Systematic review of the mutations in the active antigenic site &#xd8; of the prefusion F protein of the Respiratory Syncytial Virus (RSV) following the implementation of monoclonal antibody prophylaxis.

Maria M Berikopoulou; Elizabeth-Barbara Tatsi; Tania Siahanidou; Athanasios Michos

doi:10.1016/j.vaccine.2026.129069

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Systematic review of the mutations in the active antigenic site Ø of the prefusion F protein of the Respiratory Syncytial Virus (RSV) following the implementation of monoclonal antibody prophylaxis.

Maria M Berikopoulou·Elizabeth-Barbara Tatsi·Tania Siahanidou·Athanasios Michos

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Abstract

BACKGROUND: Monoclonal antibody (mAb) nirsevimab, which targets the antigenic site Ø of the prefusion F protein (pre-F) of RSV, was introduced for RSV prophylaxis in several countries. METHODS: A systematic search was conducted between January 1, 2022, and July 31, 2026 for studies analyzing substitutions within the epitope of pre-F RSV protein, which is the target of nirsevimab, after the implementation of the mAb. We searched across PubMed, Scopus, Web of Science and ClinicalTrial.gov for studies involving children with confirmed RSV infection, that conducted genomic analysis. RESULTS: Seven studies (five observational and two randomized controlled trials) including 2156 RSV-positive samples (RSV-A: 1347, RSV-B: 809) were analyzed. RSV-A strains showed limited variability within antigenic site Ø, with K65R being the most common substitution and K209E being the only intermediate-resistance RSV-A substitution. RSV-B strains demonstrated substantially higher substitution frequencies, particularly involving I206M, Q209R, and S211N. Most identified substitutions appeared to represent naturally occurring polymorphisms and retained susceptibility to nirsevimab, while multiple RSV-B substitutions and combinations involving residues 64-68 and 204-208 demonstrated reduced susceptibility or high-level resistance. Resistance-associated variants were detected in 28 of 2156 (1.3%) RSV-positive samples and exclusively among nirsevimab breakthrough infections. In a sub-analysis restricted to nirsevimab-treated individuals, resistance-associated variants were significantly more frequent among RSV-B than RSV-A (9.8% vs 0.5%; p < 0.001). CONCLUSION: Most substitutions that were detected within the nirsevimab antigenic site reflect ongoing natural RSV evolution and do not significantly affect nirsevimab susceptibility. However, detection of resistance-associated variants highlights the importance of continuous genomic and phenotypic surveillance.

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Humans Respiratory Syncytial Virus Infections Respiratory Syncytial Virus, Human Mutation Viral Fusion Proteins Antibodies, Monoclonal Drug Resistance, Viral Epitopes Antibodies, Monoclonal, Humanized Antiviral Agents Fusion protein Nirsevimab RSV Respiratory Syncytial Virus Substitutions Journal Article Systematic Review Review

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Maria M Berikopoulou, Elizabeth-Barbara Tatsi, Tania Siahanidou, Athanasios Michos. 2026-08-22. Systematic review of the mutations in the active antigenic site Ø of the prefusion F protein of the Respiratory Syncytial Virus (RSV) following the implementation of monoclonal antibody prophylaxis.. https://doi.org/10.1016/j.vaccine.2026.129069

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Antibodies, Monoclonal, Humanized subject Humans subject Journal Article subject Journal Article; Systematic Review; Review resource Mutation subject Systematic reviews study

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