title: Novel HIV IL-4R antagonist vaccine strategy can induce both high avidity CD8 T and B cell immunity with greater protective efficacy.
abstract: We have established that the efficacy of a heterologous poxvirus vectored HIV vaccine, fowlpox virus (FPV)-HIV gag/pol prime followed by attenuated vaccinia virus (VV)-HIV gag/pol booster immunisation, is strongly influenced by the cytokine milieu at the priming vaccination site, with endogenous IL-13 detrimental to the quality of the HIV specific CD8+ T cell response induced. We have now developed a novel HIV vaccine that co-expresses a C-terminal deletion mutant of the mouse IL-4, deleted for the essential tyrosine (Y119) required for signalling. In our vaccine system, the mutant IL-4C118 can bind to IL-4 type I and II receptors with high affinity, and transiently prevent the signalling of both IL-4 and IL-13 at the vaccination site. When this IL-4C118 adjuvanted vaccine was used in an intranasal rFPV/intramuscular rVV prime-boost immunisation strategy, greatly enhanced mucosal/systemic HIV specific CD8+ T cells with higher functional avidity, expressing IFN-γ, TNF-α and IL-2 and greater protective efficacy were detected. Surprisingly, the IL-4C118 adjuvanted vaccines also induced robust long-lived HIV gag-specific serum antibody responses, specifically IgG1 and IgG2a. The p55-gag IgG2a responses induced were of a higher magnitude relative to the IL-13Rα2 adjuvant vaccine. More interestingly, our recently tested IL-13Rα2 adjuvanted vaccine which only inhibited IL-13 activity, even though induced excellent high avidity HIV-specific CD8+ T cells, had a detrimental impact on the induction of gag-specific IgG2a antibody immunity. Our observations suggest that (i) IL-4 cell-signalling in the absence of IL-13 retarded gag-specific antibody isotype class switching, or (ii) IL-13Rα2 signalling was involved in inducing good gag-specific B cell immunity. Thus, we believe our novel IL-4R antagonist adjuvant strategy offers great promise not only for HIV-1 vaccines, but also against a range of chronic infections where sustained high quality mucosal and systemic T and B cell immunity are required for protection.
authors.affiliation: Molecular Mucosal Vaccine Immunology Group, Department of Immunology, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Jackson
authors.affiliation: Molecular Mucosal Vaccine Immunology Group, Department of Immunology, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Worley
authors.affiliation: Molecular Mucosal Vaccine Immunology Group, Department of Immunology, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Shubhanshi
authors.initials: S
authors.lastname: Trivedi
authors.affiliation: Molecular Mucosal Vaccine Immunology Group, Department of Immunology, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia. Electronic address: Charani.Ranasinghe@anu.edu.au.
authors.forename: Charani
authors.initials: C
authors.lastname: Ranasinghe
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology; D015658:HIV Infections / Q000517:prevention & control*; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D018793:Interleukin-13 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008807:Mice, Inbred BALB C; D011498:Protein Precursors / Q000276:immunology; D019948:Receptors, Interleukin-4 / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D015483:HIV Antibodies; D007074:Immunoglobulin G; D018793:Interleukin-13; D007376:Interleukin-2; D011498:Protein Precursors; D019948:Receptors, Interleukin-4; D014409:Tumor Necrosis Factor-alpha; C059767:p55 gag precursor protein, Human immunodeficiency virus 1; D015847:Interleukin-4; D007371:Interferon-gamma
keywords: CD8+ T cell avidity; HIV vaccines; IL-13Ra2 adjuvanted vaccines; IL-4R antagonist; IgG1 and IgG2a; Mucosal/systemic immunity