferably at least one attenuated or inactivated pathogenic bacterium; an active vaccine which is an ex vivo generated dendritic, natural killer or B cell population presenting at least one MHC-lb / E-restricted antigen and at least oneMHC-II restricted antigen, and wherein the MHC-lb / E-restricted antigen is a pathogen-specific antigen; a passive vaccine which is an ex vivo generated autologous MHC-lb / E-restricted CD8+T cell population, recognizing an MHC-lb / E-restricted pathogen-specific antigen; an active vaccine which is at least one lipid nanoparticle (LNP) containing, or conjugated to, at least one nucleic acid molecule comprising a single chain trimer of HLA-E with a pathogen-specific antigen or peptide.Lentivirus and plasmid

[0281] According to one embodiment of the invention, the tolerogenic vaccine is a live viral vector comprising at least one HIV-related antigen.

[0282] In one embodiment, the live viral vector, as described hereinabove, is an active vaccine.

[0283] In one embodiment, the live viral vector, as described hereinabove, is selected from the group of cytomegalovirus, lentivirus, vaccinia virus, adenovirus and plasmid.

[0284] In one embodiment, the live viral vector, as described hereinabove, is a recombinant vector selected from the group of recombinant cytomegalovirus, recombinant lentivirus, recombinant vaccinia virus, recombinant adenovirus and recombinant plasmid.

[0285] The live viral vector may be a replicative or non-replicative vector.

[0286] According to one embodiment, the live viral vector is a recombinant vaccinia virus. Recombinant vaccinia viruses have been produced from different Vaccinia virus strains. For example, a variety of highly attenuated, host-restricted, non- or poorly- replicating poxvirus strains for use as substrates in recombinant vaccine development have been developed, including the Orthopoxviruses, Modified Vaccinia Ankara (MVA), NYVAC, Avipoxviruses, AL VAC, and TRO VAC.Live CMV vector

[0287] According to one embodiment of the invention, the tolerogenic vaccine is a CMV vector.CMV vector construction

[0288] In one embodiment, the CMV vector is an active vaccine.

[0289] In one embodiment, the CMV vector comprises a nucleic acid sequence that encodes at least one human immunodeficiency virus (HIV) antigen.

[0290] In one embodiment, the tolerogenic vaccine is a recombinant CMV expressing at least one HIV-related antigen, wherein said antigen is a heterologous antigen. Thus, in one embodiment, the HIV-related antigen can be derived from any protein that is not natively expressed in CMV.

[0291] In one embodiment, the CMV vector does not express an active ULI 28 and ULI 30 proteins, or orthologs thereof.

[0292] As used herein, the term "ortholog" refers to homologous genes of CMVs that infect other species.

[0293] In one embodiment, the CMV vector does not express an active ULI 46 and ULI 47 proteins, or orthologs thereof.

[0294] 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 and the at least one active US28 protein can be orthologs or homologs of UL40, US27 and US28.

[0295] In some examples, the CMV vector does not express an active UL128, UL130, ULI 46 or ULI 47 protein due to the presence of a mutation in the nucleic acid sequence encoding ULI 28, ULI 30, ULI 46 or ULI 47, or orthologs thereof.

[0296] As used herein, the term "mutation" may refer to any mutation that results in a lack of expression of active ULI 28, U I 30, ULI 46 or ULI 47 protein. Such mutations can include point mutations, frameshift mutations, deletions of less than all of the sequence that encodes the protein (truncation mutations), or deletions of all of the nucleic acid sequence that encodes the protein, or any other mutations. For example, CMV comprising said mutation are described in WO2014138209, which is incorporate by reference herein in its entirety.

[0297] In further examples, the vector does not express an active ULI 28, ULI 30, ULI 46 or ULI 47 protein, or an ortholog thereof, due to the presence of a nucleic acid sequence in the vector that comprises an antisense or RNAi sequence (siRNA or miRNA) that inhibits the expression of the ULI 28, ULI 30, ULI 46 or ULI 47 protein, or an ortholog thereof.

[0298] In one embodiment, mutations and / or antisense and / or RNAi can be used in any combination to generate a CMV vector lacking active ULI 28, ULI 30, ULI 46 or ULI 47, or an ortholog thereof.

[0299] In one embodiment, the CMV vectors comprises all of the above modifications and further comprises a nucleic acid sequence that serves as a miRNA response element (MRE) that silences expression in the presence of a miRNA expressed by endothelial cells.

[0300] As used herein, the term "miRNA response element" or "MRE" refers to any sequence that directly base pairs with and interacts with the miRNA somewhere on the mRNA transcript. Thus, a miRNA may silence the translation of one or more specific mRNA molecules by binding to a miRNA recognition element (MRE). Often, the MRE is present in the 3' untranslated region (UTR) of the mRNA, but it may also be present in the coding sequence or in the 5' UTR. MREs are not necessarily perfectly complementary to miRNAs, usually having only a few bases of complementarity to the miRNA and often containing one or more mismatches within those bases of complementarity. The MRE may be any sequence capable of being bound by a miRNA sufficiently that the translation of a gene to which the MRE is operably linked.Examples of such genes include without limitation IE2 and UL79 genes, or orthologs thereof, or any CMV gene that is essential or augmenting for growth in vivo. For example, CMV comprising said MRE are described in WO201875591, which is incorporate by reference herein in its entirety.

[0301] In one embodiment, the MRE may be any miRNA recognition element that silences expression in the presence of a miRNA expressed by endothelial cells. In one embodiment, an 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.

[0302] In one embodiment, the MRE silences expression in the presence of miR- 126- 3p.

[0303] In one embodiment, the MRE silences the expression of UL122 (IE2) and UL79 in the presence of miR- 126-3 p.

[0304] One of skill in the art may select a validated, putative, or mutated MRE sequence from the literature that would be predicted to induce silencing in the presence of a miRNA expressed in an endothelial cell or a myeloid cell such as a macrophage. The person of skill in the art may then obtain an expression construct whereby a reporter gene (such as a fluorescent protein, enzyme or other reporter gene) has expression driven by a promoter such as a constitutively active promoter or cellspecific promoter. The MRE sequence may then be introduced into the expression construct. The expression construct may be transfected into an appropriate cell, and the cell transfected with the miRNA of interest. A lack of expression of the reporter gene indicates that the MRE silences gene expression in the presence of the miRNA.

[0305] In one embodiment, the CMV vector comprises a first nucleic acid sequence encoding at least one HIV-related antigen, and does not express an active UL128, ULI 30, ULI 46 and ULI 47 proteins or orthologs thereof, and expresses at least one active UL40, US27 and / or US28 proteins or an orthologs thereof.

[0306] In another embodiment, the CMV vector comprises a first nucleic acid sequence encoding at least one HIV-related antigen, optionally a second nucleic acidsequence comprising a first microRNA recognition element (MRE) operably linked to a CMV gene that is essential or augmenting for CMV growth, wherein the MRE silences expression in the presence of a microRNA that is expressed by a cell of endothelial lineage, and does not express an active ULI 28, ULI 30, ULI 46 and ULI 47 proteins or orthologs thereof, and expresses at least one active UL40, US27 and / or US28 proteins or an orthologs thereof.

[0307] In one embodiment, the CMV vector can comprise additional inactivating mutations known in the art to provide different immune responses, such as an inactivating US 11 mutation or an inactivating UL82 (pp71) mutation, or any other inactivating mutation.

[0308] In one embodiment, the CMV vector may also comprise at least one inactivating mutations in one or more viral genes encoding viral proteins known in the art to be essential or augmenting for viral dissemination (z.e., spread from cell to cell) in vivo. Such inactivating mutations may result from point mutations, frameshift mutations, truncation mutations, or a deletion of all of the nucleic acid sequence encoding the viral protein. Inactivating mutations include any mutation in a viral gene which finally leads to a reduced function or to a complete loss of function of the viral protein.

[0309] In one embodiment, the CMV vectors described herein can contain mutations that can prevent host to host spread, thereby rendering the virus unable to infect immunocompromised or other subjects that could face complications as a result of CMV infection. In another embodiment, the CMV vectors described herein can also contain mutations that result in the presentation of immunodominant and non- immunodominant epitopes as well as non-canonical MHC restriction. Such CMV mutations are described in, for example, US Patent Publications 2013-0136768; 2014- 0141038; and PCT application publication WO 2014 / 138209, all of which are incorporated by reference herein.

[0310] In one embodiment, mutations in the CMV vectors described herein do not affect the ability of the vector to re-infect a subject that has been previously infectedwith CMV. Accordingly, in one embodiment, the CMV vector is capable of repeatedly infecting an organism.

[0311] In one embodiment, the CMV vector is a human CMV (hCMV) or rhesus CMV (RhCMV) vector.Vectors preparation

[0312] In one embodiment, the CMV vectors disclosed herein can be prepared by inserting DNA comprising a sequence that encodes the HIV-related antigen into an essential or non-essential region of the CMV genome.

[0313] In one embodiment, the method can further comprise deleting one or more regions from the CMV genome. In one embodiment, the method can comprise in vivo recombination. Thus, the method can comprise transfecting a cell with CMV DNA in a cell-compatible medium in the presence of donor DNA comprising the heterologous DNA flanked by DNA sequences homologous with portions of the CMV genome, whereby the heterologous DNA is introduced into the genome of the CMV, and optionally then recovering CMV modified by the in vivo recombination.

[0314] In one embodiment, the method can also comprise cleaving CMV DNA to obtain cleaved CMV DNA, ligating the heterologous DNA to the cleaved CMV DNA to obtain hybrid CMV-heterologous DNA, transfecting a cell with the hybrid CMV- heterologous DNA, and optionally then recovering CMV modified by the presence of the heterologous DNA. Since in vivo recombination is comprehended, the method accordingly also provides a plasmid comprising donor DNA not naturally occurring in CMV encoding a polypeptide foreign to CMV, the donor DNA is within a segment of CMV DNA that would otherwise be co-linear with an essential or non-essential region of the CMV genome such that DNA from an essential or nonessential region of CMV is flanking the donor DNA. The heterologous DNA can be inserted into CMV to generate the recombinant CMV in any orientation that yields stable integration of that DNA, and expression thereof, when desired.

[0315] In one embodiment, the DNA encoding the HIV-related antigen in the recombinant CMV vector can also include a promoter. The promoter can be from any source such as a herpes virus, including an endogenous CMV promoter, such as a HCMV, RhCMV, murine CMV (MCMV), or other CMV promoter. The promoter can also be a non-viral promoter such as the EFla promoter. The promoter can be a truncated transcriptionally active promoter which comprises a region transactivated with a transactivating protein provided by the virus and the minimal promoter region of the full-length promoter from which the truncated transcriptionally active promoter is derived. The promoter can be composed of an association of DNA sequences corresponding to the minimal promoter and upstream regulatory sequences. A minimal promoter is composed of the CAP site plus TATA box (minimum sequences for basic level of transcription; unregulated level of transcription); "upstream regulatory sequences" are composed of the upstream element(s) and enhancer sequence(s). Further, the term "truncated" indicates that the full-length promoter is not completely present, ie., that some portion of the full-length promoter has been removed. And, the truncated promoter can be derived from a herpesvirus such as MCMV or HCMV, e.g., HCMV-IE or MCMV-IE. There can be up to a 40% and even up to a 90% reduction in size, from a full-length promoter, based upon base pairs. The promoter can also be a modified non-viral promoter. As to HCMV promoters, reference is made to U. S. Pat. Nos. 5,168,062 and 5,385,839 which are incorporated herein by reference. As to transfecting cells with plasmid DNA for expression therefrom, reference is made to Feigner et al. (1994), J. Biol. Chem. 269, 2550-2561 which is incorporated herein by reference. And, as to direct injection of plasmid DNA as a simple and effective method of vaccination against a variety of infectious diseases reference is made to Ulmer et al. (1993), Science. 259:1745-49, which is incorporated herein by reference. It is therefore within the scope of this invention that the vector can be used by the direct injection of vector DNA.

[0316] Also disclosed is an expression cassette that can be inserted into a recombinant virus or plasmid comprising the truncated transcriptionally active promoter. The expression cassette can further include a functional truncated polyadenylation signal; for instance an SV40 polyadenylation signal which is truncated, yet functional.Considering that nature provided a larger signal, it is indeed surprising that a truncated polyadenylation signal is functional. A truncated polyadenylation signal addresses the insert size limit problems of recombinant viruses such as CMV. The expression cassette can also include heterologous DNA with respect to the virus or system into which it is inserted; and that DNA can be heterologous DNA as described herein.

[0317] For the disclosed HIV-related antigen to be expressed in the vector, the protein coding sequence of the HIV-related antigen should be "operably linked" to regulatory or nucleic acid control sequences that direct transcription and translation of the protein.Non-pathogenic bacterium

[0318] According to another embodiment of the invention, the tolerogenic vaccine comprises at least one HIV-related antigen and a non-pathogenic bacterium.

[0319] In one embodiment, the tolerogenic vaccine comprises at least one HIV- related antigen and at least one non-pathogenic bacterium.

[0320] In one embodiment, the tolerogenic vaccine that comprises at least one HIV- related antigen and a non-pathogenic bacterium is an active vaccine.Non-pathogenic bacterium

[0321] As used herein, the term "non-pathogenic bacterium" refers to bacteria that do not generally induce any pathology in mammals, preferably in humans.

[0322] In one embodiment, the non-pathogenic bacterium is living.

[0323] In one embodiment, the non-pathogenic bacterium described herein is a commensal bacterium.

[0324] As used herein, the term "commensal bacterium" or refers to microorganism, which is present on body surfaces covered by epithelial cells and is exposed to the external environment (e.g., gastrointestinal and respiratory tract, vagina, skin, etc.). Among the numerous proposed health benefits attributed to intestinal commensal bacteria, their capacity to interact with the host immune system is now welldemonstrated. Commensal bacteria are well-known to the skilled artisan. Non-limiting examples include Bacillus sp. (e.g., B. coagulans), Lactobacillus sp., Bifidobacterium animalis. Bifidobacterium breve, Bifidobacterium infanlis. Bifidobacterium longum. Bifidobacterium bifidum, Bifidobacterium lactis, Escherichia coli, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus johnsonii, Lactobacillus 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, and the like.

[0325] In one embodiment, the commensal bacterium is selected from the group of Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium bifidum, Bifidobacterium breve, Lactococcus lactis, Streptococcus thermophilus, Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus reuteri.

[0326] In one embodiment, the commensal bacterium is Lactobacillus sp., preferably Lactobacillus plantarum.

[0327] In another embodiment, the commensal bacterium is Lactobacillus sp., preferably Lactobacillus rhamnosus.

[0328] In another embodiment, the bacterium is Mycobacterium sp., preferably Mycobacterium bovis.

[0329] In one embodiment, a combination of non-pathogenic bacteria, such as two or more commensal bacteria, may be used.

[0330] In another embodiment, the non-pathogenic bacterium described herein is selected from attenuated or inactivated pathogenic bacteria.

[0331] As used herein, the terms "pathogenic bacteria" refer to bacteria inducing pathologies in humans. Such bacteria are well known from the skilled person and include inter alia Listeria species (e.g., Listeria monocytogenes), Cory neb acterium species, Mycobacterium species, Rhococcus species, Eubacteria species, Bortadellaspecies and Nocardia species. Preferably, a pathogenic bacterium is selected among Mycobacterium species, and is more preferably Mycobacterium bovis.

[0332] As used herein, the terms "attenuated pathogenic bacteria" refer to bacteria which are less virulent compared to their wild-type counterpart because of one or several mutations or of one or more attenuation treatments (e.g., chemical treatment and / or successive passages on specific media). Such attenuated pathogenic bacteria are well known from the one of skill in the art. Non-limiting examples of attenuated pathogenic bacteria include attenuated Salmonella typhimurium and Mycobacteria. Methods of preparation of such inactivated pathogenic bacteria form part of the common general knowledge in the art. As an example of such methods, one can cite phage mediated lysis, chemical inactivation such as formalin treatment, thermal inactivation, physical inactivation such as lyophilisation (e.g., Extended Freeze Drying) or U.V or gamma irradiation or microwave exposure, or any combination thereof.

[0333] In one embodiment, the non-pathogenic bacterium described herein may be recombinant or not.

[0334] In one embodiment, the attenuated pathogenic bacterium described herein is an attenuated derivative of pathogenic bacteria like BCG. In one embodiment, said attenuated derivative of pathogenic bacteria corresponds to recombinant Salmonella typhimurium or recombinant Mycobacteria (e.g., BCG) which expresses or produces at least one HIV protein. In another embodiment, said derivative of pathogenic bacteria does not express any HIV protein.Tolerogenic adjuvant

[0335] In one embodiment, the non-pathogenic bacterium described herein is to be used as a tolerogenic adjuvant of the tolerogenic vaccine. Accordingly, in one embodiment, the non-pathogenic bacterium is a tolerogenic adjuvant.

[0336] As used herein, the term "tolerogenic adjuvant" is an entity that, when administered by the mucosal or the intradermal or the intraepithelial route togetherwith an appropriate HIV-related antigen as defined hereafter, will induce and will preferably maintain a state of immunotolerance to the antigen, thus enabling to treat an HIV infection in humans.

[0337] In one embodiment, the tolerogenic adjuvant, when combined to an HIV- related antigen induces or maintains immunotolerance to the viral antigen, thereby treating a related HIV.

[0338] In one embodiment, non-pathogenic bacteria, especially probiotics and commensal bacteria, may be used as tolerogenic adjuvant in the context of the present invention. In a particular embodiment, Lactobacillus sp., preferably Lactobacillus plantarum and / or Lactobacillus rhamnosus. may be used as tolerogenic adjuvant in the context of the present invention.

[0339] In another embodiment, Mycobacterium sp. , preferably Mycobacterium bovis, may be used as tolerogenic adjuvant in the context of the present invention.

[0340] In one embodiment, a combination of non-pathogenic bacteria, such as two or more commensal bacteria, may be used as the tolerogenic adjuvant in the context of the present invention.

[0341] In another embodiment, instead of or additionally to being attenuated, pathogenic bacteria described herein may be inactivated to be used as tolerogenic adjuvant in the context of the present invention, but attenuated pathogenic bacteria may also be used after having been inactivated.

[0342] In some embodiment, the tolerogenic adjuvant, comprising a non-pathogenic bacterium or an attenuated pathogenic bacterium, further comprises a prebiotic.

[0343] As used herein, “prebiotics” are substances which induce the growth or activity of certain bacteria. Prebiotics are of different nature including e.g. sugars, such as oligosaccharides and polysaccharides.

[0344] Any prebiotic may be used in combination with the non-pathogenic bacterium or the attenuated pathogenic bacterium described herein.

[0345] In some embodiments, the tolerogenic adjuvant comprises at least one prebiotic selected from the group consisting of fructooligosaccharides (FOS), galactooligosaccharides (GOS), inulin, trans-galactooligosaccharides (TOS), beneo synergy 1 (SYN1), oligofructose-inulin, lactulose, oat fibera, germinated barley, hydrolyzed guar guma, resistant starcha, plantago ovataa, beta glucana and pectina.Ex vivo generated APCs presenting an MHC-lb / E-restricted antigen

[0346] According to another embodiment of the invention, the tolerogenic vaccine is an ex vivo generated dendritic, natural killer or B cell population presenting MHC-II and MHC-lb / E-restricted antigens.

[0347] In one embodiment, the ex vivo generated dendritic, natural killer or B cell population presenting MHC-II and MHC-lb / E-restricted antigens is an active vaccine.

[0348] In one embodiment, the MHC-lb / E-restricted antigen is an HIV-related pathogen-specific antigen.

[0349] In one embodiment, the HIV-related antigen or HIV-specific antigen is an HIV or SIV-derived MHCIb / E-binding antigen.

[0350] In one embodiment, the HIV-derived MHCIb / E-binding antigen described herein is selected from the group of SEQ ID NO: 1 to SEQ ID NO: 4, SEQ ID NO: 56 to SEQ ID NO: 58, and SEQ ID NO: 63.

[0351] In one embodiment, the HIV-derived MHCIb / E-binding antigen has an amino acid sequence selected from the group consisting of the sequence RMYSPVSIL (SEQ ID NO: 1), the sequence PEIVIYDYM (SEQ ID NO: 2), the sequence TALSEGATP (SEQ ID NO: 3) the sequence RIRTWKSLV (SEQ ID NO: 4), the sequence VLKYWWNLL (SEQ ID NO: 56) (Env), the sequence ILPCRIKQI (SEQ ID NO: 57) (Env), the sequence AISPRTLNA (SEQ ID NO: 58) (Gag), and the sequence RMYSPTSIL (SEQ ID NO: 63).

[0352] 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 forinstance the HLA-DR-binding antigens having one of the 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).

[0353] In one embodiment, the HLA-DR-restricted peptides are derived from HIV, preferably from HIV-1.

[0354] In one embodiment, the HLA-DR-restricted peptides are HIV-derived HLA- DR-binding antigen having an amino acid sequence selected from the group consisting of the sequence QGQMVHQAISPRTLN (SEQ ID NO: 7) (Gag p24), the sequence GEIYKRWIILGLNKI (SEQ ID NO: 8) (Gag p24), the sequence KRWIILGLNKIVRMY (SEQ ID NO: 9) (Gag p24) and the sequence FRKYTAFTIPSINNE (SEQ ID NO: 10) (Pol RT).

[0355] In one embodiment, dendritic, natural killer or B cell population presenting MHC-II and MHC-lb / E-restricted peptides is an allogenic cell population. In a preferred embodiment, dendritic, natural killer or B cell population presenting MHC- II and MHC-lb / E-restricted restricted peptides is an autologous cells population.

[0356] As used herein, "allogeneic cells" refers to cells isolated from one subject (the donor) and infused in another (the recipient or host).

[0357] As used herein, "autologous cells" refers to cells that are isolated and infused back into the same subject (recipient or host).

[0358] The present invention thus also relates to an ex vivo method for generating dendritic, natural killer or B cell population presenting MHC-II and MHC-lb / E- restricted peptides.

[0359] In one embodiment, the ex vivo method for generating dendritic, natural killer or B cell population presenting MHC-II and MHC-lb / E-restricted peptides, comprises:a. optionally, reducing MHC-la expression in immature dendritic, natural killer or B cells with an agent inhibiting TAP expression or activity, b. loading immature dendritic cells with HLA-DR and / or MHC-lb / E-restricted peptide, and c. maturing the loaded immature dendritic, natural killer or B cells.Isolation of MO-DC precursors

[0360] In one embodiment, the immature dendritic cells are produced from monocytes dendritic cell precursors (MO-DC) precursors.

[0361] As used herein, the term "monocytes dendritic cell precursors" refers to monocytes and other bone marrow precursors (e.g., myeloid precursor). These cells can be isolated from any tissue where they reside, particularly lymphoid tissues such as the spleen, bone marrow, lymph nodes and thymus. Monocytes dendritic cell precursors can be isolated from umbilical cord blood. Monocytes dendritic cell precursors also can be isolated by any technic well known in the art from peripheral blood mononuclear cells or bone marrow samples. Monocytes dendritic cell precursors also can be isolated from frozen samples. Methods for isolating MO-DC precursors and the immature dendritic cells from the various sources provided above, including blood and bone marrow, can be accomplished in a number of ways. Typically, a cell population is collected from the individual and enriched for the MO-DC precursors. For example, a mixed population of cells comprising the MO-DC precursors can be obtained from peripheral blood by leukapheresis, apheresis, density centrifugation, differential lysis, filtration, antibody panning (e.g., flow cytometry, positive or negative selection) or preparation of a buffy coat. In one embodiment, the MO-DC precursors are non-activated thus, in one embodiment, the method selected must not activate the MO-DC precursors. For example, if antibody panning is selected to enrich the cell population for precursors the antibodies selected must not activate the cells (e.g., through the induction of the influx of calcium ions which can result as a consequence of crosslinking the molecules on the surface to which the antibodies bind). Typically, when antibody panning, antibodies are used that eliminatemacrophage, B cells, Natural Killer cells, T cells and the like. Antibodies can also be used to positively select for monocyte like cells that express CD14.

[0362] In one embodiment, the MO-DC precursors and the immature dendritic cells can be obtained from autologous PBMCs (peripheral blood mononuclear cells). In one embodiment, the MO-DC precursors and the immature dendritic cells can be obtained from autologous tissues. In one embodiment, the MO-DC precursors and the immature dendritic cells can be obtained from an HLA-matched healthy individual.

[0363] In one embodiment, the immature dendritic cells can by obtain from induced pluripotent stem cells (iPS). In one embodiment, the immature dendritic cells can by obtain from CD34+dendritic cell precursors. In one embodiment, the immature dendritic cells can by obtain from human dendritic cell lines. In one embodiment, the immature dendritic cells can by obtain from CD34+dendritic cell precursor cell lines. A non-limiting example of a cell line that can be used to generate immature dendritic cell is the CD34+human acute myeloid leukemia cell line (MUTZ-3), see, for example, Masterson et al., (2002) Blood, 100:701-703.

[0364] In another embodiment, the MO-DC precursors and the immature dendritic cells can be obtained from an HLA-matched healthy individual for conversion to immature dendritic cells, maturation, activation and administration to an HLA- matched subject in need thereof.Production of immature dendritic cells

[0365] In one embodiment, the cell populations enriched form non-activated MO-DC precursors or CD34+dendritic cell precursors are cultured ex vivo or in vitro for differentiation, maturation and / or expansion.

[0366] Briefly, ex vivo differentiation typically involves culturing the MO-DC precursors or CD34+dendritic cell precursors, or populations of cell comprising nonactivated MO-DC precursors or CD34+dendritic cell precursors, in the presence of one or more differentiation agents. Such agents generally comprise granulocytemacrophage 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 agents can be used alone or in combination. For example, the GM-CSF can be used alone or in combination with one or more cytokines, such as IL-4, IL-6, IL-3, SC and / or Flt3-L. In one embodiment, the non-activated MO-DC precursors or CD34+dendritic cell precursors are differentiated to form immature dendritic cells capable of inducing the activation and proliferation of a substantial number of T cells.

[0367] Suitable culture conditions to product and maintained immature dendritic cell precursors are well known in the art. Such culture media include, without limitation, AIM-V®, RPMI 1640, DMEM, X-VIVO 15®, and the like supplemented cytokines. The culture media can be supplemented with serum, amino acids, vitamins, divalent cations, and the like, to promote differentiation of the cells into dendritic cells. In one embodiment, the dendritic cell precursors can be cultured in a serum-free media. Such culture conditions can 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 of GM-CSF, IL-4 is added to the culture medium at a concentration of about 2 to about 200 ng / ml, or typically 20 ng / ml of 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 of 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 of 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 of 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 of Flt3-L. Precursors, when differentiated to form immature dendritic cells, generally demonstrate a typical expression pattern of cell surface proteins seen for immature dendritic cells, e.g., the cells are typically CD I4 , HLA-DR+, CD1 lc+, CD83 and express low levels of CD86. A non-limiting example of production of immature dendritic cell precursors is described in Example 2. At this stage, the immature dendritic cells are able to capture soluble antigens via specialized uptake mechanisms.Reduction ofMHC-la expression

[0368] In one embodiment, the expression of MHC-la in immature dendritic cells or in dendritic cells is reduced by an agent inhibiting TAP expression or activity.

[0369] According to one embodiment, the immature dendritic cells or the dendritic cells express a reduced level of the major histocompatibility class la (MHC-la) molecules on their surface. According to one embodiment, the immature dendritic cells or the dendritic cells do not express the major histocompatibility class la (MHC-la) on their surface.

[0370] The "MHC class la presentation" refers to the "classical" presentation through HLA-A, HLA-B and / or HLA-C molecules whereas the MHC class lb presentation refers to the "non-classical" antigen presentation through HLA-E, HLA- F, HLA-G and / or HLA-H molecules.

[0371] Methods for inhibiting MHC-la molecules expression are well-known. For example, the inhibition of the TAP transporter (transporter associated with antigen processing) leads to a decreased expression of MHC-la molecules thereby promoting HLA-E molecules expression on the surface of dendritic cells.

[0372] Exemplary methods to inhibit the TAP transporter in the endoplasmic reticulum include, but are not limited to, CRISPR-CAS-9 technology, silencing RNA, transfected DCs with the UL-10 viral protein from the CMV (cytomegalovirus) or the use of viral proteins.

[0373] Examples of viral genes or proteins silencing TAP expression include, but are not limited to, HSV-1 ICP47 protein, varicella-virus UL49.5 protein, cytomegalovirus US6 protein or gamma herpesvirus EBV BNLF2a protein, HIV nef protein.

[0374] Another method is the use of a chemical product to inhibit the expression of MHC class la molecules without changing 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.

[0375] In one embodiment, the TAP inhibitor is RNA synthesized from the pGem4Z vector containing the UL49.5 gene from BHV-1.

[0376] 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.

[0377] Depletion of MHC-la can be monitored by methods known in the art. For example, antibodies can also be used to monitor that immature dendritic cells or dendritic cells are MHC-la' / low.Loading MHC-la depleted immature dendritic cells

[0378] 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-la in immature dendritic cells or dendritic cells has been previously reduced. In another embodiment, the expression of MHC-la in immature dendritic cells has not been previously reduced.

[0379] In one embodiment, the immature dendritic cells or dendritic cells present peptides or antigens that specifically bind to HLA-DR and / or MHC-lb / E molecules. Thus, in one embodiment, the immature dendritic can be loaded (or pulsed) by contacting immature dendritic cells or dendritic cells with a predetermined peptide or antigen either prior to, after to or during maturation. In one embodiment, the MHC-la depleted immature dendritic cells or dendritic cells present peptides or antigens that specifically bind to HLA-DR and / or MHC-lb / E molecules. Thus, in one embodiment, the MHC-la depleted immature dendritic can be loaded (or pulsed) by contacting immature dendritic cells with a predetermined peptide or antigen either prior to, after to or during maturation.

[0380] Suitable predetermined antigens for use in the present invention can include any infectious-diseases related antigen. Infectious-diseases related antigens are described hereafter and include, for example, HIV or SIV MHC-lb / E peptides or antigens.

[0381] Methods for contacting dendritic cells with antigen 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 by reference herein). Typically, the immature dendritic immature cells obtained by the methods of the present invention can be cultured in the presence the predetermined antigen under suitable culture conditions, as described above. Optionally, the immature dendritic cells can be admixed with the predetermined antigen in a typical dendritic cell culture media with or without GM-CSF, and / or a maturation agent. Following at least about 10 minutes to about 2 days of culture with the antigen, the antigen can be removed and culture media supplemented with a maturation agent. GM-CSF and others cytokines (e.g., such as IL-4) can also be added to the culture media.

[0382] In one embodiment, the immature dendritic cells or dendritic cells can be transfected with a plasmid coding for MHC-lb / E molecules. In another embodiment, the immature dendritic cells or dendritic cells can be transfected with a plasmid coding for peptide- MHC-lb / E complex.Dendritic cells maturation

[0383] In one embodiment, the immature dendritic cell (optionally MHC-la depleted and previously loaded) can be matured with a maturation agent.

[0384] In one embodiment, the immature dendritic cells can be matured to form mature dendritic cells. Mature dendritic cells lose the ability to take up antigen and the cells display up-regulated 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-lb / E antigens and are generally identified as MHC- la10"', CD80+, CD83+, and CD86+. Greater MHC expression leads to an increase in antigen density on the DC surface, while up regulation of co-stimulatory moleculesCD80 and CD86 strengthens the T cell activation signal through the counterparts of the co-stimulatory molecules, such as CD28 on the T cells.

[0385] Methods to prepare mature dendritic cells are well known in the art. For example, immature dendritic cells can be matured by contacting the immature dendritic cells with effective amounts or concentrations of a dendritic cell maturation agent. Dendritic cell maturation agents can include, for example, BCG, IFNy, LPS, TNFa, IL-ip, IL-6, PGE2, Poly EC, TLR7 / 8-ligand, or a combination thereof.

[0386] For example, the immature DCs are typically contacted with effective amounts of LPS for about one hour to about 48 hours, preferably for 24 hours. The immature dendritic cells can be cultured and matured in suitable maturation culture conditions. Suitable tissue culture media include AIM-V®, RPMI 1640, DMEM, X- VIVO 15®, and the like. The tissue culture media can be supplemented with amino acids, vitamins, cytokines, such as GM-CSF, divalent cations, and the like, to promote maturation of the cells.

[0387] As exemplary purpose, dendritic cells can be matured in presence of IL-ip, IL-6, PGE2, TNF-a, LPS, Poly EC. Typically about 2 ng / ml of IL-ip, 30 ng / ml of IL- 6, Ipg / ml of PGE2, 10 ng / ml of TNF-a, 250 ng / ml of LPS, 150 ng / ml of Poly LC are generally used.

[0388] Maturation of dendritic cells can be monitored by methods known in the art for dendritic cells. Cell surface markers can be detected in assays familiar to the art, such as flow cytometry, immunohistochemistry, and the like. The cells can also be monitored for cytokine production (e.g., by ELISA, another immune assay, or by use of an oligonucleotide array). Mature DCs of the present invention also lose the ability to uptake antigen, which can be analyzed by uptake assays familiar to one of ordinary skill in the art.Final DCs

[0389] Thus, the present invention also relates to a mature dendritic cell population presenting MHC-II and MHC-lb / E-restricted peptides obtainable or obtained by the ex vivo method as described here above.Natural killers or B cells presenting MHC-lb / E-restricted antigen

[0390] Instead of dendritic cells, other immune cell types may be used to obtain a mature immune cell population presenting MHC-II and MHC-lb / E-restricted peptides or antigen.

[0391] In one embodiment, the tolerogenic vaccine is an active vaccine which is an ex vivo generated natural killer cell population presenting at least one MHC-lb / E- restricted antigen and at least one MHC-II restricted antigen.

[0392] In one embodiment, the natural killer cell is a K562 cell line.

[0393] In some embodiment, the natural killer cell is modified to express MHC-lb / E.

[0394] In another embodiment, the tolerogenic vaccine is an active vaccine which is an ex vivo generated natural B population presenting at least one MHC-lb / E-restricted antigen and at least one MHC-II restricted antigen.

[0395] In one embodiment, the B cell is a cell line.

[0396] In some embodiment, the B cell is modified to express MHC-lb / E.

[0397] Thus, the present invention also relates to a mature natural killer cell population presenting MHC-II and MHC-lb / E-restricted peptides obtainable or obtained by the ex vivo method as described here above.

[0398] The present invention also relates to a mature B cell population presenting MHC-II and MHC-lb / E-restricted peptides obtainable or obtained by the ex vivo method as described here above.Ex vivo generated MHC-lh / E-restricted CD8+T cells

[0399] According to another embodiment of the invention, the tolerogenic vaccine is an ex vivo generated MHC-lb / E-restricted CD8+T cells population.

[0400] In one embodiment, ex vivo generated MHC-lb / E-restricted CD8+T cells population is a passive vaccine.

[0401] In one embodiment, the MHC-lb / E-restricted CD8+T cells population recognizes an MHC-lb / E-restricted HIV-related antigen.

[0402] The present invention thus also relates to an ex vivo method for generating MHC-lb / E-restricted CD8+T cells population.

[0403] In one embodiment, the ex vivo method for generating MHC-lb / E-restricted CD8+T cells population, comprises: a. culturing naive CD8+T cells in the presence of dendritic, natural killer or B cells population presenting MHC-lb / E-restricted peptides enabling generation of MHC-lb / E-restricted CD8+T cells, and b. expanding the MHC-lb / E-restricted CD8+T cells.Isolation ofT cells

[0404] In one embodiment, the CD8+T cells, preferably naive CD8+T cells, are isolated by any technic well known in the art from a blood sample. In one embodiment, CD8+T cells, preferably naive CD8+T cells, are isolated from PBMCs (peripheral blood mononuclear cells) by flow cytometry. In one embodiment, the CD8+T cells, preferably naive CD8+T cells, may be isolated from frozen PBMCs. In one embodiment, the CD8+T cells are allogenic T cells, preferably allogenic naive T cells. In another embodiment, the CD8+T cells are autologous T cells, preferably autologous naive T cells. T cell isolation or purification can be achieved by positive, or negative selection, including but not limited to, the use of antibodies directed to CD8, CD56, CD57, CD45RO, CD45RA, CCR7, and the like. For example, naive CD8+T cell isolation can be performed in a one-step or two step procedure. A two-step procedurecan comprise a first step wherein naive T cells are enriched by depletion of non-naive T cells, and a second step wherein the enriched naive T cells are labeled with CD8 antibodies for subsequent positive selection of the CD8+naive T cells.Co-culture of naive T cells and MHC-Ib / E dendritic cells

[0405] In one embodiment, the CD8+T cells, preferably naive CD8+T cells, more preferably autologous naive CD8+T cells, are stimulated with peptide or antigen pulsed dendritic cells (for example MHC-Ib / E-antigen pulsed tolerogenic dendritic cells) in presence of stimulating agent. After stimulation, cells can be washed, for example with PBS, and can be stained with anti-CD8 antibodies and using MHC- peptide pentamer for sorting. The purified CD8+T cells are enriched and may be used for the following activation step.

[0406] In one embodiment, the CD8+T cells, preferably naive CD8+T cells, more preferably autologous naive CD8+T cells are co-incubated with dendritic cells presenting MHC-lb / E-restricted peptides. In one embodiment, said dendritic cells presenting MHC-lb / E-restricted peptides also present MHC-II-restricted peptide.

[0407] In one embodiment, the dendritic cells do not express MHC-la 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 MHC-la molecules on their surface (i.e., relative to all MHC molecules expressed at the surface of the dendritic cell). In one embodiment, the dendritic cells express at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85, 90% or 95% of MHC-Ib molecules on their surface. In one embodiment, dendritic cells express only MHC-Ib molecules on their surface.

[0408] In one embodiment, dendritic cells express MHC -II molecules on their surface. In one embodiment, dendritic cells express MHC-II molecules and MHC-Ib molecules on their surface.

[0409] In one embodiment, the CD8+T cells, preferably naive CD8+T cells, more preferably autologous naive CD8+T cells, are contacted with the tolerogenic dendriticcells as described hereinabove. Accordingly, at the end of the culture, the T cells are suppressor MHC-lb / E-restricted CD8+T cells and can induce immunotolerance.

[0410] In one embodiment, the culture for generating the MHC-lb / E-restricted CD8+T cells of the invention is performed during 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 more. In one embodiment, the culture for generating the MHC-lb / E-restricted CD8+T cells of the invention is performed during at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks or more. In one embodiment, the culture for generating the MHC-lb / E-restricted CD8+T cells of the invention is performed during at least 1 month, at least 2 months, at least 3 months or more.

[0411] In one embodiment, MHC-Ib / E natural killer cells or MHC-Ib / E B cells are used instead of MHC-Ib / E dendritic cells in the method described herein for generating an autologous MHC-lb / E-restricted CD8+T cell population.Expansion

[0412] In one embodiment, the MHC-lb / E-restricted CD8+T cell population generated ex vivo is isolated by flow cytometry based on their ability to binds to specific HLA-E antigens or peptides (e.g., specific tetramers).

[0413] In one embodiment, the isolated MHC-lb / E-restricted CD8+T cell population thus obtained is then expanded ex vivo by culturing these cells in the presence of at least one T cell activator. Examples of T cell activator include, but are not limited to, to be completed. Alternatively, other examples of T cell activators that may be used during expansion include, but are not limited to, mitogen such as PMA / ionomycin, super-antigen, anti-CD3 antibody 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.

[0414] Feeder cells include, but are not limited to, ACD3 cells (T cell-depleted accessory cells), irradiated PBMCs, irradiated DCs, artificial APCs (antigen presenting cells), Sf9 cells, insect cells, a pool of PBMCs or a pool of B cells fromdifferent subjects, KCD40L cells EBV-transformed B cell lines and EBV-transformed lymphoblastoid cells (LCL).

[0415] In another embodiment, the isolated MHC-lb / E-restricted CD8+T cell population thus obtained is then expanded ex vivo by culturing these cells in the presence of an antigen-specific T cell activator (e.g., anti-CD3 / CD28 antibodies, PMA / iono, cytokines and the likes). In one embodiment, the antigen-specific T cell activator can be used in the presence of feeder cells as described here above.

[0416] In one embodiment, the culture for expanded the ex vivo MHC-lb / E-restricted CD8+T cells of the invention is performed during 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 more. In one embodiment, the culture for expanded the ex vivo MHC-lb / E-restricted CD8+T cells of the invention is performed during at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks or more. In one embodiment, the culture for expanded the ex vivo MHC-lb / E-restricted CD8+T cells of the invention is performed during at least 1 month, at least 2 months, at least 3 months or more.Final T cells

[0417] Thus, the present invention also relates to an MHC-lb / E-restricted CD8+ T cell obtainable or obtained by the ex vivo method as described here above.LNP containing single chain trimers of HLA-E with a pathogen-specific antigen

[0418] According to another embodiment of the invention, the tolerogenic vaccine is a lipid nanoparticle (LNP) containing, or conjugated to, nucleic acid molecules being single chain trimers of HLA-E with a pathogen-specific antigen or peptide.

[0419] The construct comprising the single chain trimers of HLA-E with a pathogenspecific antigen or peptide is a nucleic acid molecule, such as e.g. a DNA or a RNA molecule.

[0420] In some embodiments, the construct comprising the single chain trimers of HLA-E with a pathogen-specific antigen or peptide comprises or consists of:- a signal peptide,- a pathogen-specific antigen or peptide,- a first linker,- beta2-microglobulin sequence,- a second linker, and- an HLA-E sequence.

[0421] The signal peptide preferably directs the polypeptide to lysosomes.

[0422] 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.

[0423] In some embodiments, the pathogen-specific antigen or peptide is an HIV- derived MHCIb / E-binding antigen having an amino acid sequence selected from the group consisting of the sequence RMYSPVSIL (SEQ ID NO: 1), the sequence PEIVIYDYM (SEQ ID NO: 2), the sequence TALSEGATP (SEQ ID NO: 3) the sequence RIRTWKSLV (SEQ ID NO: 4), the sequence VLKYWWNLL (SEQ ID NO: 56) (Env), the sequence ILPCRIKQI (SEQ ID NO: 57) (Env), the sequence AISPRTLNA (SEQ ID NO: 58) (Gag), and the sequence RMYSPTSIL (SEQ ID NO: 63).

[0424] The beta2-microglobulin is preferably human beta2-microglobulin. Typically, the beta2-microglobulin may have the amino acid sequence of SEQ ID NO: 78 and / or the nucleic acid sequence of SEQ ID NO: 79.

[0425] The first and second linkers may be any linkers, preferably flexible linkers. In some embodiments, the first and second linkers are Glycine-Serine linkers (i.e. linkers containing several Gly and Ser residues), or linkers derived thereof.

[0426] In some embodiments, the first linker has the amino acid sequence (GGGGS)s (SEQ ID NO: 80) and / or the nucleic acid sequence of SEQ ID NO: 81.

[0427] 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.

[0428] In some embodiments, the first linker is a “trap” linker, wherein a Glycine has been replaced by a Cysteine, i.e. a Glycine-Serine linker containing a Cysteine. For instance, the first “trap” linker may have the amino acid sequence of SEQ ID NO: 84 and / or the nucleic acid sequence of SEQ ID NO: 85.

[0429] In some embodiments, the HLA-E is HLAE*01 :03.

[0430] 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.

[0431] In other embodiments, the HLA-E chain comprises a Y84C mutation. In particular, 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.

[0432] The construct comprising the single chain trimers of HLA-E with a pathogenspecific antigen may further comprise a disulfide “trap” engineered between the cysteine at position 84 of HLA-E and a cysteine comprised in the sequence of the first linker (between the peptide and beta2-microglobulin). In such embodiments, the first linker is a first “trap” linker comprising a cysteine, for instance a “trap” linker having the amino acid sequence of SEQ ID NO: 84.

[0433] Typical constructs comprising the single chain trimers of HLA-E with a pathogen-specific antigen or peptide are described in Yang et al. Sci Immunol. 2021 March 25; 6(57) and in WO 2022 / 118030, which are herein incorporated by reference.

[0434] In some embodiments, the construct comprising the single chain trimers of HLA-E with a pathogen-specific antigen or peptide has an amino acid sequence selected from the group consisting of SEQ ID NO: 64, 66, 68, 70, 72 and 74.

[0435] In some embodiments, the construct comprising the single chain trimers of HLA-E with a pathogen-specific antigen or peptide has a nucleic acid sequence selected from the group consisting of SEQ ID NO: 65, 67, 69, 71, 73 and 75.

[0436] Such construct comprising the single chain trimers of HLA-E with a pathogenspecific antigen or peptide may be comprised in a plasmid.

[0437] Transfection or transduction of such a plasmid into cells leads to the expression of the HLA-E-antigen complex at the cell surface of the cells (Yang et al. Sci Immunol. 2021 March 25; 6(57)).

[0438] Without being bound by any theory, administration of a lipid nanoparticle (LNP) containing, or conjugated to, nucleic acid molecules being single chain trimers of HLA-E with a pathogen-specific antigen or peptide, in a subject in need thereof, may induce in vivo generation of dendritic, natural killer and / or B cells presenting MHC-lb / E-restricted antigens.HIV immunogen of the tolerogenic vaccineHIV antigens

[0439] The tolerogenic vaccine is specific for at least one HIV immunogen, which is an HIV antigen as described below.

[0440] When the disease to be prevented or treated is acquired immune deficiency syndrome (AIDS) or a simian immunodeficiency virus (SIV) infection, the tolerogenic vaccine comprises or encodes an antigen of HIV or SIV origin respectively.

[0441] In one embodiment, the HIV or SIV antigen is selected from the group consisting of any HIV or SIV strains.

[0442] In one embodiment, the HIV antigen described herein is an antigen of HIV origin. In one embodiment, the HIV antigen described herein is an HIV antigen.

[0443] Due to the great variability in the HIV genome, which results from mutation, recombination, insertion and / or deletion, HIV has been classified in groups, subgroups, types, subtypes and genotypes. There are two major HIV groups (HIV-1 and HIV-2) and many subgroups because the HIV genome mutates constantly. The major difference between the groups and subgroups is associated with the viral envelope. HIV-1 is classified into a main group (M), said group M being divided into least nine genetically distinct subtypes. These are subtypes A, B, C, D, F, G, H, J and K. Many other subtypes resulting from in vivo recombination of the previous ones alsoexist (e.g., CRF). In one embodiment, the HIV antigen is related to a specific HIV group, subgroup, type, subtype or to a combination of several subtypes.

[0444] 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 and subtype B (HXB2).

[0445] In one embodiment, the HIV antigen described herein is non-infectious.

[0446] In one embodiment, the HIV antigen is an inactivated whole HIV virus.

[0447] As used herein, "inactivated whole HIV" means a complete HIV particle, which has been inactivated, and which is no more infectious.

[0448] 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 of inactivated autologous HIV virus.

[0449] As used herein, "an antigen made of inactivated autologous HIV virus" refers to an antigen comprising or consisting of the HIV virus infecting the human to be treated and appropriately inactivated for a safe therapeutic administration to humans. Thus, in practice, to prepare the vaccine composition of the invention, the HIV virus is isolated from the human to be treated, more particularly from the CD4+T cells of said human. The thus isolated HIV virus is cultured and inactivated.

[0450] In one embodiment, the HIV antigen is selected from the group consisting of a HIV gag, a HIV env, a HIV rev, a HIV tat, a HIV nef, a HIV pol, and a HIV vif.

[0451] In one embodiment, the HIV antigen comprises one or more epitopes of a HIV gag, a HIV env, a HIV rev, a HIV tat, a HIV nef, a HIV pol, and a HIV vif proteins.

[0452] In one embodiment, the HIV antigen comprises at least a HIV gag and / or HIV pol protein. Alternatively or additionally, said antigen derived from a HIV virus may comprise one or more proteins encoded by gag such as the capsid protein (p24) and the matrix protein (pl), and / or one or more proteins encoded by pol such as the integrase, the reverse transcriptase and the protease.MHCIb / E-binding antigen

[0453] In one embodiment, the HIV antigen described herein is a MHCIb / E-binding antigen. In one embodiment, the pathogen-specific antigen is a MHCIb / E-binding peptide.

[0454] In one embodiment, the HIV antigen described herein is an HIV or SIV- derived MHCIb / E-binding peptide. In one embodiment, the HIV antigen is an HIV or SIV-derived MHCIb / E-binding antigen.

[0455] In one embodiment, the HIV-derived MHCIb / E-binding antigen or peptide described herein is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 4, SEQ ID NO: 56 to SEQ ID NO:58, and SEQ ID NO: 63.

[0456] In one embodiment, the HIV-derived MHCIb / E-binding antigen has the amino acid sequence RMYSPVSIL (SEQ ID NO: 1). In one embodiment, the HIV-derived MHCIb / E-binding antigen has the amino acid sequence PEIVIYDYM (SEQ ID NO: 2). In one embodiment, the HIV-derived MHCIb / E-binding antigen has the amino acid sequence TALSEGATP (SEQ ID NO: 3). In one embodiment, the HIV-derived MHCIb / E-binding antigen has the amino acid sequence RIRTWKSLV (SEQ ID NO: 4). In one embodiment, the HIV-derived MHCIb / E-binding antigen has the amino acid sequence VLKYWWNLL (SEQ ID NO: 56) (Env). In one embodiment, the HIV- derived MHCIb / E-binding antigen has the amino acid sequence ILPCRIKQI (SEQ ID NO: 57) (Env). In one embodiment, the HIV-derived MHCIb / E-binding antigen has the amino acid sequence AISPRTLNA (SEQ ID NO: 58) (Gag). In one embodiment, the HIV-derived MHCIb / E-binding antigen has the amino acid sequence RMYSPTSIL (SEQ ID NO: 63).

[0457] 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).Particulate antigens

[0458] In one embodiment, the HIV antigen described herein is a particulate antigen.

[0459] In one embodiment, the HIV antigen described herein may result from the expression of a viral nucleic acid sequence advantageously contained into an appropriate recombinant microorganism. In one embodiment said recombinant microorganism is a CMV, preferably a CMV vector as described herein above. In another embodiment, said recombinant microorganism is a bacterium, preferably a different bacterium from the non-pathogenic bacterium as described herein above.

[0460] In one embodiment, the HIV antigen described herein can be codon optimized. Many viruses, including HIV and other lentiviruses, use a large number of rare codons and, by altering these codons to correspond to codons commonly used in the desired subject (for example, humans), enhanced expression of the antigens can be achieved. For example, rare codons used in HIV proteins can be mutated into those that appear frequently in highly expressed human genes (Andre et al. (1998) J Virol 72, 1497- 1503).

[0461] In one embodiment, the HIV antigen described herein can be consensus sequences or mosaic antigens containing sequence fragments from different clades or strains of pathogens.

[0462] “Consensus sequences” represent the most common amino acid in each position among an alignment of available viral sequences.

[0463] “Mosaic immunogens” may for instance be in silico-derived recombinant protein sequences optimized for maximal inclusion of potential T cell epitopes based on the diversity in a target population and used in combinations for complementarity.

[0464] In one embodiment, the particulate antigen described herein is a viral antigen.

[0465] In one embodiment, the particulate antigen is selected from viral particles, recombinant viral particles, virus-like particles, recombinant viral particles, polymericmicroparticles presenting on their surface one or more viral peptides or epitopes, conjugate viral proteins and concatemer viral proteins.

[0466] In one embodiment, the particulate antigen described herein may be one or more viral proteins or peptides, recombinant or not, either in the form of conjugates or of concatemers.Immunogenic apoptotic bodies

[0467] In one embodiment, the HIV antigen described herein is derived from immunogenic apoptotic bodies from infected cells or derived from tissue lysate.

[0468] Infected cells may derive from tissue biopsy or from expansion of circulatory infected cells.

[0469] Immunogenic apoptotic bodies from infected cells may be obtained for example with anthracyclines including doxorubicin, daunorubicin, idarubicin and mitoxanthrone; oxaliplatin, UVC, UVB or y-radiation treated infected cells releasing apoptotic bodies.

[0470] Examples of tissue lysate include, but are not limited to, lymph nodes, synovial liquid or inflammatory tissue lysate.

[0471] In one embodiment, the immunogenic bodies are obtained from HIV infected CD4+T cells.

[0472] In some embodiments, the tolerogenic vaccine comprises, or consists of, Ad26.Mos4.HIV, Ad26.Mos.HIV, ChAdOxl.tHIVconsvl, MVA.tHIVconsv3, MVA.tHIVconsv4, ChAdV63.HIVconsv, and / or MVA.HIVconsv.Effector vaccine

[0473] In one embodiment, the effector vaccine is a preventive vaccine. In another embodiment, the effector vaccine is a therapeutic vaccine. As used herein, a therapeutic vaccine may be a prophylactic vaccine or a curative vaccine. In someembodiments, the effector vaccine is a prophylactic vaccine. In other embodiments, the effector vaccine is a curative vaccine.

[0474] In one embodiment, the effector vaccine induces an immune response against at least one HIV-related immunogen. In one embodiment, the effector vaccine is thus specific for at least one HIV immunogen.

[0475] In some embodiments, the effector vaccine comprising at least one HIV immunogen lyses infected CD4+ cells expressing at least one HIV peptide in an HLA- la (A, B, C) restriction.

[0476] In some embodiments, the effector vaccine comprising at least one HIV immunogen induces broadly neutralizing antibodies (bnAbs) and / or CD8 cytotoxic T cells.HIV immunogen of the effector vaccine

[0477] The effector vaccine is specific for at least one HIV immunogen.

[0478] When the disease to be prevented or treated is acquired immune deficiency syndrome (AIDS) or a simian immunodeficiency virus (SIV) infection, the effector vaccine comprises or encodes an immunogen of HIV or SIV origin respectively.

[0479] In one embodiment, the HIV or SIV immunogen is selected from the group consisting of any HIV or SIV strains.

[0480] In one embodiment, the HIV immunogen described herein is an immunogen of HIV origin. In one embodiment, the HIV immunogen described herein is an HIV immunogen.

[0481] Due to the great variability in the HIV genome, which results from mutation, recombination, insertion and / or deletion, HIV has been classified in groups, subgroups, types, subtypes and genotypes. There are two major HIV groups (HIV-1 and HIV-2) and many subgroups because the HIV genome mutates constantly. The major difference between the groups and subgroups is associated with the viralenvelope. HIV-1 is classified into a main group (M), said group M being divided into least nine genetically distinct subtypes. These are subtypes A, B, C, D, F, G, H, J and K. Many other subtypes resulting from in vivo recombination of the previous ones also exist (e.g., CRF). In one embodiment, the HIV immunogen is related to a specific HIV group, subgroup, type, subtype or to a combination of several subtypes.

[0482] 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 and subtype B (HXB2).

[0483] In one embodiment, the HIV immunogen described herein is non-infectious. In one embodiment, the HIV immunogen is an inactivated whole HIV virus.

[0484] In one embodiment, the HIV immunogen is an autologous HIV immunogen. In another embodiment, the HIV immunogen is not an autologous HIV immunogen.

[0485] In one embodiment, the HIV immunogen comprises one or more epitopes of a HIV gag, a HIV env, a HIV rev, a HIV tat, a HIV nef, a HIV pol, and a HIV vif proteins.

[0486] In one embodiment, the HIV immunogen comprises at least a HIV gag and / or HIV pol protein. Alternatively or additionally, said immunogen derived from a HIV virus may comprise one or more proteins encoded by gag such as the capsid protein (p24) and the matrix protein (pl), and / or one or more proteins encoded by pol such as the integrase, the reverse transcriptase and the protease.

[0487] In some embodiments, the HIV immunogen comprises, or consists of, one or more proteins encoded by env, such e.g. gpl20, gpl40, gpl60, or epitopes thereof.

[0488] In some embodiments, said at least one HIV immunogen is a Tat toxoid as described in patent applications W003013593, incorporated herein by reference.

[0489] Preferably, the HIV immunogen is a native-like protein.

[0490] In some embodiments, the HIV immunogen comprises a combination of naturally-occurring sequences of one or more HIV protein(s).I l l

[0491] Preferably, the HIV immunogen comprises several peptides, antigens or epitopes derived from different HIV viral strains.

[0492] In some embodiments, the HIV immunogen comprises conserved elements or regions of HIV. Preferably, the HIV immunogen comprises multiple HIV conserved epitopes. In some embodiments, the HIV immunogen comprises mosaics of conserved HIV epitopes.

[0493] In some embodiments, the HIV immunogen comprises at least one consensus sequence or region of HIV. “Consensus sequences” represent the most common amino acid in each position among an alignment of available viral sequences. Preferably, the HIV immunogen comprises multiple HIV consensus sequences or epitopes.

[0494] In some embodiments, the HIV immunogen comprises at least one mosaic immunogen. “Mosaic immunogens” may for instance be in silico-derived recombinant protein sequences optimized for maximal inclusion of potential T cell epitopes based on the diversity in a target population and used in combinations for complementarity.

[0495] Preferably, the HIV immunogen comprises at least one mosaic immunogen comprising sequences derived from different HIV subtypes, clades or strains. More preferably, the HIV immunogen comprises multiple HIV protein, peptide or epitope sequences, each of them being derived from different HIV subtypes, clades or strains. Examples of HIV mosaic immunogen are further described below.Aelix's mosaic immunogen

[0496] In some embodiments, the HIV mosaic immunogen is a polypeptide comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 segments derived of the HIV-1 genome selected from the group consisting of SEQ ID NO: 18 to SEQ ID NO: 33, and variants thereof at least 85%, 90% or 95% identical to the sequences SEQ ID NO: 18 to SEQ ID NO: 33.

[0497] In some embodiments, the HIV immunogen is a polypeptide comprising the sequences SEQ ID NO: 18 to SEQ ID NO: 33.

[0498] In some embodiments, the segments derived of the HIV-1 genome selected from the group consisting of SEQ ID NO: 18 to SEQ ID NO: 33, and variants thereof, are linked by triple alanine linkers within the HIV immunogen.University of Oxford's mosaic immunogen

[0499] In other embodiments, the HIV immunogen is an HIV protein mosaic conserved region polypeptide.

[0500] Exemplary amino acid sequences of HIV protein mosaic conserved region polypeptides include SEQ ID NO: 34 to 51. In some examples, the mosaic conserved region polypeptides include, consist essentially of, or consist of an amino acid sequence at least 85%, 90% or 95% identical to the amino acid sequence set forth as one of SEQ ID NOs: 34-51.

[0501] In some embodiments, an immunogenic polypeptide comprises one or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) of the disclosed mosaic conserved region polypeptides (such as one or more of SEQ ID NOs: 34-51). In some examples, two or more of the mosaic conserved region polypeptides are linked to form a single immunogenic polypeptide (for example, a chimeric or fusion polypeptide).

[0502] In particular examples, the two or more linked mosaic conserved region polypeptides include two or more (such as 2, 3, 4, 5, 6, 7, 8) of SEQ ID NOs: 34-41, or sequences having at least 85%, 90% or 95% identity to any one of SEQ ID NOs: 34-41. In one example, an immunogenic polypeptide includes amino acid sequences including, consisting essentially of, or consisting of all of SEQ ID NOs: 34-41. In another particular example, the two or more linked conserved region polypeptides include two or more (such as 2, 3, 4, 5, 6 or 7) of SEQ ID NOs: 34, 35, 36, 39, 40, 41 and 50, or sequences having at least 85%, 90% or 95% identity to any one of SEQ ID NOs: 34, 35, 36, 39, 40, 41 and 50. In one example an immunogenic polypeptide includes amino acid sequences including, consisting essentially of, or consisting of all of SEQ ID NOs: 34, 35, 36, 39, 40, 41 and 50. In yet another example, the two or more linked conserved region polypeptides include two or more (such as 2, 3, 4, 5, 6 or 7) of SEQ ID NOs: 35, 36, 38, 39, 40, 41 and 50, such as an immunogenic polypeptide including amino acids sequences including, consisting essentially of, or consisting of all of SEQ ID NOs: 35, 36, 38, 39, 40, 41 and 50.

[0503] In other particular examples, the two or more linked conserved region polypeptides include two or more (such as 2, 3, 4, 5, 6, 7 or 8) 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, an immunogenic polypeptide includes all of SEQ ID NOs: 34- 42. In another particular example, the two or more linked conserved regions include two or more (such as 2, 3, 4, 5, 6 or 7) of SEQ ID NOs: 42, 43, 44, 47, 48, 49, and 51. In one example, an immunogenic polypeptide includes amino acid sequences including, consisting essentially of, or consisting of all of SEQ ID NOs: 42, 43, 44, 47, 48, 49, and 51. In yet another example, the two or more linked conserved regionpolypeptides include two or more (such as 2, 3, 4, 5 or 6) of SEQ ID NOs: 43, 44, 47,48, 49, and 51, such as an immunogenic polypeptide including amino acids sequences including, consisting essentially of, or consisting of all of SEQ ID NOs: 43, 44, 47, 48,49, and 51.

[0504] In some embodiments, the disclosed immunogenic polypeptides include one or more peptide linkers, for example to attach two or more conserved region polypeptides in a single polypeptide chain. Linker peptides are typically a short amino acid sequence providing a flexible linker that permits attachment of polypeptides, such as a conserved region polypeptide, without disruption of the structure, aggregation (e.g., multimerization), or activity of the polypeptide component. Typically, a linear linking peptide consists of between two and 25 amino acids. Usually, the linear linking peptide is between two and 15 amino acids in length, although in certain circumstances it can be only one, such as a single glycine residue. In one example, the linker polypeptide is two to three amino acids in length, such as a serine and an arginine, or two serine residues and an arginine residue, or two arginine residues and a serine residue, two glycines and a serine, two serines and a glycine or any combination thereof.

[0505] 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 responses directed towards non-naturally occurring peptide junctions in the fusion polypeptides.

[0506] The immunogenic polypeptides disclosed herein can be chemically synthesized by standard methods, or can be produced recombinantly, for example by expression of the polypeptide from a nucleic acid molecule that encodes the polypeptide. They can also be isolated by methods including preparative chromatography and immunological separations.Janssen's mosaic immunogen

[0507] In other embodiments, the HIV mosaic immunogen comprises at least two recombinant Adenovirus 26 (Ad26) vectors each expressing a different HIV antigen or combination of HIV antigens.

[0508] In some embodiments, the HIV immunogen is the Ad26.Mos4.HIV vaccine, which is composed of four recombinant Ad26 vectors each expressing a different HIV antigen or combination of HIV antigens, specifically Ad26.Mosl.Gag-Pol (Ad26 vector encoding a mosaic Gag-Pol fusion protein having SEQ ID NO: 52), Ad26.Mos2.Gag-Pol (Ad26 vector encoding a mosaic Gag-Pol fusion protein having SEQ ID NO: 53), Ad26.Mosl.Env (Ad26 vector encoding a mosaic Env protein having SEQ ID NO: 54), and Ad26.Mos2S.Env (Ad26 vector encoding a mosaic Env protein having SEQ ID NO: 55).

[0509] In some embodiments, the HIV immunogen comprises at least 2, 3 or 4 recombinant Ad26 vectors each expressing a different HIV antigen or combination of HIV antigens, selected from the group consisting of SEQ ID NO: 52-55, and variants thereof at least 85%, 90% or 95% identical to the sequences SEQ ID NO: 52-55.Type of effector vaccine

[0510] In some embodiments, the effector vaccine is:- a protein-based vaccine,- a DNA-based vaccine- an RNA-based vaccine, and / or- a passive vaccine comprising broadly neutralizing anti-HIV antibodies.Protein-based vaccine

[0511] 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.

[0512] Preferably, the HIV immunogen is a native-like protein (NLP) having the conformation of the native protein.

[0513] In some embodiments, the HIV immunogen is a stabilized recombinant protein.

[0514] For instance, when the HIV immunogen is derived from Env, the HIV immunogen may be a stabilized recombinant Env gpl 0 trimer that mimic the conformation of native Env trimers. One approach involves stabilizing the gpl20-gp41 interactions with an intermolecular disulfide bond (SOS gpl40), preferably modified with an isoleucine to proline (I559P) substitution to improve trimerization (SOSIP gpl40).

[0515] In some embodiments, the HIV immunogen is a single-chain gpl40. Such single-chain gpl40 may be designed to make the Env cleavage-independent, for instance by replacing the cleavage site between gpl20 and gp41 with gly cine / serine linkers. Another strategy, similar to the single-chained gpl40 design, substitutes a flexible gly cine / serine linker (G4S) for the cleavage site to yield cleavage-independent Env mimics called native flexibly linked (NFL) trimers. Alternatively, the cleavage site may be replaced with long linkers, resulting in an uncleaved prefusion-optimized (UFO) trimer that assume a native-like conformation similar to that of a SOSIP trimer.

[0516] For instance, when the HIV immunogen is derived from Env, the HIV immunogen may be a Env gpl60 trimer, a stabilized Env gpl60 trimer, a stabilized Env gpl40 trimer (SOS gpl40 or SOSIP gpl40), a stabilized Env single-chain gpl40 trimer, a stabilized native flexibly linked (NFL) Env gpl 0 trimer.

[0517] Preferably, the HIV immunogen comprises several proteins, peptides, antigens or epitopes derived from different HIV viral strains. For instance, the HIV immunogen may be a mosaic polypeptide or immunogen as described hereinabove.

[0518] In some embodiments, the HIV immunogen is a mosaic immunogen comprising Gag, Pol and Env proteins, peptides or epitopes.

[0519] In some embodiments, the at least one HIV immunogen is in a soluble form.

[0520] In some embodiments, the at least one HIV immunogen is displayed at the surface of a nanoparticle, such as e.g. a virus-like particles (VLP).

[0521] Non-limiting examples of effector vaccines being protein-based vaccines comprising an HIV gpl20 immunogen include AIDSVAX BZE, CH505TF, CH505w53, CH505w78, CH505 M5, IHV01 or A244.

[0522] AIDSVAX BZE is a bivalent HIV gpl20 glycoprotein encompassing both subtype B (MN) and subtype E (A244) proteins.

[0523] IHV01 is Full-Length Single Chain (FLSC) gpl20-CD4 chimera subunitHIV- 1.

[0524] A244 is gpl20 envelope glycoprotein HIV-1 subtype CRF_01AE A244.

[0525] Non-limiting examples of effector vaccines being protein-based vaccines comprising an HIV gpl40 immunogen include CN54gpl40, Clade C gpl40, mosaic gpl40, HIV type 1 Clade C glycoprotein 140, BG505 SOSIP.664 gpl40, ConM SOSIP, mosaic SOSIPs, EDC ConM SOSIP, ConS UFO, EDC ConS UFO, BG505 SOSIP.664 gpl40, BG505 SOSIP.GT1.1, gpl45 C.6980, or CD40.HIVRI.Env.

[0526] CN54gpl40 is an HIV-1 envelope protein from the clade C strain 97 / CN / 54 isolate.

[0527] CD40.HIVRI.Env is an adjuvanted anti-CD40 mAb fused to Env gpl40 HIV clade C ZM-96.

[0528] Other non-limiting examples of effector vaccines being protein-based vaccines comprising trimeric HIV immunogen include VRC-HIVRGP096-00-VP (Trimer 4571), ConM SOSIP.v7, CH505 TF chTrimer, or Trimer 4571.

[0529] In some embodiments, the effector vaccine comprises, or consists of, AIDSVAX BZE, CN54gpl40, Clade C gpl40, Mosaic gpl40, HIV type 1 Clade C glycoprotein 140, CH505TF, CH505w53, CH505w78, CH505 M5, BG505 SOSIP.664 gpl40, VRC-HIVRGP096-00-VP (Trimer 4571), ConM SOSIP.v7, ConM SOSIP,Mosaic SOSIPs, EDC ConM SOSIP, ConS UFO, EDC ConS UFO, BG505 SOSIP.664 gpl40, BG505 SOSIP. GTE 1, IHV01, A244, gpl45 C.6980, CD40.HIVRI.Env, CH505 TF chTrimer, and / or Trimer 4571.RNA-based vaccine

[0530] 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.

[0531] In some embodiments, the least one RNA is an mRNA.

[0532] Chemical and structural modifications may be made to the mRNA protect the mRNA from degradation and facilitate cellular uptake, such as addition of carrier molecules, including lipid nanoparticles (LNPs).

[0533] In some embodiments, the effector vaccine is an RNA-based vaccine comprising at least one RNA sequence carried by a lipid nanoparticle (LNP).

[0534] Once administered to the subject, said at least one RNA sequence enables the synthesis of at least one HIV-derived protein, peptide, antigen or epitope. Preferably, the synthetized protein, peptide or antigen is a native-like protein, such as e.g. a trimeric Env protein.

[0535] In some embodiments, the HIV immunogen synthetized from the at least one RNA sequence is a mosaic immunogen as described hereinabove. In some embodiments, the HIV immunogen synthetized from the at least one RNA sequence is a mosaic immunogen comprising Gag, Pol and Env proteins, peptides or epitopes.

[0536] Non-limiting examples of effector vaccines being RNA-based vaccines include BG505 MD39.3, BG505 MD39.3 gpl51, BG505 MD39.3 gpl51 CD4KO, eOD-GT8 60mer mRNA Vaccine (mRNA- 1644), Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core), HIVARNA01.3, or HTI (HIVACAT).

[0537] In some embodiments, the effector vaccine comprises, or consists of, BG505 MD39.3, BG505 MD39.3 gpl51, BG505 MD39.3 gpl51 CD4KO, eOD-GT8 60mer mRNA Vaccine (mRNA-1644), Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2- Core), HIVARNA01.3, or HTI (HIVACAT).DNA-based vaccine

[0538] In some embodiments, the effector vaccine is a DNA-based vaccine encoding at least one HIV-derived protein, peptide or epitope.

[0539] In some embodiments, the effector vaccine is a DNA-based vaccine comprising a plasmid.

[0540] Non-limiting examples of effector vaccines being DNA-based vaccines comprising a plasmid 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.

[0541] DNA-HIV-PT123 is a 3-plasmid DNA vaccine encoding clade C ZM96 Gag, clade C ZM96 Env and CN54 Pol-Nef.

[0542] Env(A,B,C,A / E) / gag(C) DNA vaccine is a polyvalent DNA vaccine encoding Env from HIV-1 clades A, B, C, and A / E and clade C Gag.

[0543] DNA-HIV-PT123 HIV-1 vaccine is a DNA vaccine encoding clade C ZM96 Gag, clade C ZM96 Env, and CN54 Pol-Nef.

[0544] In some embodiments, the effector vaccine is a DNA-based vaccine comprising a non-replicating viral vector.

[0545] Said non-replicating viral vector may be an Adenovirus (Ad), such as e.g. Ad5, or other serotypes with lower seroprevalence, such as Ad26 or Ad35, or a chimeric form of adenovirus such as Ad5H3, or the chimpanzee-adenovirus vector.

[0546] In some embodiments, the non-replicating viral vector is Ad26, Ad35, Ad5H3 or the chimpanzee-adenovirus vector.

[0547] Non-limiting examples of effector vaccines being DNA-based vaccines comprising an adenoviral vector include Ad4-Envl45NFL, Ad4-Envl50KN, AdC6- HIVgpl40, or AdC7-HIVgpl40.

[0548] In some embodiments, the viral vector is a poxvirus vector, such as e.g. an orthopoxvirus, an avipoxvirus, NYVAC, ALVAC (canarypox), TROVAC (fowl poxvirus), or a vaccinia virus such as the Modified Vaccinia Ankara (MV A),

[0549] In some embodiments, the viral vector is a recombinant modified vaccinia virus Ankara (MV A) vector.

[0550] Non-limiting examples of effector vaccine being a DNA-based vaccine comprising an MVA vector include MVA-CMDR, MVA HIV-B, MVA-BNHIV, MVA / HIV62B or MVA-CMDR.

[0551] MVA-CMDR is a non-replicating, highly attenuated strain of vaccina virus that has been genetically engineered to express the HIV-1 genes env gpl60 CM235 Subtype E and gag and pol CM240 Subtype A (with deleted integrase and nonfunctional reverse transcriptase).

[0552] MVA-BNHIV is a monovalent vaccine comprising a single Modified Vaccinia Ankara - Bavarian Nordic (MVA-BN®) vector encoding Mos 1. Env, Mos2S.Env, Mosl.Gag-Pol, and Mos2.Gag-Pol HIV-1.

[0553] In some embodiments, the effector vaccine is a DNA-based vaccine comprising a replicating viral vector.

[0554] In some embodiments, the effector vaccine is a DNA-based vaccine comprising a replicating recombinant cytomegalovirus (CMV) vector.

[0555] Non-limiting examples of effector vaccines being DNA-based vaccines comprising a CMV vector include VIR-1111.

[0556] Other non-replicating viral vectors may also be used such as, e.g., pox vector, canarypox vector, alphavirus vector, adenovirus-associated virus vector. . .

[0557] Other examples of effector vaccines being DNA-based vaccines comprising a viral vector includes ALVAC-HIV (vCP1521) (canarypox vector), DREP-HIV-PT1 (alphavirus-based DNA replicon), EBT-101 (adenovirus-associated virus serotype 9 (AAV9) vector).

[0558] ALVAC-HIV (vCP1521) is a canarypox vector encoding HIV-1 CRF01 AE Env, clade B Gag, and the protease-encoding portion of the Pol protein.

[0559] DREP-HIV-PT1 is an alphavirus-based DNA replicon in which the sequences coding for the viral capsid and envelope have been replaced by the sequences encoding HIV-1 gpl40.

[0560] AdC6-HIVgpl40 and AdC7-HIVgpl40 are chimpanzee adenovirus vectors encoding clade C gpl40 (GLA emulsion).

[0561] EBT-101 is an HIV- 1 -specific clustered regularly interspaced short palindromic repeats (CRISPR) / Cas9 gene editing system delivered by adenovirus- associated virus serotype 9 (AAV9) vector.

[0562] In some embodiments, the effector vaccine is a DNA-based vaccine comprises a sequence encoding at least one HIV-derived protein, peptide or epitope.

[0563] Once administered to the subject, said sequence encoding at least one HIV- derived protein, peptide or epitope enables the synthesis of the at least one HIV- derived protein, peptide, antigen or epitope. Preferably, the synthetized protein, peptide or antigen is a native-like protein, such as e.g. a trimeric Env protein.

[0564] For instance, the effector vaccines DREP-HIV-PT1, AdC6-HIVgpl40, AdC7- HIVgpl40 comprise sequences encoding HIV-1 gpl40.

[0565] 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 instance, the DNA-based vaccine may comprise sequences of gag, pol and env epitopes.

[0566] Non-limiting examples of effector vaccines being DNA-based vaccines comprising sequences of multiple HIV-derived proteins, peptides, or epitopes include, e g., 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.

[0567] 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-Envl45NFL, Ad4-Envl50KN, Env-C plasmid DNA, DNA-HIV-PT123 HIV-1 vaccine, DREP-HIV-PT1, AdC6-HIVgpl40, AdC7-HIVgpl40, MVA HIV-B, MVA-BNHIV, p24CE, p55gag, MVA / HIV62B, HIVIS DNA, MVA-CMDR, and / or EBT-101.

[0568] In some embodiments, the DNA-based vaccine comprises at least one sequence of a mosaic immunogen as described hereinabove. In some embodiments, the mosaic immunogen comprises gag, pol and / or env sequences.

[0569] Non-limiting examples of effector vaccines being DNA-based vaccines comprising at least one sequence of a mosaic immunogen include, e.g., Ad26.Mos4.HIV, MVA mosaic gpl40 protein, Ad26.Mos.HIV, ChAdOxl.tHIVconsvl, ChAdOxl-HTI, MVA-HTI, MVA.tHIVconsv3, MVA.tHIVconsv4, ChAdV63.HIVconsv, or MVA.HIVconsv.

[0570] In some embodiments, the effector vaccine is a DNA-based vaccine comprising an adenovirus vector and at least one sequence of a mosaic immunogen, wherein said effector vaccine comprises, or consists of, Ad26.Mos4.HIV, Ad26.Mos.HIV, ChAdOxl.tHIVconsvl, ChAdOxl-HTI, and / or ChAdV63. HIVconsv.

[0571] Ad26.Mos4.HIV is an adenovirus vector Ad26 coding 4 mosaic Env, Gag, and Pol antigens: Mosl.Gag-Pol, Ad26.Mos2.Gag-Pol, Ad26.Mosl.Env,Ad26.Mos2S.Env.

[0572] Ad26.Mos.HIV is an adenovirus vector Ad26 coding 3 mosaic Env, Gag, and Pol antigens: Ad26.Mos.l.Env, Ad26.Mosl.Gag-Pol, Ad26.Mos2.Gag-Pol.

[0573] ChAdOxl-HTI is a chimpanzee adenovirus vector encoding HIVACAT T cell immunogen (HTI).

[0574] In some embodiments, the effector vaccine is a DNA-based vaccine comprising an MVA vector and at least one sequence of a mosaic immunogen, wherein said effector vaccine comprises, or consists of, MVA mosaic gpl40 protein, MVA- HTI, MVA.tHIVconsv3, MVA.tHIVconsv4, and / or MVA.HIVconsv.

[0575] MVA mosaic gpl40 protein is a recombinant live attenuated MVA virus- vectored vaccine that has been genetically engineered to express 2 mosaic Gag, Pol, and Env sequences.

[0576] MVA-HTI is an MVA vector encoding HIVACAT T cell immunogen (HTI).

[0577] In some embodiments, the effector vaccine comprises, or consists of, Ad26.Mos4.HIV, MVA mosaic gpl40 protein, Ad26.Mos.HIV, ChAdOxl.tHIVconsvl, ChAdOxl-HTI, MVA-HTI, MVA.tHIVconsv3, MVA.tHIVconsv4, ChAdV63.HIVconsv, and / or MVA.HIVconsv.

[0578] In some embodiments, the effector vaccine comprises, or consists of, Ad26.Mos4.HIV and MVA-BNHIV.

[0579] In some embodiments, the effector vaccine comprises, or consists of, ChAdOxl.tHIVconsvl, MVA.tHIVconsv3, and MVA.tHIVconsv4.

[0580] In some embodiments, the effector vaccine comprises, or consists of, ChAdOxl.HTI and MVA.HTI.Broadly neutralizing anti-HIV antibodies

[0581] In some embodiments, the effector vaccine is a passive vaccine comprising at least one broadly neutralizing anti-HIV antibody.

[0582] Broadly neutralizing antibodies (bnAb) may be isolated from an HIV- seropositive subject. Broadly neutralizing antibodies have the potential to provide complete protection from HIV infection. In particular, broadly neutralizing antibodies broadly protect against heterologous HIV-1 strains.

[0583] Broadly neutralizing anti -HIV antibodies may for instance bind to one or more epitope(s) comprised in the CDR2 domain of the viral CD4 receptor, in the CD4 binding site, in the gp41, in the gpl20, in the V1V2 region of the HIV-1 envelope, or in the V3 glycan.

[0584] 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.

[0585] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the CDR2 domain of the viral CD4 receptor include UB-421 (semzuvolimab).

[0586] 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.

[0587] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the gp41 include 10E8.4 / iMab.

[0588] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the gpl20 include VH3810109 (also known as GSK3810109 or N6-LS).

[0589] Non-limiting examples of broadly neutralizing anti-HIV antibodies that target the V1V2 region of the HIV-1 envelope include CAP256V2LS, PGDM1400LS, PGDM1400, SAR441236.

[0590] 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, Elipovimab.

[0591] 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.

[0592] 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.

[0593] When a combination of several broadly neutralizing anti-HIV antibodies are used, the at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 broadly neutralizing anti-HIV antibodies preferably bind to different epitopes, and more preferably to different targets chosen among the group comprising the CDR2 domain of the viral CD4 receptor, the CD4 binding site, the gp41, the gpl20, the V1V2 region of the HIV-1 envelope, and the V3 glycan.

[0594] In some embodiments, the at least one broadly neutralizing anti-HIV antibody targets the CD4 binding site and the VI V2 region of the HIV-1 envelope. For instance, the at least one broadly neutralizing anti-HIV antibody may be SAR441236.

[0595] In some embodiments, the at least one broadly neutralizing anti-HIV antibody targets the CD4 binding site, the V1V2 region of the HIV-1 envelope, and the V3 glycan. For instance, the at least one broadly neutralizing anti-HIV antibody may be PGDM1400LS or PGDM1400.

[0596] In some embodiments, the at least one broadly neutralizing anti-HIV antibody is a combination of antibodies selected from the group consisting of:- 3BNC117-LS and 10-1074-LS;- 3BNC117-LS-J and 10-1074-LS-J;- PGT121.414.LS and VRC07-523LS;- PGT121, PGDM1400 and VRC07-523LS;- PGDM1400LS, VRC07-523LS and PGT121.414.LS; andCAP256V2LS, VRC07-523LS and PGT121.

[0597] In one embodiment, the at least one broadly neutralizing anti-HIV antibody is a combination of PGT121, PGDM1400 and VRC07-523LS.

[0598] In other embodiments, the effector vaccine comprises a viral vector comprising nucleic acid sequences encoding at least one broadly neutralizing anti-HIV antibody.

[0599] An illustrative example of effector vaccine comprises a viral vector comprising nucleic acid sequences encoding at least one broadly neutralizing anti-HIV antibody is AAV8-VRC07, which is an adeno-associated virus (AAV) encoding VRC07 antibody.

[0600] In some embodiments, effector vaccine comprises, or consists of, AAV8- VRC07.In summary

[0601] In some embodiments, 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) a non-replicating viral vector, such as an adenovirus, or a live attenuated viral vector, such as a CMV, and b) at least one DNA sequence encoding at least one HIV-derived protein, peptide or epitope, or at least one DNA sequence encoding an antigenbinding fragment of at least one broadly neutralizing anti-HIV antibody, or at least one DNA sequence encoding a mosaic immunogen, an RNA-based vaccine comprising at least one RNA sequence encoding at least one HIV-derived trimeric protein, polypeptide or peptide, and / ora passive vaccine comprising at least one broadly neutralizing anti-HIV antibody.

[0602] In some embodiments, the effector vaccine comprising at least one HIV immunogen further comprises at least one MHCIb / E-binding antigen, protein, peptide or epitope. In those embodiments, the effector vaccine and the tolerogenic vaccine may be a same molecule, compound, combination or composition.

[0603] For instance, the effector vaccine and the tolerogenic vaccine may both comprise, or consist of, Ad26.Mos4.HIV, Ad26.Mos.HIV, ChAdOxl.tHIVconsvl, MVA.tHIVconsv3, MVA.tHIVconsv4, ChAdV63.HIVconsv, and / or MVA.HIVconsv.Composition / Pharmaceutical composition / V accine / Medicament

[0604] The invention further relates to composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, and c) optionally a type III interferon or an agent stimulating the production of type III interferon.

[0605] In some embodiments, the agent(s) of the composite vaccine is / are comprised in a composition.

[0606] In some embodiments, said composition consists essentially of said agent(s).

[0607] As used herein, "consisting essentially of an agent", with reference to a composition, means that the agent is the only one therapeutic agent or agent with a biologic activity within said composition.

[0608] In some embodiments, said composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.

[0609] As used herein, the term "excipient" refers to any and all conventional solvents, dispersion media, fillers, solid carriers, aqueous solutions, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. In general, the nature of the excipient will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (such as powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, for example, FDA Office or EMA. In some embodiments, the excipient is an adjuvant, a stabilizer, an emulsifier, a thickener, a preservative, an antibiotic, an organic or inorganic acid or its salt, a sugar, an alcohol, an antioxidant, a diluent, a solvent, a filler, a binder, a sorbent, a buffering agent, a chelating agent, a lubricant, a coloring agent, or any other component

[0610] By "pharmaceutically acceptable" is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the subject to which it is administered. Examples of pharmaceutically acceptable excipient include, but are not limited to, water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like or combinations thereof.

[0611] Pharmaceutically acceptable excipients that may be used in the pharmaceutical combination of the 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 orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (for example sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene- polyoxypropylene- block polymers, polyethylene glycol and wool fat.

[0612] Adjuvants that may be used in the pharmaceutical combination of the invention, in particular in the effector vaccine and / or the tolerogenic vaccine, include, but are not limited to, an 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.

[0613] Optionally, in some embodiments, the composite vaccine further comprises a Toll-like receptor agonist, such as e.g. a TLR4 agonist, a TLR7 agonist, or a TLR9 agonist.Type III interferon

[0614] In some embodiments, the type III interferon and / or the agent stimulating the production of type III interferon is / are comprised in a composition.

[0615] In some embodiments, said composition consists essentially of the type III interferon. In some embodiments, said composition consists essentially of the agent stimulating the production of type III interferon. In some embodiments, said composition consists essentially of the type III interferon and the agent stimulating the production of type III interferon.

[0616] In one embodiment, said composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.

[0617] In some embodiments, said composition is a vaccine composition. In some embodiments, said vaccine composition further comprises at least one adjuvant.

[0618] In some embodiments, the type III interferon and / or the agent stimulating the production of type III interferon is / are comprised in a medicament.

[0619] In one embodiment, the type III interferon is comprised in a medicament. In one embodiment, the agent stimulating the production of type III interferon is comprised in a medicament. In one embodiment, the type III interferon and the agent stimulating the production of type III interferon are comprised in a medicament.Type III interferon conjugated to a delivery vehicle

[0620] In one embodiment, the type III interferon is conjugated to a delivery vehicle.

[0621] By the term “conjugated” is meant that the type III interferon is physically or chemically coupled, adhered, absorbed or encapsuled to a delivery vehicle. Examples of conjugation include, without limitation, covalent linkage and electrostatic complexation. The terms "complexed," "complexed with," and "conjugated" are used interchangeably herein. In one embodiment, more than one copy or type of type III interferon is conjugated to a delivery vehicle.

[0622] Delivery vehicles are well known in the art. For example, the delivery vehicle can be chosen from a cationic lipid, a liposome, a cochleate, a virosome, an immune- stimulating complex (ISCOM®), a microparticle, a microsphere, a nanosphere, a unilamellar vesicle (LUV), a multilamellar vesicle, an emulsome, and a polycationic peptide, a lipoplexe, a polyplexe, a lipopolyplexe, a water-in-oil (W / O) emulsion, an oil-in-water (O / W) emulsion, a water-in-oil-in water (W / O / W) multiple emulsion, a micro-emulsion, a nano-emulsion, a micelle, a dendrimer, a virosome, a virus-like particle, a polymeric nanoparticle (such as a nanobead, a nanosphere or a nanocapsule), a polymeric microparticle (such as a microsphere or a microcapsule), a chitosan, a poly(lactic acid) (PLA) polymer, a poly(lactic-co-glycolide) (PLGA) polymer, a cyclodextrin, a niosome, or an ISCOM® and, optionally, a pharmaceutically acceptable carrier. In one embodiment, the delivery vehicle is in an adapted form for an oral administration, an injection, a topical administration or a rectal administration.

[0623] In one embodiment, the type III interferon is within, or conjugated to, a nanoparticle, such as e.g. a nanobead, a nanosphere or a nanocapsule. Preferably, the nanoparticle has a diameter of between 50 and 300 nm, more preferably of between 70 and 200 nm, even more preferably of between 100 and 150 nm.

[0624] In some embodiments, the type III interferon is within, or conjugated to, a liposome. The liposome may for instance be a lipid nanoparticle (LNP).

[0625] In some embodiments, the lipid nanoparticle (LNP) contains, or conjugated to, DNA molecules or epitopes. In some embodiments, the lipid nanoparticle (LNP) contains, or conjugated to, RNA molecules or epitopes. In some embodiments, the lipid nanoparticle (LNP) contains, or conjugated to, DNA and RNA molecules or epitopes.Anti-IFNa agent

[0626] In one embodiment, the interferon-alpha blocking agent is comprised in a composition. In one embodiment, said composition comprises at least one interferonalpha blocking agent selected among: an agent neutralizing circulating interferon alpha, and / or an agent blocking interferon-alpha signaling, and / or an agent depleting IFN-a producing cells, and / or an agent blocking IFN-a production.

[0627] In one embodiment, said composition consists essentially of the agent neutralizing circulating interferon alpha. In one embodiment, said composition consists essentially of the agent blocking IFN-a signaling. In one embodiment, said composition consists essentially of the agent depleting IFN-a producing cells. In one embodiment, said composition consists essentially of the agent blocking IFN-a production.

[0628] In one embodiment, said composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.

[0629] In some embodiments, said composition is a vaccine composition. In some embodiments, said vaccine composition further comprises at least one adjuvant.

[0630] In one embodiment, the interferon-alpha blocking agent is comprised in a medicament.

[0631] In one embodiment, said medicament comprises at least one interferon-alpha blocking agent selected among: an agent neutralizing circulating interferon alpha, and / or an agent blocking interferon-alpha signaling, and / or an agent depleting IFN- producing cells, and / or an agent blocking IFN-a production.

[0632] In one embodiment, the agent neutralizing circulating interferon alpha is comprised in a medicament. In one embodiment, the agent blocking interferon-alpha signaling is comprised in a medicament. In one embodiment, the agent depleting IFN- a producing cells is comprised in a medicament. In one embodiment, the agent blocking IFN-a production is comprised in a medicament.

[0633] In some embodiments, the agent neutralizing circulating interferon alpha is within, or conjugated to, a liposome. The liposome may for instance be a lipid nanoparticle (LNP).CD8 vaccine

[0634] In one embodiment, the tolerogenic vaccine specific for at least one HIV- related antigen is comprised in a composition.

[0635] In one embodiment, said composition consists essentially of the tolerogenic vaccine specific for at least one HIV-related antigen.

[0636] In one embodiment, said composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.

[0637] In one embodiment, said composition is a vaccine composition. In one embodiment, said vaccine composition further comprises at least one adjuvant.

[0638] In one embodiment, the tolerogenic vaccine specific for at least one HIV- related antigen is comprised in a medicament.

[0639] In one embodiment, when tolerogenic vaccine according to the invention comprises an HIV-related antigen and a non-pathogenic bacterium, the HIV-related antigen and the non-pathogenic bacterium are two separate and distinct components that are contained as a mixture into a pharmaceutical composition. In another embodiment, when tolerogenic vaccine according to the invention comprises an HIV- related antigen and a non-pathogenic bacterium, the HIV-related antigen and the non- pathogenic bacterium, are the same component that are contained into a pharmaceutical composition.Antigen conjugated to a delivery vehicle

[0640] In one embodiment, the tolerogenic vaccine is a composition, a pharmaceutical composition or a medicament, wherein the tolerogenic vaccine is conjugated to a delivery vehicle.

[0641] In one embodiment, the tolerogenic vaccine comprises at least one HIV- related antigen and a non-pathogenic bacterium, wherein the at least one HIV-related antigen and / or the non-pathogenic bacterium is / are conjugated to a delivery vehicle. In one embodiment, the at least one HIV-related antigen is conjugated to a delivery vehicle. In one embodiment, the non-pathogenic bacterium is conjugated to a delivery vehicle. In one embodiment, the at least one HIV-related antigen and non-pathogenic bacterium are conjugated to a delivery vehicle.

[0642] By the term “conjugated” is meant that the HIV-related antigen and / or non- pathogenic bacterium is / are physically or chemically coupled, adhered, absorbed or encapsuled to a delivery vehicle. Examples of conjugation include, without limitation, covalent linkage and electrostatic complexation. The terms "complexed," "complexed with," and "conjugated" are used interchangeably herein. In one embodiment, more than one copy or type of HIV-related antigen is conjugated to a delivery vehicle. In one embodiment, more than one copy or type of non-pathogenic bacterium is conjugated to a delivery vehicle.

[0643] Delivery vehicles are well known in the art. For example, the delivery vehicle can be chosen from a cationic lipid, a liposome, a cochleate, a virosome, an immune-stimulating complex (ISCOM®), a microparticle, a microsphere, a nanosphere, a unilamellar vesicle (LUV), a multilamellar vesicle, an emulsome, and a polycationic peptide, a lipoplexe, a polyplexe, a lipopolyplexe, a water-in-oil (W / O) emulsion, an oil-in-water (O / W) emulsion, a water-in-oil-in water (W / O / W) multiple emulsion, a micro-emulsion, a nano-emulsion, a micelle, a dendrimer, a virosome, a virus-like particle, a polymeric nanoparticle (such as a nanobead, a nanosphere or a nanocapsule), a polymeric microparticle (such as a microsphere or a microcapsule), a chitosan, a poly(lactic acid) (PLA) polymer, a poly(lactic-co-glycolide) (PLGA) polymer, a cyclodextrin, a niosome, or an ISCOM® and, optionally, a pharmaceutically acceptable carrier. In one embodiment, the delivery vehicle is in an adapted form for an oral administration, an injection, a topical administration or a rectal administration.

[0644] In one embodiment, the tolerogenic vaccine is within, or conjugated to, a nanoparticle, such as e.g. a nanobead, a nanosphere or a nanocapsule. Preferably, the nanoparticle has a diameter of between 50 and 300 nm, more preferably of between 70 and 200 nm, even more preferably of between 100 and 150 nm.

[0645] In some embodiments, the tolerogenic vaccine is within, or conjugated to, a liposome. The liposome may for instance be a lipid nanoparticle (LNP).

[0646] Microfold cells (or M cells) are found in the gut-associated lymphoid tissue (GALT) of the Peyer's patches in the small intestine, and in the mucosa-associated lymphoid tissue (MALT) of other parts of the gastrointestinal tract. These cells are known to initiate mucosal immunity responses.

[0647] In some embodiments, the delivery vehicle is coated with, or conjugated to, molecules, such as e.g. lectins or peptides, that enhance delivery to M cells.

[0648] M cells express a specific carbohydrate moiety (a-L-fucose) on the apical surface. Lectin subtypes, such as Ulex europaeus agglutinin 1 (UEA-1) and Aleuria aurantia, have shown their high specificity for a-L-fucose on M cells. Thus, in some embodiments, the delivery vehicle is coated with, or conjugated to, at least one lectin chosen from Ulex europaeus agglutinin 1 (UEA-1) and Aleuria aurantia.

[0649] M cells also express claudin 4 and TM4SF3. Delivery system using surface- conjugated peptides having high affinity to claudin 4, such as e.g. CTGKSC (SEQ ID NO: 11), LRVG (SEQ ID NO: 12), or CKSTHPLSC (CKS9) (SEQ ID NO: 13), may also be used. Thus, in some embodiments, the delivery vehicle is coated with, or conjugated to, at least one peptide chosen from CTGKSC (SEQ ID NO: 11), LRVG (SEQ ID NO: 12), and CKSTHPLSC (CKS9) (SEQ ID NO: 13).Effector vaccine

[0650] In one embodiment, the effector vaccine specific for at least one HIV-related antigen is comprised in a composition.

[0651] In one embodiment, said composition consists essentially of the effector vaccine specific for at least one HIV-related antigen.

[0652] In one embodiment, said composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.

[0653] In one embodiment, said composition is a vaccine composition. In one embodiment, said vaccine composition further comprises at least one adjuvant.

[0654] In some embodiments, the effector vaccine is a composition comprising the following adjuvants:

[0655] In one embodiment, the effector vaccine specific for at least one HIV-related antigen is comprised in a medicament.Antigen conjugated to a delivery vehicle

[0656] In one embodiment, the effector vaccine is a composition, a pharmaceutical composition or a medicament, wherein the effector vaccine is conjugated to a delivery vehicle.

[0657] In one embodiment, the effector vaccine comprises at least one HIV-related antigen conjugated to a delivery vehicle.

[0658] By the term “conjugated” is meant that the HIV-related antigen is physically or chemically coupled, adhered, absorbed or encapsuled to a delivery vehicle. Examples of conjugation include, without limitation, covalent linkage and electrostatic complexation. The terms "complexed," "complexed with," and "conjugated" are used interchangeably herein. In one embodiment, more than one copy or type of HIV- related antigen is conjugated to a delivery vehicle.

[0659] Delivery vehicles are well known in the art. For example, the delivery vehicle can be chosen from a cationic lipid, a liposome, a cochleate, a virosome, an immune- stimulating complex (ISCOM®), a microparticle, a microsphere, a nanosphere, a unilamellar vesicle (LUV), a multilamellar vesicle, an emulsome, and a polycationic peptide, a lipoplexe, a polyplexe, a lipopolyplexe, a water-in-oil (W / O) emulsion, an oil-in-water (O / W) emulsion, a water-in-oil-in water (W / O / W) multiple emulsion, a micro-emulsion, a nano-emulsion, a micelle, a dendrimer, a virosome, a virus-likeparticle, a polymeric nanoparticle (such as a nanobead, a nanosphere or a nanocapsule), a polymeric microparticle (such as a microsphere or a microcapsule), a chitosan, a poly(lactic acid) (PLA) polymer, a poly(lactic-co-glycolide) (PLGA) polymer, a cyclodextrin, a niosome, or an ISCOM® and, optionally, a pharmaceutically acceptable carrier.

[0660] In one embodiment, the effector vaccine is within, or conjugated to, a nanoparticle, such as e.g. a nanobead, a nanosphere or a nanocapsule. Preferably, the nanoparticle has a diameter of between 50 and 300 nm, more preferably of between 70 and 200 nm, even more preferably of between 100 and 150 nm.

[0661] In some embodiments, the effector vaccine is within, or conjugated to, a liposome. The liposome may for instance be a lipid nanoparticle (LNP).Combination of type III interferon + anti-IFNa agent

[0662] Another object of the invention is a composition, e.g. a pharmaceutical composition, comprising an interferon-alpha blocking agent, and a type III interferon and / or an agent stimulating the production of type III interferon, and optionally at least one pharmaceutically acceptable excipient.

[0663] Another object of the invention is a combination, a pharmaceutical composition, a kit-of-parts or a medicament comprising an interferon-alpha blocking agent, and a type III interferon and / or an agent stimulating the production of type III interferon.

[0664] In some embodiments, the composition, pharmaceutical composition, combination, pharmaceutical combination, medicament or kit-of-parts as described hereinabove is for use in the prophylactic treatment or in the curative treatment of HIV in a subject in need thereof.Specific combinations of agents

[0665] In some embodiments, the methods of the invention comprise administering to a subject in need thereof:Ad26.Mos4.HIV (e.g. during the prime phase),- MVA-BNHIV (e.g. during the boost phase), and the broadly neutralizing antibody PGT121, PGDM1400 and VRC07-523LS.

[0666] In some embodiments, the methods of the invention comprise administering to a subject in need thereof:- Eiger BioPharmaceuticals Inc.’s pegylated interferon lambda named “Peginterferon lambda” or “lambda PEG-rIL-29”, the anti-IFNARl MAb Anifrolumab (Saphnelo®, AstraZeneca), Ad26.Mos4.HIV (e.g. during the prime phase),- MVA-BNHIV (e.g. during the boost phase), and the broadly neutralizing antibody PGT121, PGDM1400 and VRC07-523LS.

[0667] In some embodiments, the methods of the invention comprise administering to a subject in need thereof:- Eiger BioPharmaceuticals Inc.’s pegylated interferon lambda named “Peginterferon lambda” or “lambda PEG-rIL-29”, an anti-IFN-a antibody, such as Sifalimumab, Rontalizumab or S95021, Ad26.Mos4.HIV (e.g. during the prime phase),- MVA-BNHIV (e.g. during the boost phase), and the broadly neutralizing antibody PGT121, PGDM1400 and VRC07-523LS.

[0668] In some embodiments, the methods of the invention comprise administering to a subject in need thereof:- an RNA-LNP encoding IFN-X1 , IFN-X2, IFN-X3 and / or IFN-X4, an anti-IFN-a antibody, such as Sifalimumab, Rontalizumab or S95021, Ad26.Mos4.HIV (e.g. during the prime phase),- MVA-BNHIV (e.g. during the boost phase), and the broadly neutralizing antibody PGT121, PGDM1400 and VRC07-523LS.

[0669] In some embodiments, the methods of the invention comprise administering to a subject in need thereof:ChAdOxl.tHIVconsvl (e.g. during the prime phase),- MVA.tHIVconsv3 (e.g. during the boost phase), and- MVA.tHIVconsv4 (e.g. during the boost phase).

[0670] In one embodiment, the methods of the invention comprise administering to a subject in need thereof:- Eiger BioPharmaceuticals Inc.’s pegylated interferon lambda named “Peginterferon lambda” or “lambda PEG-rIL-29”, the anti-IFNARl MAb Anifrolumab (Saphnelo®, AstraZeneca), ChAdOxl.tHIVconsvl (e.g. during the prime phase),- MVA.tHIVconsv3 (e.g. during the boost phase), and- MVA.tHIVconsv4 (e.g. during the boost phase).

[0671] In some embodiments, the methods of the invention comprise administering to a subject in need thereof:- Eiger BioPharmaceuticals Inc.’s pegylated interferon lambda named “Peginterferon lambda” or “lambda PEG-rIL-29”, an anti-IFN-a antibody, such as Sifalimumab, Rontalizumab or S95021, ChAdOxl.tHIVconsvl (e.g. during the prime phase),- MVA.tHIVconsv3 (e.g. during the boost phase), and- MVA.tHIVconsv4 (e.g. during the boost phase).

[0672] In some embodiments, the methods of the invention comprise administering to a subject in need thereof:- an RNA-LNP encoding IFN-X1 , IFN-X2, IFN-X3 and / or IFN-X4, an anti-IFN-a antibody, such as Sifalimumab, Rontalizumab or S95021, Ad26.Mos4.HIV (e.g. during the prime phase),- MVA-BNHIV (e.g. during the boost phase), and the broadly neutralizing antibody PGT121, PGDM1400 and VRC07-523LS.

[0673] In some embodiments, the methods of the invention comprise administering to a subject in need thereof:ChAdOxl HTI (e.g. during the prime phase),- MVA.HTI (e.g. during the boost phase), and optionally, vesatolimod (also named GS-9620) (TLR7 agonist).

[0674] In some embodiments, the methods of the invention comprise administering to a subject in need thereof:- Eiger BioPharmaceuticals Inc.’s pegylated interferon lambda named “Peginterferon lambda” or “lambda PEG-rIL-29”, the anti-IFNARl MAb Anifrolumab (Saphnelo®, AstraZeneca), ChAdOxl .HTI (e.g. during the prime phase),- MVA.HTI (e.g. during the boost phase), and optionally, vesatolimod (also named GS-9620) (TLR7 agonist).

[0675] In some embodiments, the methods of the invention comprise administering to a subject in need thereof:- Eiger BioPharmaceuticals Inc.’s pegylated interferon lambda named “Peginterferon lambda” or “lambda PEG-rIL-29”, an anti-IFN-a antibody, such as Sifalimumab, Rontalizumab or S95021, ChAdOxl .HTI (e.g. during the prime phase),- MVA.HTI (e.g. during the boost phase), and optionally, vesatolimod (also named GS-9620) (TLR7 agonist).

[0676] In some embodiments, the methods of the invention comprise administering to a subject in need thereof:- an RNA-LNP encoding IFN-X1 , IFN-X2, IFN-X3 and / or IFN-X4, an anti-IFN-a antibody, such as Sifalimumab, Rontalizumab or S95021, Ad26.Mos4.HIV (e.g. during the prime phase),- MVA-BNHIV (e.g. during the boost phase), and the broadly neutralizing antibody PGT121, PGDM1400 and VRC07-523LS.

[0677] In some embodiments, the methods of the 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 with a pathogen-specific antigen.

[0678] In some embodiments, the effector vaccine is an RNA-based vaccine comprising at least one RNA sequence carried by a lipid nanoparticle (LNP).

[0679] Preferably, the agents of the composite vaccine are administered intramuscularly.

[0680] Optionally, the methods of the invention further comprise administering to a subject in need thereof a Toll-like receptor agonist, such as e.g. a TLR4 agonist, a TLR7 agonist, or a TLR9 agonist.Administration Forms

[0681] The combinations, compositions, medicaments or kits-of-parts as described hereinabove are to be administered either simultaneously, separately or sequentially with respect to each other.

[0682] In one embodiment, the tolerogenic vaccine, the effector vaccine, the interferon-alpha blocking agent, the type III interferon and / or an agent stimulating the production of type III interferon, are to be administered either simultaneously, separately or sequentially with respect to each other.

[0683] According to some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove will be formulated for administration to the subject.

[0684] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove may be administered orally, intragastrically, parenterally, topically, by inhalation spray, rectally, nasally, buccally, preputiallly, vaginally or via an implanted reservoir.

[0685] In some embodiments, the oral administration comprises mucosal administration. A "mucosal administration" is a delivery to a mucosal surface, such as sub-lingual, tracheal, bronchial, pharyngeal, esophageal, gastric, and mucosae of the duodenum, small and large intestines, including the rectum mucosae. Yet preferably, the mucosal surface refers to digestive mucosa.

[0686] In one embodiment, the administration of each part of the composite vaccine, combination, composition, medicament or kit-of-parts according to the invention can be done by the same route of administration or by a different route of administration.Oral / intragastric

[0687] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are in an adapted form for an oral or an intragastric administration. Thus, in some embodiments, the combinations, compositions, medicaments or kits-of-parts as described hereinabove is to be administered orally or intragastrically to the subject, for example as a powder, a tablet, a capsule, and the like or as a tablet formulated for extended or sustained release.

[0688] Examples of forms adapted for oral or intragastric administration include, without being limited to, liquid, paste or solid compositions, and more particularly tablets, tablets formulated for extended or sustained release, capsules, pills, dragees, liquids, gels, syrups, slurries, suspensions, and the like.

[0689] In some embodiments, the type III interferon and / or the agent stimulating the production of type III interferon as described hereinabove is / are in an adapted form for an oral or intragastric administration. Thus, in some embodiments, the type III interferon and / or the agent stimulating the production of type III interferon as described hereinabove is / are to be administered orally or intragastrically to the subject, for example as a capsule or as a tablet.

[0690] In some embodiments, the agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling as described hereinabove is / are in an adapted form for an oral or intragastric administration. Thus, in some embodiments,the agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling as described hereinabove is / are to be administered orally or intragastrically to the subject, for example as a capsule or as a tablet.

[0691] In one embodiment, the tolerogenic vaccine as described hereinabove is in an adapted form for an oral or intragastric administration. Thus, in one embodiment, the tolerogenic vaccine as described hereinabove is to be administered orally or intragastrically to the subject, for example as a capsule or as a tablet.

[0692] In one embodiment, the effector vaccine as described hereinabove is in an adapted form for an oral or intragastric administration. Thus, in one embodiment, the effector vaccine as described hereinabove is to be administered orally or intragastrically to the subject, for example as a capsule or as a tablet.Injection

[0693] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are in a form adapted for parenteral administration.

[0694] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are in an adapted form for an injection such as, for example, for intravenous, subcutaneous, intramuscular, intraperitoneal intradermal, transdermal injection or infusion. Thus, the combination, pharmaceutical combination, medicament or kit-of-parts according to the invention is to be injected to the subject, by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection or infusion.

[0695] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are in an adapted form for an injection such as, for example, for intravenous, intramuscular, intraperitoneal injection or infusion. Thus, the combinations, compositions, medicaments or kits-of-parts as described hereinabove are to be injected to the subject, by intravenous, intramuscular, intraperitoneal, injection or infusion.

[0696] Sterile injectable forms of the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove may be a solution or an aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic pharmaceutically acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of 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 manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0697] In some embodiments, the type III interferon and / or the agent stimulating the production of type III interferon as described hereinabove is / are in an adapted form for a parenteral administration and / or injection. Thus, in another embodiment, the type III interferon and / or the agent stimulating the production of type III interferon as described hereinabove is / are to be administered parenterally and / or injected to the subject, by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection or infusion, preferably by intravenous injection

[0698] In some embodiments, the interferon-alpha blocking agent as described hereinabove is in an adapted form for a parenteral administration and / or injection. Thus, in another embodiment, the interferon-alpha blocking agent as describedhereinabove is to be administered parenterally and / or injected to the subject, by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection or infusion, preferably by intravenous injection.

[0699] In some embodiments, the tolerogenic vaccine as described hereinabove is in an adapted form for a parenteral administration and / or injection. Thus, in another embodiment, the tolerogenic vaccine as described hereinabove is to be administered parenterally and / or injected to the subject, by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection or infusion, preferably by intravenous injection.

[0700] In some embodiments, the effector vaccine as described hereinabove is in an adapted form for a parenteral administration and / or injection. Thus, in another embodiment, the effector vaccine as described hereinabove is to be administered parenterally and / or injected to the subject, by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection or infusion, preferably by intravenous injection.Topical

[0701] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are in a form adapted for topical administration. Thus, the agents, combinations, compositions, medicaments or kits-of- parts as described hereinabove are to be administered topically.

[0702] Examples of forms adapted for topical administration include, without being limited to, liquid, paste or solid compositions, and more particularly aqueous solutions, drops, dispersions, sprays, microcapsules, micro-or nanoparticles, polymeric patch, or controlled-release patch, and the like.

[0703] In some embodiments, the type III interferon and / or the agent stimulating the production of type III interferon as described hereinabove is / are in a form adapted for topical administration. Thus, the tolerogenic vaccine specific for at least one HIV-related antigen as described hereinabove according to the invention is to be administered topically.

[0704] In some embodiments, the interferon-alpha blocking agent as described hereinabove is in a form adapted for topical administration. Thus, the agent interferonalpha blocking agent as described hereinabove is to be administered topically.

[0705] In some embodiments, the tolerogenic vaccine as described hereinabove is in a form adapted for topical administration. Thus, the tolerogenic vaccine as described hereinabove according to the invention is to be administered topically.

[0706] In some embodiments, the effector vaccine as described hereinabove is in a form adapted for topical administration. Thus, the effector vaccine as described hereinabove according to the invention is to be administered topically.Rectal

[0707] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are in a form adapted for rectal administration. Thus, in some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are to be to be administered rectally.

[0708] Examples of forms adapted for rectal administration include, without being limited to, suppository, micro enemas, enemas, gel, rectal foam, cream, ointment, and the like.

[0709] In some embodiments, the type III interferon and / or the agent stimulating the production of type III interferon as described hereinabove is / are in a form adapted for rectal administration. Thus, in some embodiments, the type III interferon and / or the agent stimulating the production of type III interferon as described hereinabove is / are to be to be administered rectally.

[0710] In some embodiments, the interferon-alpha blocking agent as described hereinabove is in a form adapted for rectal administration. Thus, in one embodiment,the interferon-alpha blocking agent as described hereinabove is to be to be administered rectally.

[0711] In some embodiments, the tolerogenic vaccine as described hereinabove is in a form adapted for rectal administration. Thus, in one embodiment, the tolerogenic vaccine as described hereinabove is to be to be administered rectally.

[0712] In some embodiments, the effector vaccine as described hereinabove is in a form adapted for rectal administration. Thus, in one embodiment, the effector vaccine as described hereinabove is to be to be administered rectally.Frequency of administration

[0713] In some embodiments, the agent is administered daily. In some embodiments, the methods disclosed herein involve repeated administrations at intervals less than once daily. For example, in certain embodiments, the methods disclosed herein involve administration of the agent every other day, five times per week, four times per week, three times per week, two times per week, one time per week, one time every two weeks, one time every three weeks, one time every four weeks, one time every five weeks, one time every six weeks, one time every seven weeks, or one time every eight weeks. In some embodiments of the methods disclosed herein, the methods involve administration of the agent once every month, once every two months, once every three months, once every four months, once every five months, once every six months, or once every year.

[0714] In some embodiments, the type III interferon agent and / or an agent stimulating the production of type III interferon is administered once a day for 2 to 5 days. In some embodiments, the type III interferon agent and / or an agent stimulating the production of type III interferon is administered every two days for 2 to 5 days.

[0715] In some embodiments, the type III interferon agent and / or an agent stimulating the production of type III interferon is administered every two days for 8 to 15 days.

[0716] In some embodiments, the anti-IFNa agent is administered once or twice during the 8 to 15 days period.

[0717] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are administered once, twice, three, four, five, six, seven, eight, nine, ten times or more.

[0718] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are administered once a day for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days.

[0719] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are administered once a month for 1, 2, 3, 4,5, 6, 7, 8, 9, 10 or more months.

[0720] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are administered once a year for 1, 2, 3, 4, 5,6, 7, 8, 9, 10 or more years.

[0721] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are to be administered at least 2 times (e.g., at days 0 and 14).

[0722] In some embodiments, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are to be administered at least 7 times (e.g., at days 0, 1, 3, 7, 28 and 29).Sequential administration

[0723] The agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are to be administered either simultaneously, separately or sequentially with respect to each other.

[0724] Thus, the agents, combinations, compositions, medicaments or kits-of-parts as described hereinabove are to be administered can be administered at the same time or at different time.

[0725] For simultaneous administration the agents may be administered as one composition or as separate compositions, as appropriate.Prime / boost

[0726] In one embodiment, the administration of each agent or each part of the combinations, compositions, medicaments or kits-of-parts as described hereinabove can be done according to a prime / boost mode. Thus, the present invention also include a variety of prime-boost regimens.

[0727] In one embodiment, the prime / boost mode comprises the steps of administrating: one or more priming immunizations, and one or more boosting immunizations.

[0728] In prime / boost regimens, the composition of each agent or each part of the combinations, compositions, medicaments or kits-of-parts as described hereinabove may be the same or different for each immunization and the type of composition, the route, and formulation of each agent or each part of the combinations, compositions, medicaments or kits-of-parts as described hereinabove may also be varied. For example, if an expression vector is used for the priming and boosting steps, it may either be of the same or different type (e.g., DNA or bacterial or viral expression vector). For example, one useful prime-boost regimen provides for at least two priming immunizations, two weeks apart, followed by at least one boosting immunizations (e.g., at 4-5 and / or 8-9 weeks) after the last priming immunization. It should also be readily apparent to one of skill in the art that there are several permutations and combinations that are encompassed using the DNA, bacterial and viral expression vectors or bacteria of the disclosure to provide priming and boosting regimens. For example, CMV vectors may be used repeatedly while expressing different antigens derived from the same or different pathogens.

[0729] In some embodiments, the prime / boost regimen is a heterologous prime / boost regimen. In this case, the agents used for the boost immunization(s) are different from those used for the prime immunization.

[0730] For instance, when the prime immunization is done with a DNA-based vaccine, in particular a DNA-based vaccine comprising a vector (such as a viral vector), the boost immunization is preferably done using a different vector.

[0731] In one embodiment, the boosting immunization step comprises the administration of a non-infectious dose of SIV or HIV, or an attenuated SIV or HIV (e.g., HIV or SIV depleted in protein nef). In one embodiment, the boosting immunization is in a form adapted for oral, rectal or vaginal administration.

[0732] Attenuated SIV or HIV virus are well known in the art. A non-limiting example of said attenuated virus is an HIV or SIV depleted in protein.

[0733] In some embodiments, the type III interferon and / or the agent stimulating the production of type III interferon and the interferon-alpha blocking agent are to be administered at time and route of administration separately from the tolerogenic vaccine and / or the effector vaccine.

[0734] In one embodiment, the tolerogenic vaccine and / or the effector vaccine is to be administered at least 2 times (e.g., at days 0 and 14). In another embodiment, the type III interferon and / or the agent stimulating the production of type III interferon and the interferon-alpha blocking agent are to be administered at least 2 times before the administration of the tolerogenic vaccine and / or the effector vaccine (e.g., at days -7 and day -3), and at least 9 times after the administration of the tolerogenic vaccine and / or the effector vaccine (e.g., at days 3, 11, 38, 45, 52, 59, 66, 73 and 80).

[0735] In one embodiment, the tolerogenic vaccine and / or the effector vaccine is to be administered at least 7 times (e.g., at days 0, 1, 3, 7, 28 and 29). In another embodiment, the type III interferon and / or the agent stimulating the production of type III interferon and the interferon-alpha blocking agent are to be administered before administrations of the first part (e.g., at days -3, 0, 28 and 29), and at least 1 more time (e.g., at days 57).

[0736] In one embodiment, the tolerogenic vaccine and / or the effector vaccine is to be administered at least 7 times during the priming and boost steps (e.g., at days0,1, 2, 3, 5 for priming and days 28 and 29 for the first boost). The type III interferon and / or the agent stimulating the production of type III interferon and the interferonalpha blocking agent is to be administered at least one time during the priming and first boost steps (e.g. from day 0 to 40) and at least one time after the last administration of the tolerogenic vaccine and / or the effector vaccine. The type III interferon and / or the agent stimulating the production of type III interferon and the interferon-alpha blocking agent is to be administered 0, 1, 2 or 3 days before each administration of the tolerogenic vaccine and / or the effector vaccine.

[0737] In some embodiments, the at least one broadly neutralizing antibody (bnAb) or the antiretroviral (ART) agent is administered every day throughout the duration of the method of the invention.

[0738] In some embodiments, the priming dose of the tolerogenic vaccine and / or of the effector vaccine is administered between day 1 and day 5, e.g. at day 1, 2, 3, 4 and / or 5.

[0739] In some embodiments, the boosting dose of the tolerogenic vaccine and / or of the effector vaccine is administered between day 21 and day 28, e.g. at day 21, 22, 23, 24, 25, 26, 27 and / or 28.

[0740] Typically, the methods of the invention may comprise administering to a subject in need thereof: during a first period of time, at least one broadly neutralizing antibody (bnAb) or antiretroviral (ART) agent, for example every day, and during a second period of time: ix. said at least one broadly neutralizing antibody (bnAb) or antiretroviral (ART) agent, for example every day, x. at Day -2: a type III interferon or an agent stimulating the production of type III interferon, xi. at Day 0: a prime of a tolerogenic vaccine specific for at least one HIV antigen,xii. at Day 5, Day 15 and Day 26: a type III interferon or an agent stimulating the production of type III interferon and an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, xiii. at Day 28: a boost of a tolerogenic vaccine specific for at least one HIV antigen, and during a third period of time: xiv. said at least one broadly neutralizing antibody (bnAb) or antiretroviral (ART) agent, for example every day, xv. at Day 54: a type III interferon or an agent stimulating the production of type III interferon and an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, xvi. at Day 56: a prime of an effector vaccine comprising at least one HIV immunogen, xvii. at Day 61, Day 71 and Day 82: a type III interferon or an agent stimulating the production of type III interferon and an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, xviii. at Day 84: a boost of an effector vaccine comprising at least one HIV immunogen.

[0741] Also typically, the methods of the invention may comprise administering to a subject in need thereof:1) all along the vaccination procedure, at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb), for example every day, and2) during the priming phase: a) at Day -2: a type III interferon or an agent stimulating the production of type III interferon,b) at Day 0: a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, c) at Day 5, Day 15 and Day 26: a type III interferon or an agent stimulating the production of type III interferon and an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, and3) during the boosting phase, following the priming phase: a) at Day 28: a tolerogenic vaccine specific for at least one HIV immunogen and / or an effector vaccine comprising at least one HIV immunogen, and b) at Day 33 and Day 43: a type III interferon or an agent stimulating the production of type III interferon and an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling.

[0742] In some embodiments, the boosting phase is repeated until HIV neutralizing antibodies are detected in the subject’s serum.Subject in need thereof

[0743] The term “subject” herein refers to a human or other mammals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as non-human primates, mammalian wildlife, and the like, that are in need of therapeutic or preventative treatment for an HIV infection.

[0744] In some embodiments, the subject is a mammal, a primate, preferably a human.

[0745] 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.

[0746] In some embodiments, the subject is HIV-negative.

[0747] In some embodiments, the subject has a relatively high CD4+T cell count (such as e.g. superior to 500 CD4+T cells per microliter, superior to 600 CD4+T cells per microliter, 700 CD4+T cells per microliter).

[0748] In some embodiments, the subject is not under antiviral treatment before the initiation of the method of the invention, i.e. before being administered the composite vaccine described hereinabove.

[0749] In some embodiments, the subject is under ART or combined ART (cART) treatment before the initiation of the method of the invention, i.e. before being administered the composite vaccine described hereinabove.

[0750] In some embodiments, the subject may have contracted or be at risk of contracting an HIV infection.

[0751] In some embodiments, the subject has been identified as an individual who is at risk of sexual transmission of HIV. In some embodiments, the individual has been identified as: having anal sex with at least two different sexual partners and no consistent condom use over the last 6 months; having history of sexually transmitted diseases (STDs) during the last 12 months (e.g, syphilis, gonorrhea, chlamydiae, HBV or HCV infection); using psycho-active drugs during sexual intercourses (e.g, cocaine, gammahydroxybutyric acid (GHB), methylenedioxymethamphetamine (MDMA), mephedrone); having sexual intercourse with one or more partners originating from a region with high prevalence of HIV infection (> 1%) (e.g, South America, Sub-Saharan Africa, South-East Asia, Eastern Europe, French Guyana) and no consistent condom use; a sex worker; having a sexual partner who is an intravenous drug user sharing inj ection material; and / or having an HIV-infected sexual partner with a detectable plasma viral load (e.g, >50 copies (cp) / milliliter (mL)).Prevention and event driven administration

[0752] In some embodiments, the methods disclosed herein comprise event driven administration of the agent to the subject. As used herein, the terms “event driven” or “event driven administration” refer to administration of the agent (1) prior to an event (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 prior to the event) that would expose the subject to HIV (or that would otherwise increase the subject’s risk of acquiring HIV); and / or (2) during an event (or more than one recurring event) that would expose the subject to HIV (or that would otherwise increase the subject’s risk of acquiring HIV); and / or (3) after an event (or after the final event in a series of recurring events) that would expose the subject to HIV (or that would otherwise increase the subject’s risk of acquiring HIV).

[0753] In some embodiments, the event driven administration is performed preexposure of the subject to the HIV. In some embodiments, the event driven administration is performed post-exposure of the subject to the HIV.

[0754] As used herein, the term “period of exposure” refers to a period of time, ranging from a single event or to multiple events over an extended period of time, in which a subject is exposed to HIV.

[0755] Also provided herein is a method of reducing the risk of acquiring HIV in a subject, comprising administering to the subject the composite vaccine of the invention.

[0756] In some embodiments, methods for reducing the risk of acquiring HIV comprise administration of the composite vaccine to a subject. In certain embodiments, methods for reducing the risk of acquiring HIV comprise administration of the composite vaccine to a subject at risk of acquiring HIV. Examples of subjects at high risk for acquiring HIV include, without limitation, a subject who is at risk of sexual transmission of HIV.

[0757] In some embodiments, the reduction in risk of acquiring HIV is at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95% (compared to a subject having not been administered the agent according to any of the methods provided herein).Dosage

[0758] It will be understood that the total daily usage of the first part, the total daily usage of the second part and the total daily usage of third part in the combination, the pharmaceutical combination, medicament or kit-of-parts according to the invention will be decided by the attending physician within the scope of sound medical judgment. The specific dose for any particular subject will depend upon a variety of factors such as the infectious disease to be treated; the age, body weight, general health, sex and diet of the subject, and like factors well-known in the medical arts. Hence, the combination, the pharmaceutical combination, medicament or kit-of-parts according to the invention can be administered one or more times to the subject. Preferably, there is a set time interval between separate administrations of the combination, the pharmaceutical combination, medicament or kit-of-parts according to the invention. While this interval varies for every subject, typically it ranges from 1 days to several weeks, and is often 1, 2, 4, 6 or 8 days, or 1, 2, 4, 6 or 8 weeks. In one embodiment of the present invention, the interval is typically from 1 to 6 weeks. In one embodiment of the present invention, the interval is longer, advantageously about 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks,26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks,42 weeks, 44 weeks, 46 weeks, 48 weeks, 50 weeks, 52 weeks, 54 weeks, 56 weeks,58 weeks, 60 weeks, 62 weeks, 64 weeks, 66 weeks, 68 weeks 70 weeks or 80 weeks.In one embodiment, the administration regimes typically have from 1 to 20 administrations of the 3 different parts according to the invention, but may have as few as one or two or four or eight or ten. In another embodiment the administration regimes is annual, biannual or other long interval (5-10 years).

[0759] In some embodiments, the administration regimes typically have from 1 to 15 administrations, but may have as few as one or two or four or eight or ten.

[0760] As an example, when the tolerogenic vaccine comprises a CMV vector as described herein above, and the subject to be treated is a mammal, a primate or a human, the therapeutically effective dose of said CMV vector can range from a few to a few hundred micrograms (e.g., 5 to 500 pg per administration). The CMV vector can be administrated in any suitable amount to achieve expression at these dosage levels. In non-limiting examples, CMV vectors may be administered in an amount of at least 101, 102, 103, 104, 105, 106, 107or 108pfu per administration. Thus, CMV vectors may be administered in at least 101pfu, or in a range from about 101pfu to about 108pfu per administration. The CMV vector may be lyophilized for resuspension at the time of administration or may be in solution.

[0761] In one embodiment, the amount of CMV vectors, as described hereinabove, administered to the subject is at least of 101, 102, 103, 104, 105, 106, 107or 108pfu. In one embodiment, the amount of CMV vectors, as described hereinabove, administered per administration ranges from about 101to about 108, preferably from about 102to about 107, more preferably from about 103to about 106, and even more preferably from about 104to about 105, including all integer values within those ranges. In one embodiment, the daily amount of CMV vectors, as described hereinabove, administered per day to the subject is at least of 101per day, 102per day, 103per day,104per day, 105per day, 106per day, 107per day, 108per day of pfu. In one embodiment, the daily amount of CMV vectors, as described hereinabove, administered per day ranges from about 101to about 108per day, preferably from about 102to about 107per day, more preferably from about 103to about 106per day, and even more preferably from about 104to about 105per day, including all integer values within those ranges. In one embodiment, the amount of CMV vectors, as described hereinabove, administered to the subject is at least of 101, 102, 103, 104, 105, 106, 107or 108viruses / kg body.

[0762] As an example, when the tolerogenic vaccine comprises a non-pathogenic bacterium as described herein above, and when the subject to be treated is a human, the therapeutically effective dose of said non-pathogenic bacteria (i.e., Lactobacillus sp. , Lactobacillus plantarum, or Mycobacterium sp.) can range from about 101to about1018cfu per administration and the therapeutically effective dose of said HIV antigen can range from about 101to about 1014viruses per administration.

[0763] In one embodiment, the amount of non-pathogenic bacteria, as described hereinabove, administered to the subject is at least of 101, 102, 103, 104, 105, 106, 107, 108, 109, IO10, 1011, 1012, 1013or 1014cfu. In one embodiment, the amount of non- pathogenic bacteria, as described hereinabove, administered per administration ranges from about 101to about 1018, preferably from about 102to about 1016, more preferably from about 104to about 1014, and even more preferably from about 106to about IO12,including all integer values within those ranges. In one embodiment, the daily amount of non-pathogenic bacteria, as described hereinabove, administered per day to the subject is at least of 101per day, 102per day, 103per day, 104per day, 105per day, 106per day, 107per day, 108per day, 109per day, IO10per day, 1011per day, 1012per day, 1013per day, 1014per day, 1015per day, 1016per day, 1017per day or 1018per day of cfu. In one embodiment, the daily amount of non-pathogenic bacteria, as described hereinabove, administered per day ranges from about 101to about 1018per day, preferably from about 102to about 1016per day, more preferably from about 104to about 1014per day, and even more preferably from about 106to about 1012per day, including all integer values within those ranges. In one embodiment, the amount of non-pathogenic bacteria, as described hereinabove, administered to the subject is at least of 101, 102, 103, 104, 105, 106, 107, 108, 109, IO10, 1011, 1012, 1013or 1014bacteria / kg body.

[0764] In one embodiment, the amount of inactivated SIV or HIV viruses, as described hereinabove, administered to the subject is at least of 101, 102, 103, 104, 105, 106, 107, 108, 109, IO10, 1011, 1012, 1013, or 1014viruses. In one embodiment, the amount of inactivated SIV or HIV viruses, as described hereinabove, administered per administration ranges from about 101to about 1018, preferably from about 102to about 1016, more preferably from about 104to about 1014, and even more preferably from about 106to about 1012, including all integer values within those ranges. In one embodiment, the daily amount of inactivated SIV or HIV viruses, as described hereinabove, administered per day to the subject is at least of 101per day, 102per day,103per day, 104per day, IO5per day, 106per day, 107per day, 108per day, 109per day, 1010per day, 10nper day, 1012per day, 1013per day, 1014per day, IO15per day, 1016per day, 1017per day or 1018per day of viruses. In one embodiment, the daily amount of inactivated SIV or HIV viruses, as described hereinabove, administered per day ranges from about 101to about 1018per day, preferably from about 102to about 1016per day, more preferably from about 104to about 1014per day, and even more preferably from about 106to about 1012per day, including all integer values within those ranges. In one embodiment, the amount of inactivated SIV or HIV viruses, as described hereinabove, administered to the subject is at least of 101, 102, 103, 104, 105, 106, 107, 108, 109, IO10, 1011, 1012, 1013, or 1014=viruses / kg body.

[0765] In some embodiments, the subject is a mammal, a primate, preferably a human, and the therapeutically effective dose of the agent, composition, pharmaceutical composition, medicament or kit-of-parts according to the invention is a daily dose to be administered in one, two, three or more takes or in one, two, three or more takes.BRIEF DESCRIPTION OF THE DRAWINGS

[0766] Figure 1. Antiviral activity of type I and type III interferons. (A) Expression of ISGs in HepG2. HepG2 cells were treated with IFNa2a or IFNkl-4 (lO ng / ml). After 4 h of stimulation, qRT-PCR were used to examine the mRNA levels of of the interferon-induced genes, IFIT1, MX1 and OASL and fold-changes was calculated by 2’AACtmethod as compared with non-treated cell control and using endogenous S14 mRNA level for normalization. (B) Antiviral activity of type I and III IFNs against EMCV. IFNa2a or IFNX1 / 2 / 3 / 4 (10 ng / ml) were added to HepG2 cells 24 h prior to challenge with EMCV. Forty-eight after infection with EMCV, cells were assayed for viability with a bioassay. A570 values were directly proportional to cell viability and therefore antiviral activity of the respective IFNs. IFN-a treatment without viral challenge was used as a baseline of the viability of the cells.

[0767] Figure 2. Anti-proliferative activity of type I and type III interferons againstCD4+T cells. CFSE-stained CD4+T cells (10xl04 / well) were stimulated for 5 days in 96 round-bottomed microwells with allogeneic poly I:C matured DC in absence (control) or presence of 10 ng / ml of IFN-a2a, or IFNkl or IFNX2 or IFNX3 or IFNX4. When indicated, anti-interferon type I receptor antibody was added. The percentage of CFSE dilution was evaluated by flow cytometry.

[0768] Figure 3. IFN-a2a but not IFN-type III induces the expression of ISGs in CD4+T cells. CD4+T cells were treated with IFNa2a or IFNX1 / 2 / 3 / 4 (10 ng / ml). After 4 h of stimulation, qRT-PCR were used to examine the mRNA levels of the interferon- induced genes, IFIT1, MX1 and OASL and fold-changes was calculated by 2'AACtmethod as compared with non-treated cell control and using endogenous S14 mRNA level for normalization.

[0769] Figure 4. IFN-a2a but not IFN-type III stimulates the phosphorylation of Statl in CD4+T cells. CD4+T cells were stimulated with 10 ng mN1of IFN- / J , IFN- X2, IFN- 3, IFN-X4, or IFN-a2a for 20 min, or were left unstimulated (control). Increases in pSTATl were evaluated as a ratio of induction over baseline levels (MFI fold change = MFI cytokine-stimulated / MFI untreated cells).

[0770] Figure 5. IFN-a2a but not IFN-type III increases CD38 expression in CD3 / CD28 stimulated CD4+T cells. CFSE-stained CD4+T cells (4xl04 / well) were cultured in 96 round-bottomed microwells in the presence of ACD3-feeder (4xl04 / well) and plate-bound anti-CD3 mAb (2 pg / ml), soluble anti-CD28 mAb (2 pg / ml) with increasing dose of IFN-a2a or IFN type III. CD38 Median Fluorescence Intensity (MFI) was measured by flow cytometry in CD3+7-AAD-CFSE+stimulated CD4+T cells at the end of the culture.

[0771] Figure 6. Generation and expansion of peptide-specific CD8 HLA-E restricted by peptide-loaded m-DCs. TAP-inhibited mDCs was pulsed with peptides (10 pM for 1 h) and co-cultured with autologous naive CD8+T cells at a 1 : 10 ratio. Peptide positive CD8+T cells was monitored at day 0 and one week after the last stimulation by flow cytometric analysis using MHC -peptide pentamers. Data are expressed as percentage of tetramer-positive cells among CD8+ T cells.

[0772] Figure 7. Comparison of CM CD8+ T cell distributions and serum IFN-a levels in HIV- 1 -infected subjects and critical pathogenic role of IFN-a in human HIV- 1 infection. (A) Comparison of CM CD8+ T cell distributions in HIV- 1 -infected subjects; (B) Comparison of serum IFN-a levels in HIV- 1 -infected subjects; (C) Relationship between CD8+ CM frequency and serum IFN-a level in non-treated HIV patients (EC and pre-cART group).

[0773] Figure 8. Comparative analysis of major blood immune cell subsets and serum IFNa and IFNX2 concentration in non-ECs, ECs and HDs. (A) Principal component analysis (PCA) of studied participants based on the proportion of different immune cell subpopulations (CD4+, CD8+and TCR gd T-cells, NK and DC), evaluated by flow cytometry. The first two Principal components (PCI and PC2) explaining the greatest differences among individuals are represented on a bi-plot. Each point represents one participant, colored by the group they belong to. Each group is outlined by an ellipse representing the 95% confidence interval of the sample groupings. (B) Histograms showing distributions of indicated immune cell populations between HDs (Black, n=24), ECs (green, n=16), and non-ECs (red, n=26). (C) Balloon-plot summarizing the statistically significant changes in the indicated immune cell populations between ECs and HDs, non-ECs and HDs and non-ECs and ECs. The size of the circle represents the p-value. Red and blue colors show increased or decreased frequencies of the immune cell populations. (D) Scatterplots showing IFNa and IFNX2 concentration in serum from HDs (n=51), ECs (n=18) and non-ECs (n=26). IFNa and IFNX2 levels were detected by SIMOA. (E) Scatterplot showing relationships between IFNa and IFN 2 serum levels (El), CD4+T-cells and IFNX2 (E2), and CD8+T-cells and IFNZ2 (E3) in ECs (n=18) and non-ECs (n=26). Correlations were evaluated with Spearman’s rank correlation test. Differences between unpaired samples were performed with Mann-Whitney test. Graph show the median values and p values (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001)EXAMPLES

[0774] The present invention is further illustrated by the following examples.Example 1: Effects of type I and type III interferons on innate and adaptative immune responsesMaterials and MethodsHuman cell lines

[0775] HCC HepG2 and normal kidney epithelial Vero cell lines were obtained from ATCC. Cells were grown in Dulbecco’s Modified Eagle Medium supplemented with 10% heat-inactivated Fetal Bovine Serum, 2 mM L-glutamine, 1% penicillin and streptomycin solution in hypoxia 2%. Cancer cell lines were grown to 70-100% confluency, s...

Claims

CLAIMS A composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of type III interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prophylactic treatment or curative treatment of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive patient with no AIDS symptoms or with AIDS symptoms, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of type III interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during a priming phase, and3) wherein:a) optionally the type III interferon or the agent stimulating the production of type III interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine are to be administered to the subject during a boosting phase following the priming phase. A composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of type III interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prevention of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seronegative patient, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure during a priming phase and a boosting phase, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of type III interferon,b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during the priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of type III interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine are to be administered to the subject during the boosting phase following the priming phase. A composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, c) optionally a type III interferon or an agent stimulating the production of type III interferon, and d) at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) for use in the prophylactic treatment or curative treatment of acquired immune deficiency syndrome (AIDS) in a subject in need thereof, wherein said subject is a human immunodeficiency virus (HlV)-seropositive Elite Controller patient, and wherein:1) said at least one antiretroviral (ART) agent or at least one broadly neutralizing antibody (bnAb) is to be administered to the subject all along the vaccination procedure during a priming phase and a boosting phase, and2) wherein: a) optionally the type III interferon or the agent stimulating the production of type III interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine comprising at least one HIV immunogen are to be administered to the subject during the priming phase, and3) wherein: a) optionally the type III interferon or the agent stimulating the production of type III interferon, b) the agent neutralizing circulating interferon alpha or the agent blocking interferon alpha signaling, and c) the effector vaccine are to be administered to the subject during the boosting phase following the priming phase. A composite vaccine comprising: a) an agent neutralizing circulating interferon alpha or an agent blocking interferon alpha signaling, b) an effector vaccine comprising at least one HIV immunogen, andc) optionally a type III interferon or an agent stimulating the production of type III interferon. The composite vaccine for use according to anyone of claims 1 to 3, or the composite vaccine according to claim 4, wherein the type III interferon is IFN-kl , IFN-X2, IFN- X3 and / or IFN-X4, and wherein the agent stimulating the production of type III interferon comprises a TLR ligand, a RIG-I ligand, and / or a MDA5 ligand. The composite vaccine for use according to anyone of claims 1 to 3, or the composite vaccine according to claim 4, wherein the type III interferon is at least one IFN-X1, IFN-X2, IFN-X3 and / or IFN-X4 protein, at least one plasmid comprising a DNA sequence encoding IFN-X1, IFN-X2, IFN-X3 and / or IFN-X4, or at least one RNA molecule or mRNA-LNP encoding IFN-X1, IFN-X2, IFN-X3 and / or IFN-X4. The composite vaccine for use according to anyone of claims 1-3, 5-6, or the composite vaccine according to anyone of claims 4-6, wherein the agent neutralizing circulating interferon alpha is an antiferon, an anti-IFN-a antibody, or an anti-IFN- a hyper-immune serum; and wherein the blocking agent of interferon alpha signaling is an anti-type I interferon R1 or R2 antibody, or an interferon alpha endogenous regulator including SOSC1 or an aryl hydrocarbon receptor. The composite vaccine for use according to anyone of claims 1-3, 5-7, or the composite vaccine according to anyone of claims 4-7, wherein the agent neutralizing circulating interferon alpha or blocking interferon alpha signaling is, or is combined with, an agent neutralizing circulating interferon beta or blocking interferon beta signaling. The composite vaccine for use according to anyone of claims 1-3, 5-8, or the composite vaccine according to anyone of claims 4-8, wherein said 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) a non-replicating viral vector or a live attenuated viral vector, andb) at least one DNA sequence encoding at least one HIV-derived protein, peptide or epitope, or at least one DNA sequence encoding an antigenbinding fragment of at least one broadly neutralizing anti-HIV antibody, or at least one DNA sequence encoding a mosaic immunogen, an RNA-based vaccine 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. The composite vaccine for use according to anyone of claims 1-3, 5-9, or the composite vaccine according to anyone of claims 4-9, wherein said at least one HIV immunogen is derived from gag, pol, env, nef, tat, vif and rev. The composite vaccine for use according to anyone of claims 1-3, 5-10, or the composite vaccine according to anyone of claims 4-10, wherein said at least one HIV immunogen is a native Env gpl60 trimer, a stabilized Env gpl60 trimer, a stabilized Env gpl40 trimer (SOS gpl40 or SOSIP gpl40), a stabilized Env single-chain gpl40 trimer, a stabilized native flexibly linked (NFL) Env gpl40 trimer. The composite vaccine for use according to anyone of claims 1-3, 5-11, or the composite vaccine according to anyone of claims 4-11, wherein said at least one HIV immunogen is in a soluble form, or is displayed at the surface of a nanoparticle. The composite vaccine for use according to anyone of claims 1-3, 5-12, wherein the at least one antiretroviral (ART) agent is selected from the group consisting of Nucleoside reverse transcriptase inhibitors (NRTIs), Non-nucleoside reverse transcriptase inhibitors (NNRTIs), Protease inhibitors (Pls), Integrase inhibitors (INSTIs), Fusion inhibitors (FIs), Chemokine receptor antagonists (CCR5 antagonists) and Entry inhibitors (CD4-directed post-attachment inhibitors).The composite vaccine for use according to anyone of claims 1-3, 5-13, wherein said composite vaccine generates anti-HIV specific neutralizing antibodies and / or antiHIV specific cytotoxic cells in said subject.

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