# Project 1: Definition of the structural principles underlying broadly protective humoral immunity to coronaviruses

> **NIH NIH P01** · UNIVERSITY OF WASHINGTON · 2022 · $881,853

## Abstract

PROJECT SUMMARY – PROJECT 1: Definition of the structural principles underlying broadly
protective humoral immunity
Although the COVID-19 pandemic has accelerated the development of SARS-CoV-2 vaccines at an
unprecedented pace, no licensed vaccines elicit broad protection against a large spectrum of human
coronaviruses. There is therefore an urgent need for vaccines inducing broad protection against currently
circulating and distantly related betacoronaviruses for pandemic preparedness. The proposed Project aims to
identify epitopes targeted by cross-reactive and broadly neutralizing anti-betacoronavirus antibodies to obtain
an antigenic map of targets present at the surface of betacoronavirus spike trimers to guide our vaccine design
efforts. Broadly neutralizing sarbecovirus antibodies recognizing the spike receptor-binding domain have
recently been discovered, however, they do not cross-react with members of other subgenera. Previous studies
have shown that the spike fusion machinery (S2 subunit), which is more conserved than the S1 subunit, harbors
conserved epitopes targeted by cross-reactive polyclonal antibodies. Although a few β-coronavirus cross-
reactive monoclonal antibodies are known, a deep understanding of the diversity of epitopes targeted by broadly
neutralizing antibodies and their quantitative contribution to neutralization is lacking, thereby hindering the
rational design of vaccines eliciting broad immunity. We will use three approaches to determine the molecular
determinants of broad antibody-mediated coronavirus immunity by unveiling the types, specificities, and diversity
of broadly neutralizing antibodies targeting all three main betacoronavirus subgenera (sarbecovirus,
merbecovirus, and embecovirus). First, we will characterize the binding and neutralizing breath of polyclonal
sera from nonhuman primates immunized with nanoparticle vaccines co-displaying multiple different RBD- and
spike-based antigens. Second, we will determine the epitope specificities of cross-reactive antibodies in these
sera using serological assays and by directly visualizing polyclonal antibodies in complex with vaccine-matched
and heterologous antigens using cryo-electron microscopy. Finally, we will isolate monoclonal antibodies from
nonhuman primates immunized with multivalent nanoparticle vaccines and characterize their structures at high
resolution as well as their binding, neutralizing, and protective breadth.

## Key facts

- **NIH application ID:** 10425030
- **Project number:** 1P01AI167966-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** David Veesler
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $881,853
- **Award type:** 1
- **Project period:** 2022-09-02 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425030

## Citation

> US National Institutes of Health, RePORTER application 10425030, Project 1: Definition of the structural principles underlying broadly protective humoral immunity to coronaviruses (1P01AI167966-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10425030. Licensed CC0.

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