RSV F Mutational Scan Finds Antibody Resistance Rare

A study published September 16, 2026, in Nature used pseudovirus deep mutational scanning to measure how nearly all single amino acid mutations in the respiratory syncytial virus (RSV) fusion protein (F) affect cell entry and neutralization by nirsevimab, clesrovimab, and several other antibodies. In RSV sequences, variants with high predicted escape scores for nirsevimab or clesrovimab represented less than 1% of sequences and were dispersed across phylogenetic trees, suggesting sporadic emergence without sustained spread.

Investigators created two pseudovirus libraries using F from the laboratory-adapted subtype A Long strain, with each containing nearly all possible amino acid mutations in the F ectodomain. The particles encoded no viral protein other than F and could undergo only one round of cell entry. The team measured entry into 293T cells expressing the TIM1 attachment factor and tested neutralization by IgG and Fab forms of the antibodies.

A biophysical model and neutralization experiments indicated that bivalent IgG binding can buffer mutations that reduce Fab affinity when baseline affinity is sufficiently high. The substitutions K68Q and K201S or N201S reduced nirsevimab Fab neutralization in subtype A and B backgrounds, but reduced IgG neutralization only in subtype B, consistent with nirsevimab’s higher affinity for subtype A F.

Mutations affecting nirsevimab neutralization clustered at residues 64-73 and 201-216, whereas those most affecting clesrovimab occurred at residues 426-470. When investigators tested natural strains with high escape scores, nearly all showed reduced neutralization compared with controls with low scores.

The analysis measured single mutations in one subtype A background, and the additive escape-score model overpredicted resistance for one subtype A strain with a high nirsevimab score, possibly because of an interaction between nearby mutations. The researchers incorporated the resistance scores into real-time Nextstrain phylogenies and an online experimental-data interface to support continued surveillance.

Source: Simonich CAL, McMahon TE, Juviler G, Kampman L, Chu HY, Bloom JD. Mutational constraints on RSV F and its neutralization by antibodies. Nature. Published online September 16, 2026. doi:10.1038/s41586-026-11030-4