Development and immune correlates of Zika virus vaccines

Zika virus (ZIKV) was first isolated in 1947 from a sentinel monkey placed in the Zika forest, Uganda. It is an arthropod-borne virus (arbovirus) with the main mosquito vector being Aedes aegypti . The first ZIKV outbreak of public concern was in 2007 in the Yap Islands, followed by rapid spread across Brazil. First considered a relatively benign virus, a new link between ZIKV infection and microcephaly and other congenital malformations –now collectively called congenital Zika syndrome (CZS)– led to the declaration of a Public Health Emergency of International Concern in February 2016, by the World Health Organization (WHO). Described in this thesis is the development of the first vaccines to block ZIKV infection. We established both mouse and non-human primate models to assess efficacy of our vaccines. Correlates of protection were assessed through antibody adoptive transfer and T-cell depletion studies. We concluded that our rhesus adenovirus 52 (RhAd52) based ZIKV vaccine expressing the optimized M-Env antigen led to complete and durable protection of monkeys of at least 1 year, following a single dose immunization. Protection was correlated with neutralizing antibodies. In corroboration, the potent cross-reactive DENV neutralizing antibody B10 effectively halts ZIKV replication following exposure to ZIKV and can be used as a therapeutic treatment. The encouraging data described in this thesis have led to the progression of a human adenovirus 26 (Ad26) ZIKV vaccine expressing M-Env to a phase I clinical trial, which is currently ongoing.