Structural studies of Zika virus for vaccine design

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Project Summary/Abstract Zika virus (ZIKV) is a pathogen from a family of arthropod-borne flaviviruses that includes West Nile, yellow fever, and dengue viruses. Though ZIKV is transmitted by mosquitos like other flaviviruses, ZIKV can also be transmitted sexually, and the ability of ZIKV to cause an epidemic was first realized in 2007. Infection is usually mild, producing fever, conjunctivitis, headache, rash, conjunctivitis and arthralgia in ~20% of cases and meningoencephalitis or Guillain-Barré Syndrome in rare cases. However, the major concern of ZIKV infection is during pregnancy, which can cause severe fetal consequences, including neurodevelopmental abnormalities such as microcephaly and other significant ophthalmologic and neurologic changes. Given the large-scale spread, severity of symptoms, and that there is no current treatment or prophylaxis, a safe and effective ZIKV vaccine is urgently needed. Vaccines against ZIKV are being development but there is serious concern that vaccines using whole virus or large portions of the ZIKV envelope (E) glycoprotein may induce non-neutralizing antibodies (Abs) that cross-react with and enhance subsequent flavivirus infections trough Ab-dependent enhancement (ADE). Of particular concern is the risk of severe hemorrhagic fever through ADE upon subsequent infection by dengue virus (DENV1). In contrast, a safe vaccine would selectively elicit Abs to neutralizing epitopes rather than non-neutralizing and therefore potentially infection-enhancing Abs. Design of a ZIKV vaccine requires structural knowledge of how Abs recognize ZIKV envelope proteins. In Prof. Pamela Bjorkman’s laboratory at Caltech, this project will 1) use structural biology, particularly recent advances in cryo-electron microscopy (cryo-EM), to understand the Ab response to ZIKV, and 2) use yeast display to design and test immunogens that, based on structural analysis, yield a neutralizing response and minimize production of non-protective Abs, and therefore may be used to develop a safe vaccine. This will be accomplished through collaboration with Professors Charles Rice, Margaret MacDonald, and Michel Nussenzweig at Rockefeller University. I will prepare viral material for structural analysis in the laboratory of Prof. Rice and Prof. MacDonald, and I will test candidate immunogens for efficacy and safety in mouse models in the laboratory of Prof. Nussenzweig with the aspiration that candidate immunogens will be suitable to move towards clinical testing. The training plan involves completion of the PhD under the expertise and guidance of Prof. Bjorkman at Caltech, with three-months spent in the laboratory of Prof. Rice and six-months in the laboratory of Prof. Nussenzweig at Rockefeller to ensure there is high training potential and feasibility. This training, before transitioning back to medical school at UCLA, will provide the experience and skillset to become an independent physician-scientist in academic medicine.