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

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Nirsevimab, a monoclonal antibody, was approved in 2023 by the US FDA for preventing respiratory syncytial virus (RSV) infections in infants.
• Passive immunotherapy represents a significant advancement in viral infection prevention.
• Initial studies indicated that the nirsevimab binding site on the RSV-A F protein remained unaffected in breakthrough infections.

Purpose of the Study:

• To investigate potential nirsevimab-resistant mutations outside the primary antibody binding site.
• To analyze the mutation landscape of RSV-A at a single-genome level after nirsevimab exposure.

Main Methods:

• Single-genome sequencing of RSV-A to identify mutations.
• Assessment of the S190R mutation's impact on nirsevimab binding and neutralization.
• Analysis of S190R RSV-A replication in cell lines and human organoids.

Main Results:

• A specific amino acid substitution, S190R, was identified at antigenic site V of the RSV-A F protein in most viruses post-nirsevimab exposure.
• The S190R mutation was shown to decrease nirsevimab's binding and neutralization efficacy by affecting antibody access to site Ø epitopes.
• Replication studies revealed that the S190R mutation compromises the viral fitness of RSV-A.

Conclusions:

• The S190R mutation represents a potential viral mechanism for escaping nirsevimab-mediated immunity.
• Understanding these resistance mechanisms is crucial for developing and maintaining effective RSV prevention strategies.