Assessing epitope-specific antibody immunity to zika following infection and vaccination

The National Institute of Allergy and Infectious Diseases awarded Emory University $250,675 on August 19, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to assess epitope-specific antibody immunity to Zika virus following infection and vaccination.

The project develops and applies blockade-of-binding (BOB) assays to determine how BOB responses correlate with neutralizing antibody responses, define serological measures associated with protective immunity to Zikv, and assess the impact of dengue virus infection on antibody responses to Zikv. The research hypothesis posits that antibodies against quaternary epitopes are crucial for durable protective immunity against Zikv. In the first aim, the recipient will determine major Zikv epitopes targeted by antibodies following infection and vaccination, leveraging access to longitudinal samples from human challenge studies with Zikv, vaccine trials, endemic cohorts, and murine vaccine studies. Antibody depletion studies with Zikv envelope protein, envelope domain 3, and stabilized Zikv envelope dimers will define critical binding determinants. Passive transfer of well-characterized human serum into mice challenged with lethal Zikv infection will assess markers of protection. The second aim will assess the impact of dengue virus infection on antibody responses to Zikv. Work is performed in Decatur, Georgia, with performance completion targeted for July 31, 2028. The award is classified as a Project Grant, a developmental R21 mechanism designed to pave the way for larger proposals comprehensively defining critical determinants of protective immunity to Zikv.

Abstract

Zika virus (ZIKV) emerged during an unprecedented pandemic in 2015-2016, causing thousands of cases of congenital disease, and IT continues to pose a risk to billions of people living in the tropics. Despite the enormous threat ZIKV presents, there remain no licensed vaccines to protect vulnerable populations. Several obstacles impede licensure of an efficacious zika vaccine. Among them is an incomplete understanding of immunity to ZIKV and a lack of adequate tools with which to assess immunogenicity of zika vaccine candidates. Therefore, we begin to address these knowledge gaps in a targeted R21 developmental grant that will pave the way for larger proposals to comprehensively define critical determinants of protective immunity to ZIKV induced by infection and vaccination. In this project, we will further develop and apply our recently developed blockade-of- binding (BOB) assays to determine how BOB responses correlate with neutralizing antibody (NAB) responses, define serological measures associated with protective immunity, and assess the impact of infection by dengue virus (DENV), a closely related flavivirus, on AB responses to ZIKV. Our overarching hypothesis is that AB against quaternary epitopes are crucial for durable protective immunity against ZIKV. In aim 1, we determine the major ZIKV epitopes targeted by AB following infection and vaccination. Leveraging access to longitudinal samples from human challenge studies with ZIKV, vaccine trials, cohorts in endemic areas, and murine vaccine studies. AB depletion studies with ZIKV envelope (E) protein, E domain 3, and stabilized ZIKV E dimers will define critical binding determinants of epitope-specific responses. Finally, passive transfer of well-characterized human serum into mice challenged with lethal ZIKV infection will assess markers of protection. In aim 2, we will assess the impact of DENV infection on the epitope-specific AB response to ZIKV by testing BOB responses in samples from a pediatric cohort in nicaragua with defined flavivirus infection history and comparing immunogenicity of a purified inactivate zika vaccine (ZPIV) by testing samples from trials conducting in flavivirus- endemic VS non-endemic sites. This project directly test our hypotheses that vaccines able to elicit AB immunity that reacts broadly across antigenic regions on the ZIKV surface, including at quaternary epitopes, will best confer protective immunity. Thus, this work addresses a significant vaccinology and global health problem by employing and evaluating innovative assays, infection models, and vaccine platforms. The results will have a major impact for ongoing zika vaccine development work and justify an expanded proposal to comprehensively define determinants of immunity to ZIKV following infection and vaccination.