Nirsevimab binding-site conservation in respiratory syncytial virus fusion glycoprotein worldwide between 1956 and 2021: an analysis of observational study sequencing data.
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Wilkins Deidre, Langedijk Annefleur C, Lebbink Robert Jan, Morehouse Christopher, Abram Michael E, Ahani Bahar, Aksyuk Anastasia A, Baraldi Eugenio, Brady Tyler, Chen Albert Tian, Chi Hsin, Choi Eun Hwa, Cohen Robert, Danilenko Daria M, Gopalakrishnan Vancheswaran, Greenough Anne, Heikkinen Terho, Hosoya Mitsuaki, Keller Christian, Kelly Elizabeth J, Kragten-Tabatabaie Leyla, Martinón-Torres Federico, de Los Santos Abiel Homero Mascareñas, Nunes Marta C, Palomino María Angélica, Papenburg Jesse, Pernica Jeffrey M, Richmond Peter, Stein Renato T, Tuffy Kevin M, Verwey Charl, Esser Mark T, Tabor David E, Bont Louis J, INFORM-RSV Study Group
Аннотация
METHODS: We assessed the geotemporal prevalence of RSV A and B and nirsevimab binding-site conservation between 2015 and 2021 from three prospective RSV molecular surveillance studies (the US-based OUTSMART-RSV, the global INFORM-RSV, and a pilot study in South Africa). Nirsevimab binding-site substitutions were assessed in an RSV microneutralisation susceptibility assay. We contextualised our findings by assessing fusion-protein sequence diversity from 1956 to 2021 relative to other respiratory-virus envelope glycoproteins using RSV fusion protein sequences published in NCBI GenBank.
FINDINGS: We identified 5675 RSV A and RSV B fusion protein sequences (2875 RSV A and 2800 RSV B) from the three surveillance studies (2015-2021). Nearly all (25 [100%] of 25 positions of RSV A fusion proteins and 22 [88%] of 25 positions of RSV B fusion proteins) amino acids within the nirsevimab binding site remained highly conserved between 2015 and 2021. A highly prevalent (ie, >40·0% of all sequences) nirsevimab binding-site Ile206Met:Gln209Arg RSV B polymorphism arose between 2016 and 2021. Nirsevimab neutralised a diverse set of recombinant RSV viruses, including new variants containing binding-site substitutions. RSV B variants with reduced susceptibility to nirsevimab neutralisation were detected at low frequencies (ie, prevalence <1·0%) between 2015 and 2021. We used 3626 RSV fusion-protein sequences published in NCBI GenBank between 1956 and 2021 (2024 RSV and 1602 RSV B) to show that the RSV fusion protein had lower genetic diversity than influenza haemagglutinin and SARS-CoV-2 spike proteins.
INTERPRETATION: The nirsevimab binding site was highly conserved between 1956 and 2021. Nirsevimab escape variants were rare and have not increased over time.
FUNDING: AstraZeneca and Sanofi.