Anti-flavivirus B cell response analysis to aid vaccine design

Zika virus (ZIKV) is a member of flavivirus family that emerged as an infectious agent causing global health crisis during recent epidemics. ZIKV infection can cause Guillain-Barré syndrome in adults, and severe fetal neuromalformations and fetal death during pregnancy. ZIKV infection is primarily transmitted by mosquito bite, while sexual transmission and vertical transmission from infected pregnant women to fetus also contribute to the recent epidemic. Ideally, an effective ZIKV vaccine should provide sterilizing immunity that blocks the initial viral dissemination to prevent subsequent infection-caused morbidity. Currently, there is no approved ZIKV vaccine for disease prevention. The membrane (M) and envelope protein (E) expressed as prM-E form is a common antigen choice for current vaccine candidates against ZIKV, as neutralizing antibodies (nAb) against prM-E can prevent viral entry. However, such nascent PrM-E based ZIKV vaccines can increase the infectiousness of the dengue virus (DENV), another flavivirus of which endemic area largely overlaps with ZIKV. Due to the high degree of sequence homology between the E proteins of ZIKV and DENV, the ZIKV prM-E vaccine may stimulate the production of antibodies that are non-neutralizing but cross-reactive with the DENV E protein. In the event of a subsequent dengue virus infection, antibody-dependent enhancement (ADE) can occur when the suboptimal anti- ZIKV antibodies bind to the DENV virus, which thereby enhance the entry of DENV into host cells and exacerbate dengue symptoms. Strategies to prevent the induction of ADE-prone antibodies have been described recently for modified ZIKV immunogens, which unfortunately display suboptimal protection efficacy in small animals. Here, we focus on applying structure-based vaccine design to develop novel vaccine candidates with improved immunogenicity and reduced ADE potential for DENV infection. In preliminary study, our lead vaccine candidate formulated in optimized adjuvant showed nearly complete protection in immune mice challenged with ZIKV, and abolished ADE potential assessed by in vitro assays. Potent monoclonal ZIKV nAbs targeting the major ZIKV E protein nAb determinants including the quaternary E-dimer dependent epitope isolated from immune mice confirmed the design rationale. In this application, we will extend our effort via further immunogen designs guided by B cell/antibody response analysis and structural investigation of ZIKV E protein-antibody interactions to improve our lead vaccine candidate aiming at achieving sterilizing immunity, to evaluate in small animal models. If succeeds, this study will contribute to (i) the development of an effective and safe ZIKV vaccine, and (ii) deepening our understanding of immune response to flavivirus infections and immunizations.