# Anti-flavivirus B cell response analysis to aid vaccine design

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $771,355

## Abstract

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.

## Key facts

- **NIH application ID:** 10778585
- **Project number:** 5R01AI175439-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Yuxing Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $771,355
- **Award type:** 5
- **Project period:** 2023-02-06 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10778585

## Citation

> US National Institutes of Health, RePORTER application 10778585, Anti-flavivirus B cell response analysis to aid vaccine design (5R01AI175439-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10778585. Licensed CC0.

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