# Broadly Sarbecovirus-Neutralizing Antibodies Induced by Ancestral SARS-CoV-2 Infection

## TL;DR

This study shows that infection with the original SARS-CoV-2 can lead to antibodies that neutralize both SARS-CoV-1 and SARS-CoV-2 variants, offering insights for vaccine development.

## Contribution

The study identifies cross-neutralizing antibodies from ancestral SARS-CoV-2 infection and reveals their mechanisms of action.

## Key findings

- 30 monoclonal antibodies from ancestral SARS-CoV-2 infection cross-recognized SARS-CoV-1, including 25 targeting the RBD.
- mAb 12C2 neutralized both SARS-CoV-1 and SARS-CoV-2 variants through mechanisms like inhibiting membrane fusion.
- Cryo-EM showed 12C2 binds to the RBD's outer face, overlapping with the epitope of the broadly neutralizing antibody S309.

## Abstract

The COVID-19 pandemic, driven by SARS-CoV-2, continues to challenge global health due to emerging variants and the potential risk posed by related sarbecoviruses. Neutralizing antibodies targeting the spike (S) glycoprotein, particularly the receptor-binding domain (RBD), play a crucial role in viral neutralization and vaccine design. Although broadly neutralizing anti-RBD antibodies have been identified, the nature of cross-reactive humoral responses induced by natural infection with ancestral SARS-CoV-2 strains remains incompletely understood. Here, we isolated 105 S-specific monoclonal antibodies (mAbs) from individuals recovered from prototype SARS-CoV-2 infection. Of these, 30 mAbs cross-recognized SARS-CoV-1, including 25 RBD-directed mAbs, of which 12 displayed cross-neutralizing activity against both viruses. Among them, mAb 12C2 potently neutralized SARS-CoV-1 and multiple SARS-CoV-2 variants, likely through mechanisms that include inhibition of membrane fusion and potential destabilization of the S trimer. Cryo-electron microscopy revealed that 12C2 engages the outer face of the RBD, overlapping with the epitope recognized by the broadly neutralizing antibody S309 derived from SARS-CoV-1 convalescent. Collectively, these findings demonstrate that ancestral SARS-CoV-2 infection can elicit robust cross-neutralizing antibody responses and provide valuable insights for the design of broadly protective antibodies and vaccines.