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Charani Ranasinghe Molecular Mucosal Vaccine Immunology Group, Dept Immunology

Novel HIV IL-4R antagonist vaccine strategy can induce both high avidity CD8 and excellent B cell immunity. Charani Ranasinghe Molecular Mucosal Vaccine Immunology Group, Dept Immunology The John Curtin School of Medical Research The Australian National University.

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Charani Ranasinghe Molecular Mucosal Vaccine Immunology Group, Dept Immunology

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  1. Novel HIV IL-4R antagonist vaccine strategy can induce both high avidity CD8 and excellent B cell immunity Charani Ranasinghe Molecular Mucosal Vaccine Immunology Group, Dept Immunology The John Curtin School of Medical Research The Australian National University

  2. Mucosal vaccination induces high quality/avidity HIV-specific CD8 T cells Ranasinghe et al. J. Immunol 2007 • Induction of high quality/avidity HIV-specific CD8 T cells following mucosal vaccination is associated with lower expression of IL-4/IL-13 by CD8 T cells • Absence of IL-4/IL-13 induces high avidity HIV-specific CD8 T cells Ranasinghe et al. Euro J Immunol 2009 Ranasinghe et al. Mucosal Immunology 2013

  3. Construction of poxviral vector-based vaccines that co-express IL-4R antagonist using homologous recombination HIV gag/pol/env IL-4R antagonist Recombinant fowlpox virus (rFPV) - priming vaccine IL-4R antagonist HIV gag/pol Recombinant vaccinia virus (rVV) or Modified Vaccinia Ankara (rMVA) - booster vaccine intranasal/ intramuscular (i.n./i.m.) combined mucosal/systemic strategy Jackson Boyle Ranasinghe Methods in Molecular Biology (2014)

  4. Novel IL-4R antagonist adjuvanted vaccine will bind to IL-4R and transiently block IL-4/IL-13 signaling via the STAT6 pathway IL-13 IL-4 IL-13Rα1 IL-4Rα IL-4Rα γc IL-13Rα2m 12 hrs STAT6 96 hrs Jackson Worley Trivedi Ranasinghe (submitted) Ranasinghe et al Cytokine and Growth Factor Reviews (In press)

  5. i.n./i.m. IL-4R antagonist adjuvanted vaccine strategy can induce HIV-specific CD8 T cells of high avidity Inclusion of the inhibitor in the priming vaccination is crucial to induce the high avidity T cell repertoire Jackson Worley Trivedi Ranasinghe (submitted)

  6. Inclusion of the inhibitor in the i.n. rFPV priming vaccination is crucial to induce high avidity CD8 T cell repertoire FPV HIVIL-4C118/VVHIVIL-4C118 FPV HIV/VV HIV FPV HIVIL-4C118/VV HIV FPV HIV/VV HIVIL-4C118 6.9% 9.8% 21.8% 19.6% Spleen Genito-rectal nodes 0.38% 1.16% 0.76% 0.98% Kd-Gag CD8 Jackson Worley Trivedi Ranasinghe (submitted)

  7. Novel vaccines can enhance both systemic & mucosal HIV-specific poly-functional HIV-specific CD8 T cell immunity (i) FPV HIV∆10/ VV HIV∆10 (ii) FPV HIVVV HIV Spleen Iliac nodes Lung Lung nodes Ranasinghe Mucosal Immunology 2013

  8. i.n./i.m. IL-4R antagonist adjuvanted HIV vaccine strategy induces excellent CD8 T cell mediated protective immunity * * * P < 0.05 compared to control vaccination Ranasinghe et al Mucosal Immunology 2013; Jackson Worley Trivedi Ranasinghe (submitted)

  9. i.n./i.m. IL-4R antagonist adjuvanted vaccine strategy can induce Gag-specific antibody class switching 6 weeks 12 weeks * 0.0567 IgG1 *** 0.0006 * 0.0566 * 0.0256 * 0.0256 IgG2a Statistics were calculated using Mann – Whitney U test Jackson Worley Trivedi Ranasinghe (submitted)

  10. FPV-HIV IL-4RC118 (IL-4R antagonist) FPV-HIV - unadjuvanted 73.5% i.n. delivery of FPV-HIV IL-4R antagonist adjuvanted vaccine recruits unique antigen presenting cells to the lung mucosae responsible for the induction of high avidity CD8 T and excellent B cell immunity 45.1% 1.92% 1.03% CD11b CD103 CD11C+ CD11b+ CD103- Ranasinghe et al Mucosal Immunology 2013 ; Trivedi Jackson Ranasinghe (Submitted)

  11. Unique features of the novel i.n./i.m. HIV IL-4R antagonist adjuvanted vaccine strategy. • Help recruit unique antigen presenting cell subsets to the lung mucosae • Induce enhanced high quality/avidity mucosal & systemic HIV Gag-specific CD8 T cell immunity* • HIV Gag-specific antibody class switching (IgG1 and IgG2a)* • Env-specific IgG1 following a second i.m. Env protein booster** • Induce triple action immunity • The immune responses induced are consistent with • HIV controllers* and • Features of partial protective efficacy in the RV144 trial** => Platform technology against other chronic pathogens

  12. Acknowledgements Molecular Mucosal Vaccine Immunology Group: Ronald Jackson Annette Buchanan Lisa Pavlinovic, Megan Glidden, Sherry Tu Students:DanushkaWijsundara, ShubhanshiTrivedi, Matthew Worley ANU/BRF -Kerong Zhang JCSMR/MCRF -HarpreetVohra, Mick Devoy ANU/Animal services staff Collaborators: David Boyle - CSIRO AAHL John Stambas - DeakinUni/ CSIRO AAHL Robert Center - Burnet Institute/ Uni of Melbourne

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