Defining the Immunological and Structural Determinants of Protection of NS1-specific Antibodies Against Zika Virus Infection

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Zika virus is a mosquito-borne flavivirus closely related to dengue virus that can cause severe disease in humans including microcephaly in newborns and Guillain-Barré syndrome in adults. However, specific treatments and vaccines for Zika virus have yet to be developed. The goal of this project is to identify the fundamental mechanisms by which antibodies that target non-structural proteins such as NS1 provide protection against Zika virus infection and disease. While antibodies elicited by structural E proteins of flaviviruses have been shown to protect or cause antibody-enhancement (ADE) of viral replication, our current understanding of antibodies directed towards NS1 suggest that NS1-specific antibodies have the ability to protect but not cause ADE. Towards defining the protective determinants of effective vaccines and therapeutics to Zika virus, we intend to isolate NS1-specific antibodies from the plasmablast and memory B-cell compartments of individuals exposed to Zika virus. Antibodies will be characterized for their binding affinity, ability to induce Fc-mediated effector functions in vitro and their capacity to provide protection in vivo. The potential role of ADE of disease in exacerbating Zika virus infection or promoting infection of other flavivirus will also be determined. Structural analyses utilizing crystallography or cryo-electron microscopy will help determine the epitopes. Overall, this study aims to reveal important determinants in the development of antibody therapeutics and structure-based vaccine designs to protect against Zika virus infection.