# Structure-based design of coronavirus subunit vaccines

> **NIH NIH R01** · GEORGIA STATE UNIVERSITY · 2021 · $728,965

## Abstract

Project Summary
Viral subunit vaccines are safe and convenient, but generally suffer low efficacy. Our overall hypothesis is that
an intrinsic limitation is associated with subunit vaccine designs in which artificially exposed surfaces of subunit
vaccines contain epitopes unfavorable for vaccine efficacy. The receptor-binding domain (RBD) of a
coronavirus spike protein consists of a core subdomain that serves as the structural scaffold and a receptor-
binding motif (RBM) that binds the receptor and contains neutralizing epitopes. The RBDs are prime
candidates for subunit vaccine designs. In preliminary studies, we identified epitopes on the core subdomain of
MERS coronavirus (MERS-CoV) RBD that were buried in the full-length spike protein but became artificially
exposed in recombinant RBDs. We further showed that these epitopes severely reduce vaccine efficacy by
inducing strong non-neutralizing immune responses and distracting the host immune system from reacting to
the neutralizing epitopes on the RBM. This novel finding reveals an intrinsic limitation of viral subunit vaccines
that the vaccine field had been unaware of. In this proposal, we aim to characterize this intrinsic limitation and
establish novel approaches to overcome it. We use the RBDs from highly pathogenic coronaviruses, including
MERS-CoV and SARS coronavirus (SARS-CoV), as the model system. This proposal contains three major
design approaches for coronavirus RBD vaccines. First, we will identify and characterize the artificially
exposed unfavorable epitopes on the core subdomain of coronavirus RBDs. To this end, we introduce a novel
concept, neutralizing immunogenicity index (NII), to evaluate the contribution of each epitope to the overall
vaccine efficacy. We will mask the negative epitopes on the core subdomain through glycan shielding or
resurfacing. This design enhances the efficacy of the individually optimized RBD vaccines. Second, we will
construct chimeric RBDs containing the core subdomain from one coronavirus RBD as the structural scaffold
and the RBM from another coronavirus RBD as the immunogenic sites. The unfavorable epitopes on the core
subdomain should have been silenced from the first design approach. The interface of the core subdomain and
RBM will be optimized to maximize the stability of the chimeric RBD vaccines. This design prepares us for the
emergence of highly pathogenic coronaviruses in the future. Third, we will construct nanoparticle-carried
coronavirus RBD vaccines in a way that artificially exposed unfavorable epitopes on the core subdomain are
re-buried at the molecular interfaces to enhance the RBD vaccine's efficacy. We will use mice to evaluate the
immunogenicity of the above engineered RBD vaccines and will use animal models (including hDPP4-knock-in
(KI)) mice and non-human primates) to assess the selected RBD vaccines against live coronavirus challenge.
Overall, this research establishes the artificially exposed unfavorable epitopes as the ...

## Key facts

- **NIH application ID:** 10415747
- **Project number:** 7R01AI139092-05
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** Lanying Du
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $728,965
- **Award type:** 7
- **Project period:** 2021-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415747

## Citation

> US National Institutes of Health, RePORTER application 10415747, Structure-based design of coronavirus subunit vaccines (7R01AI139092-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10415747. Licensed CC0.

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