The Ranasinghe Group - Molecular Mucosal Vaccine Immunology

Molecular Mucosal Vaccine Immunology

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 vaccination1.

Although HIV is first encountered at the mucosae, no mucosal vaccine strategy has yet entered into clinical trails. 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 site2,3,4. 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 immunity3, 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 2,5 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.

Funding 2010 - 2016

Past and Current Funding

  • NH&MRC Project grant
  • 2 x NH&MRC Development grants
  • Bill & Melinda Gates Foundation, Grand Challenge Exploration Phase I
  • 5 Australian Centre for HIV & Hepatitis Virology Research grants
  • 3 x Gordon and Gretel Bootes Foundation awards.
  • Commercial funding
  • 2 DTF grants

Collaborators

National and International

  • Professor Alistair Ramsay, Louisiana Vaccine Centre, Louisiana State University, New-Orleans, USA, – Evaluation of Mucosal HIV and TB vaccines.
  • Dr John Stambas, School of Medicine, Deakin University/ CSIRO Animal Health Laboratories – HIV-1 mucosal vaccines /murine influenza-HIV-1 studies.
  • Dr Lisa Sedger, University of Technology, Sydney - Pox virus studies / TNF family members & immune responses to viral infection.
  • Dr David Boyle, CSIRO Animal Health Laboratories – Pox-viral based vaccines.
  • Professor Anthony Kelleher, Immunovirology and Pathogenesis Program NCHECR, UNSW/ St Vincent's Centre for Applied Medical Research (AMR) – Human HIV-specific T cell immunity & T cell avidity studies.
  • Dr Robert Center, Department of Microbiology and Immunology, The University of Melbourne - Evaluation of  Env-specific antibody responses to novel HIV vaccines
  • Professor Stephen Kent, Department of Microbiology and Immunology, The University of Melbourne  -  Evaluation of poxviral-based HIV vaccines
  • Dr Robert DeRose, Department of Microbiology and Immunology, The University of Melbourne -  Evaluation of poxviral-based HIV vaccines
  • Professor Kenneth Beagley,  Institute of Health and Biomedical Innovation, Queensland University of Technology -  Mucosal vaccine strategies against Chlamydia
  • Professor Andreas Suhrbier,  QIMR Berghofer Medical Research Institute – Evaluation of a murine HIV challenge model

Publications

  1. 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.
  2. Ranasinghe C, Trivedi S, Stambas J, Jackson RJ (2013) Unique IL-13Ralpha2-based HIV-1 vaccine strategy to enhance mucosal immunity, CD8(+) T-cell avidity and protective immunity. Mucosal Immunol 6: 1068-1080.
  3. Jackson RJ, Worley M, Trivedi S, Ranasinghe C (2014) Novel HIV IL-4R antagonist vaccine strategy can induce both high avidity CD8 T and B cell immunity with greater protective efficacy. Vaccine Vaccine 32: 5703–5714.
  4. Ranasinghe C, Trivedi S, Wijesundara DK, Jackson RJ: IL-4 and IL-13 receptors: Roles in immunity and powerful vaccine adjuvants. Cytokine Growth Factor Rev 23(14), 00072-00070 (2014).
  5. Trivedi S, Jackson RJ, Ranasinghe C (2014). 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.

Updated:  23 March 2017/Responsible Officer:  Director, JCSMR/Page Contact:  Web Manager