Research Project
9511753
PROJECT SUMMARY/ABSTRACT The recent acceleration in incidence and intensity of human disease caused by Zika virus (ZIKV) infection has prompted an international outcry for safe and effective countermeasures. Currently protection against mosquito bites and vector control are the only measures available to prevent ZIKV infections. A vaccine is urgently needed. The studies proposed here build on previous work that demonstrates the protective efficacy of recombinant vaccines using the Modified Vaccinia Ankara (MVA) live viral vector. GeoVax has constructed two novel MVA vaccine candidates against ZIKV: one expressing the ZIKV NS1 protein, and a second expressing ZIKV prME. Both vaccine candidates show excellent immunogenicity and protective efficacy against ZIKV infection in a stringent intracerebral challenge mouse model. In this application, we propose to evaluate the immunogenicity and protective efficacy of these two vaccine candidates in rhesus macaques (RM). The project has three specific aims. Under the first aim, GeoVax will scale up vaccine production for a large study in RM and develop methods for quality control and standardization of methods for vaccine preparation. Under the second aim, RM will be immunized with the two vaccines following either a prime-only or a prime-boost vaccination regimen. Samples will be collected from the immunized animals at discrete intervals and tested for antigen-specific antibody by ELISA, for neutralizing antibody by PRNT50, and for antigen-specific T cell responses by flow cytometry of cells stained by intracellular cytokine staining for activation of CD4+ and CD8+ populations. The protective efficacy of these vaccines in RM will be tested by challenging the immunized animals with live ZIKV and assessing viral load in serum and other tissues compared to the sham immunized control group. Under the third aim we will investigate the role of antibody in protection using passive transfer experiments in mice. Purified IgG from sera of immunized RM will be passively transferred to mice that will then be challenged with appropriate ZIKV strains and assessed for temporal viremia following intravenous challenge. Additionally, we will test RM immune sera and controls for potential antibody-dependent enhancement of infection (ADE) using Dengue serotype 2 as a model, and for the presence of autoantibodies that react with self-antigens. The vaccine candidate yielding optimal protection with minimal detrimental effects will be chosen for further development. The long term objective of this project is clinical development and testing of vaccine candidates against ZIKV infection, in response to a 2016 NIAID call to the research community highlighting its interest in funding such research. Upon completion of this two-year project, GeoVax will submit a Phase II SBIR to request funding for further development of the selected vaccine candidate in preparation for human clinical testing.
