Evaluation of Antibody Responses Elicited by Zika Vaccination in Flavivirus-naïve and -experienced Individuals

Project Title: Evaluation of Antibody Responses Elicited by Zika Vaccination in Flavivirus-naïve and - experienced Individuals Project Summary Zika virus (ZIKV) is a member of the flavivirus genus that recently precipitated widespread cases of neurological pathology and congenital neurologic defects. In response, a multilateral coalition of investigators designed and developed multiple vaccine candidates that elicited potent ZIKV-neutralizing antibodies, which were shown to correlate with disease protection in animal models. Despite these advances, it remains unclear how the ZIKV immunization antibody response is shaped in humans with and without prior exposure to other flaviviruses, such as dengue virus (DENV), Japanese encephalitis (JEV) or yellow fever virus (YFV); particularly as these viruses all have significant epidemiologic overlap with ZIKV. Our long-term goal is to understand the underlying humoral mechanisms generated by flavivirus vaccination, which can provide long-term protection in flavivirus-naïve and/or -experienced populations. Such information would guide vaccination strategies in flavivirus-endemic areas or among flavivirus-naïve individuals traveling to endemic areas. The overall objective of this proposed research is to evaluate the specificity and function of the B cell repertoire elicited by ZIKV vaccination in flavivirus- naïve and -experienced individuals. To achieve these goals, this research will utilize leading-edge technologies to sequence B cell receptors (BCRs) from flavivirus-specific, single B cells using RNAseq and Next Generation Sequencing (NGS). BCRs will be compared between Zika vaccinated individuals, and to previously published monoclonal antibodies, to determine the prevalence of B cell lineages, gene assignment, degree of somatic hypermutation (SHM), and lengths of heavy chain complementary-determining region 3 (HCDR3). Common B cell lineages will be expressed as monoclonal antibodies and evaluated for their specificity, function, structural, and ability to protect against flavivirus challenges in mouse models. A total of 40 samples will be evaluated from individuals representing 5 groups in 3 different Phase I Zika vaccine clinical trials: a) Flavivirus-naïve individuals who were vaccinated using a Zika purified inactivated whole virus vaccine (ZPIV) b) Flavivirus-naïve individuals who were vaccinated with an adeno-vectored Zika M-E (Ad26.ZIKV.M-Env) c) Individuals living in Puerto Rico with prior dengue infection who were ZPIV vaccinated d) JEV (IXIAROÃ'®) vaccinated individuals who were ZPIV vaccinated and e) YFV (YV-VAXÃ'®) vaccinated individuals who were ZPIV vaccinated. Flavivirus-naïve, Zika vaccinated individuals (Groups a-b) will be explored in Aim 1 and Flavivirus-experienced individuals, either by prior infection (Group c) or by prior vaccination (Groups d-e), will be explored in Aim 2. Aim 3 will examine a late timepoint (6 months) following the last ZPIV vaccination to determine the longevity of the circulating B cell lineages characterized in Aims 1 and 2. Evaluating prevalent B cell lineages responding to Zika vaccination will reveal the specificity, function and durability of the humoral response among individuals living in different regions. These studies will provide insights into the potency and durability of ZIKV vaccine responses in both flavivirus- naïve and -experienced individuals and may translate into vaccine strategies that yield long-lived protection.