Nirsevimab binding-site conservation in respiratory syncytial virus fusion glycoprotein worldwide between 1956 and 2021: an analysis of observational study sequencing data.

Background: Nirsevimab is an extended half-life monoclonal antibody to the respiratory syncytial virus (RSV) fusion protein that has been developed to protect infants for an entire RSV season. Previous studies have shown that the nirsevimab binding site is highly conserved. However, investigations of the geotemporal evolution of potential escape variants in recent (ie, 2015-2021) RSV seasons have been minimal. Here, we examine prospective RSV surveillance data to assess the geotemporal prevalence of RSV A and B, and functionally characterise the effect of the nirsevimab binding-site substitutions identified between 2015 and 2021.
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.
Competing Interests: Declaration of interests DW, CM, BA, AAA, TB, VG, EJK, KMT, and MTE are current employees of and hold stock or stock options in AstraZeneca. MEA and DET are former employees of and hold stock or stock options in AstraZeneca. EB has received honoraria from AstraZeneca and Sanofi for lectures, presentations, speaker bureaus, manuscript writing, or educational events. TH has participated in Data Safety Monitoring Boards and ad-hoc advisory boards for Sanofi, Data Safety Monitoring Boards for Enanta, and ad-hoc advisory boards for Janssen and has received honoraria from Janssen and Merck, Sharp & Dohme (MSD) for lectures at academic meetings. CK has received honoraria from F Hoffmann-La Roche for lectures. FM-T's research activities are supported by grants from Instituto de Salud Carlos III (grant numbers: PI16/01569, PI19/01090, PI22/00406, and CB21/06/00103), GEN-COVID (grant number: IN845D 2020/23), and Grupos de Referencia Competitiva (grant number: IIN607A2021/05), and he has received additional grants to his institution from AstraZeneca and Sanofi; he also received honoraria from GlaxoSmithKline, Pfizer, Sanofi Pasteur, MSD, Seqirus, Biofabri, and Janssen for taking part in advisory boards and expert meetings and for acting as speaker in congresses outside the scope of the submitted work, in addition to travel support from GlaxoSmithKline, MSD, Pfizer, and Sanofi. FM-T has also participated in advisory boards for Pfizer, MSD, Sanofi, and GlaxoSmithKline, and in Data Safety Monitoring Boards for Biofabri; is a member of The European Technical Advisory Group of Experts—WHO Europe and the Spanish Paediatric Infectious Diseases Society; and has also acted as principal investigator in randomised controlled trials for AstraZeneca, Biofabri Seqirus, GlaxoSmithKline, Janssen, MSD, Novavax, Novartis, Pfizer, Roche, Regeneron, and Sanofi Pasteur with honoraria paid to his institution. MCN has received grants from the Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials, Pfizer, and Sanofi Pasteur; honoraria from Sanofi for lectures presentations, speakers' bureaus, manuscript writing or educational events; payment for expert testimony from Pfizer and Sanofi Pasteur; and is a board member for Gavi vaccine alliance. JMP has received payments to his institution from the Canadian Paediatric Review and Yearly RSV Coordinators Workshop and is an unpaid co-chair of the Ontario Immunization Advisory Committee. PR has received investigator-initiated research grants to his institution from MSD and has received institutional funding from GlaxoSmithKline for local and international lectures and from AstraZeneca, GlaxoSmithKline, MSD, Sanofi, and Pfizer for participation in advisory boards. RTS has received payment or honoraria for lectures for AstraZeneca, Pfizer, and Sanofi Pasteur. CV has received payment or honoraria for lectures from AstraZeneca. LJB has not received personal fees or other personal benefits from pharmaceutical companies. His institution, University Medical Center Utrecht (UMCU), has received major funding (>€100 000 per industrial partner) from AbbVie, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics for investigator-initiated studies. UMCU has received major funding for the RSV-GOLD study from the Bill & Melinda Gates Foundation. UMCU has received major funding as part of the public private partnership IMI-funded RESCEU and PROMISE projects with partners GlaxoSmithKline, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi Pasteur. UMCU has received major funding by Julius Clinical for participating in clinical studies sponsored by AstraZeneca and Pfizer. UMCU has received minor funding (€1 000–25 000 per industrial partner) for consultation and invited lectures by AbbVie, AstraZeneca, Ablynx, Bavaria Nordic, MabXience, GlaxoSmithKline, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, Genzyme, and Janssen. LJB is the founding chairman of the ReSViNET Foundation. All other authors declare no competing interests.
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