# The S190R mutation in RSV-A F protein impairs nirsevimab binding and neutralization capacity

## TL;DR

A new mutation in the RSV-A virus reduces the effectiveness of nirsevimab, a drug used to prevent RSV infections in infants.

## Contribution

The study identifies the S190R mutation as a novel RSV-A escape mechanism from nirsevimab.

## Key findings

- The S190R mutation in RSV-A F protein reduces nirsevimab binding and neutralization.
- The mutation alters antibody accessibility to site Ø epitopes.
- The S190R mutation impairs RSV-A viral fitness in cell and organoid models.

## Abstract

In 2023, the US Food and Drug Administration approved the use of nirsevimab for the prevention of respiratory syncytial virus (RSV) infections in healthy infants. This marks an important milestone for using passive immunotherapy for the prevention of viral infections. Previous studies that examined RSV-A sequences from breakthrough infection of nirsevimab-treated infants indicated that the nirsevimab binding site in the RSV-A F protein remained intact. To explore possible nirsevimab-resistant mutations that occur outside the antibody binding site, we have dissected the RSV-A mutations landscape at a single-genome resolution following exposure to nirsevimab. We identified a single amino acid substitution (S190R) at the antigenic site V of the RSV-A F protein that emerged in the vast majority of the isolated viruses. We further demonstrated that the S190R mutation reduces the binding and neutralization capacity of nirsevimab by altering antibody accessibility to site Ø epitopes. Additionally, by analysing the replication of S190R RSV-A in cell lines and in primary human organoids, we illustrated that the S190R mutation impairs the viral fitness of RSV-A. Thus, our study provides insight into possible viral mechanisms that can contribute to RSV-A escape from nirsevimab-based immunization.