During the last ten years, our laboratory has attempted to understand the problems associated with HIV vaccine failure in humans. Our studies were the first to demonstrate that IL-4 and predominantly IL-13 play an important role in modulating “quality or avidity” of HIV-specific CD8 T cells in a vaccine route dependent manner where mucosal vaccination induced higher avidity CD8 T cells compared to systemic vaccination.
Although HIV is first encountered at the mucosae, no mucosal vaccine strategy has yet entered into clinical trials. Taken the above findings we have now designed a series of poxvirus vector-based mucosal HIV prime-boost vaccine strategies that can transiently inhibit IL-4 and/or IL-13 activity at the vaccination site. Our studies have demonstrated that these vaccines can induce robust high avidity HIV-specific mucosal and systemic CD8 T cells with boarder cytokine/chemokine profiles, resulting in better cell-mediated protective efficacy in animal models. Our recent studies have also revealed that vaccines that transiently block both IL-4 and IL-13 STAT6 cell-signalling can induce not only high avidity CD8 T cell immunity but also excellent gag-specific IgG1 and IgG2a antibody immunity, similar to what has been reported in HIV elite controllers.
We have also shown that i) different vaccine vectors (pDNA, fowlpox virus, Modified Vaccinia Ankara virus/ vaccinia virus), ii) vaccine vector combinations (what vector is used in the prime or the booster vaccination) and iii) the route of vaccine delivery (mucosal or systemic) can significantly modulate the cytokine cell milieu (IL-4/IL-13 activity) and promote the recruitment of unique antigen-presenting cell subsets to the vaccination site and alter the resulting adaptive immunity. We are currently in the process of deciphering the fundamental molecular mechanisms involved in regulation of IL-4/IL-13 expression following vaccination. Specifically, we are investigating how the vaccine vectors and adjuvants differentially induce cytokine expression during the innate immune response and how these differences ultimately influence anti-HIV immunity. We believe that these finding will provide insights into the immunological mechanisms behind effective vaccine design not only for HIV but also many other chronic mucosal pathogens that need high avidity T and B cell immunity for protection.
Find more information about the Ranasinghe Group here.
- Hamid M.A.,Jackson R.J., Roy S., Khanna M, and RANASINGHE C. Unexpected involvement of IL-13 signalling via a STAT6 independent mechanism, during IgG2a development Following viral vaccination. European Journal of Immunology 2018 Jul;48(7):1153-1163.
- Li Z., Jackson R.J., RANASINGHE C. Vaccination route can significantly alter the innate lymphoid cell subsets: A feedback between IL-13 and IFN-g. npj Vaccines. 2018 Mar 12;3:10.
- Townsend D.G., Trivedi S., Jackson RJ and RANASINGHE C. Recombinant fowlpox virus vector-based vaccines: Expression kinetics, dissemination and safety profile following intranasal delivery J. General Virology 2017;5(10):000702.
- Trivedi S, RANASINGHE C: The Influence of Immunization Route, Tissue Microenvironment, and Cytokine Cell Milieu on HIV-Specific CD8+ T Cells Measured Using Fluidigm Dynamic Arrays. PLoS One 10(5), e0126487 (2015).
- Ravichandran J, R.J. Jackson, Trivedi S., and RANASINGHE C. IL-17A expression in HIV-specific CD8 T cells is regulated by IL-4/IL-13 following HIV-1 prime-boost immunization. Interferon and Cytokine Research 35(3), 176-185 (2015).
- Trivedi S, R. J. Jackson and RANASINGHE C. Different HIV pox viral vector-based vaccines and adjuvants can induce unique antigen presenting cells that modulate CD8 T cell avidity. Virology 468-470C, 479-489 (2014).
- Jackson R.J., Worley M, Trivedi, S, and RANASINGHE C. Novel HIV IL-4R antagonist vaccine strategy can induce both high avidity CD8 T and B cell immunity with greater protective efficacy. Vaccine (Elsevier) 20(14), 01136-01130 (2014).
- Wijesundara, D.K., RANASINGHE C, R. .J. Jackson, B. A. Lidbury, C. R. Parishh and J. C. Quah. Use of an in vivo FTA assay to assess the magnitude, functional avidity and epitope variant cross-reactivity of T cell responses following HIV-1 recombinant poxvirus vaccination. PLoS One. 2014 Aug 29;9(8):e105366, doi: 10.1371/journal.pone.0105366.
- RANASINGHE C., S. Trivedi, D. Wijesundara and R. J. Jackson. IL-4 and IL-13 receptors: Roles in immunity and powerful vaccine adjuvants. Cytokine Growth Factor Rev 2014 Jul 23. pii: S1359-6101(14)00072-0. doi: 10.1016/j.cytogfr.2014.07.010.
- Wijesundara, D. K., R. J. Jackson, D. C. Tscharke, and RANASINGHE C. IL-4 and IL-13 mediated down-regulation of CD8 expression levels can dampen anti-viral CD8 T cell avidity following HIV-1 recombinant pox viral vaccination. Vaccine (Elsevier) (6): p. 01048-7 (2013).
- RANASINGHE C., S. Trivedi, J. Stambas, and R. J. Jackson. Unique IL-13Rα2 based HIV-1 vaccine strategy to enhance mucosal immunity, CD8+ T cell avidity and protective immunity. Mucosal Immunol 6(6), 1068-1080 (2013).
- RANASINGHE C. Turner SJ, McArthur C et al. (2007) Mucosal HIV-1 pox virus prime-boost immunization Induces high-avidity CD8+ T cells with regime-dependent cytokine/granzyme B profiles. J Immunol. 178(4), 2370-2379