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.