The Ranasinghe Group - Molecular Mucosal Vaccine Immunology

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.

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