# Project 1

> **NIH NIH P01** · ROCKEFELLER UNIVERSITY · 2021 · $508,499

## Abstract

Summary - Project 1 (PD: Michel Nussenzweig)
The re-emergence of Zika virus (ZIKV) poses serious threats to human health because of the dire
consequences on the fetus when infection occurs during pregnancy. Based on the distribution of its mosquito
vector, ZIKV threatens up to 40% of the world's population. There are no treatments or prophylaxis against
ZIKV, which makes the design of vaccines urgent and highly desirable. Numerous vaccine candidates are
already being pursued that use as an approach the whole virus or large portions of the virus Envelope protein
(E). Although this approach seems efficacious and promising in pre-clinical models, serious concerns exist with
regard to safety due to the phenomenon of Antibody Dependent Enhancement (ADE) and cross-reactivity with
dengue virus (DENV). A ZIKV vaccine of such design could elicit antibodies that cross-react with but do not
neutralize DENV, possibly making a vaccinated individual more susceptible to severe dengue disease through
ADE. In contrast, a vaccine designed to focus exclusively on neutralizing epitopes is more likely to be safe. The
Nussenzweig lab has discovered human antibodies that potently neutralize ZIKV by recognizing non-
overlapping epitopes on the Zika Envelope Domain III (ZEDIII), and in collaboration with the Bjorkman lab has
started to structurally define their cognate epitopes on the viral surface.
 The long-term goal of this proposal is to develop and evaluate immunogens that preferentially elicit
antibodies that target ZIKV neutralizing epitopes and do not enhance dengue infection. To accomplish this, Dr.
Nussenzweig will work with Dr. Bjorkman to characterize novel neutralizing epitopes on the viral surface of
ZIKV. This information will be harnessed to design novel immunogens that preferentially drive the generation of
neutralizing antibodies to these epitopes. For example, candidate immunogens will be designed and evaluated
to elicit human VH3-23/VK1-5 antibodies that are recurrent and potent neutralizers of ZIKV in humans.
 The Nussenzweig lab plans to 1) discover more antibodies that neutralize ZIKV in order to generate a
panel of additional non-overlapping neutralizing viral epitopes; 2) use this information to help the Bjorkman lab
design novel immunogens that preferentially elicit protective antibodies to such epitopes; 3) evaluate these
immunogens in wild type mice; 4) extend the evaluation of the most promising immunogens to genetically
humanized mice; 5) assess vaccine efficacy using ZIKV-susceptible mouse models; 6) evaluate vaccine cross-
protection by challenging the immunized mice with DENV; and 7) evaluate ADE by challenging vaccinated
mice with sub-lethal doses of DENV. Overall, the proposed experiments bear a significant translational
potential, and are expected to result in candidate vaccines for subsequent evaluation in non-human primate
models and vaccine clinical trials.

## Key facts

- **NIH application ID:** 10216967
- **Project number:** 5P01AI138938-04
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Michel C Nussenzweig
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $508,499
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216967

## Citation

> US National Institutes of Health, RePORTER application 10216967, Project 1 (5P01AI138938-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10216967. Licensed CC0.

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