# Receptor binding domain-independent pancoronavirus vaccine design by fusion of conserved T/B Epitopes

## TL;DR

A new universal coronavirus vaccine design is proposed using conserved immune targets to provide broad protection against multiple variants and future outbreaks.

## Contribution

A novel vaccine platform using conserved T/B epitopes fused with HR1/2 domains to elicit cross-protective immunity against multiple coronaviruses.

## Key findings

- The HR1-VV-HR2-VS vaccine induced stronger immune responses in mice compared to individual peptides.
- The vaccine reduced viral loads and lung pathology in mice infected with multiple coronaviruses.
- The HR1-HR2 trimeric scaffold enhances peptide immunogenicity for potential universal vaccines.

## Abstract

The persistent emergence of SARS-CoV-2 variants continues to compromise current vaccine efficacy, driving the development of broad-spectrum coronavirus vaccines to address variant evasion and future outbreaks. To develop a pan-coronavirus vaccine, we identified some conserved T/B epitopes across spike proteins of human-infecting coronaviruses, focusing on two conserved long peptides, VV and VS, which demonstrated broad immunogenicity in PBMCs from COVID-19 convalescent patients. By structurally fusing the VV and VS long peptides with heptad repeat 1/2 (HR1/2) domains from the S2 subunit, we engineered a trimeric immunogen HR1-VV-HR2-VS. This design induced superior cellular and humoral immune responses compared to individual peptide components in immunized mice. The vaccine also significantly reduced viral loads and attenuated lung pathology in mice challenged with HCoV-229E, SARS-CoV-2 prototype strain, and the KP.2 variant, demonstrating cross-protective immunity. Therefore, these results indicated that HR1-VV-HR2-VS vaccine elicits cross-protective immunity, highlighting its potential as a universal coronavirus vaccine. In addition, we developed an innovative peptide vaccine platform based on the HR1-HR2 trimeric structural protein, which serves as a potent polypeptide fusion scaffold to significantly enhance peptide immunogenicity.