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

  • Lancet Infect Dis. 2023 Jul;23(7):856-866. doi: 10.1016/S1473-3099(23)00062-2.
Deidre Wilkins  1 ,  Annefleur C Langedijk  2 ,  Robert Jan Lebbink  3 ,  Christopher Morehouse  4 ,  Michael E Abram  1 ,  Bahar Ahani  4 ,  Anastasia A Aksyuk  1 ,  Eugenio Baraldi  5 ,  Tyler Brady  1 ,  Albert Tian Chen  6 ,  Hsin Chi  7 ,  Eun Hwa Choi  8 ,  Robert Cohen  9 ,  Daria M Danilenko  10 ,  Vancheswaran Gopalakrishnan  4 ,  Anne Greenough  11 ,  Terho Heikkinen  12 ,  Mitsuaki Hosoya  13 ,  Christian Keller  14 ,  Elizabeth J Kelly  1 ,  Leyla Kragten-Tabatabaie  15 ,  Federico Martinón-Torres  16 ,  Abiel Homero Mascareñas de Los Santos  17 ,  Marta C Nunes  18 ,  María Angélica Palomino  19 ,  Jesse Papenburg  20 ,  Jeffrey M Pernica  21 ,  Peter Richmond  22 ,  Renato T Stein  23 ,  Kevin M Tuffy  1 ,  Charl Verwey  24 ,  Mark T Esser  25 ,  David E Tabor  1 ,  Louis J Bont  26 ,  INFORM-RSV Study Group
Affiliations
  • 1. Translational Medicine, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
  • 2. Division of Paediatric Infectious Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, Netherlands.
  • 3. Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, Netherlands.
  • 4. Bioinformatics, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
  • 5. Woman's and Child's Health, Neonatal Intensive Care Unit, University of Padova, Padova, Italy; Institute of Pediatric Research, Città della Speranza, Padova, Italy.
  • 6. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Biological and Biomedical Sciences, Harvard University, Cambridge, MA, USA.
  • 7. Department of Paediatrics, MacKay Children's Hospital, Taipei, Taiwan.
  • 8. Department of Pediatrics, Seoul National University Children's Hospital, Seoul, South Korea.
  • 9. Université Paris XII, Créteil, FranceAssociation Clinique et Thérapeutique Infantile du Val-de-Marne (ACTIV), Créteil, France; Clinical Research Center, Centre Hospitalier Intercommunal de Créteil (CHIC), Créteil, France.
  • 10. Smorodintsev Research Institute of Influenza, Saint Petersburg, Russia.
  • 11. Department of Women and Children's Health, King's College London, London, UK; ReSViNET foundation, Zeist, Netherlands.
  • 12. ReSViNET foundation, Zeist, Netherlands; Department of Pediatrics, University of Turku, Turku, Finland; Department of Pediatrics, Turku University Hospital, Turku, Finland.
  • 13. School of Medicine, Fukushima Medical University, Fukushima, Japan.
  • 14. University Hospital Giessen and Marburg, Marburg, Germany.
  • 15. ReSViNET foundation, Zeist, Netherlands; Julius Clinical, Zeist, Netherlands.
  • 16. ReSViNET foundation, Zeist, Netherlands; Translational Paediatrics and Infectious Diseases, Paediatrics Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain; Genetics, Vaccines and Infections Research Group (GENVIP), Instituto de Investigación Sanitaria de Santiago, University of Santiago de Compostela, Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Translational Pediatrics and Infectious Diseases Section, Pediatrics Department, Hospital Clínico Universitario de Santiago, Galicia, Spain.
  • 17. Department of Pediatrics, Division of Infectious Diseases, Jose Eluterio Gonzalez Hospital Universitario, Monterrey, Mexico.
  • 18. ReSViNET foundation, Zeist, Netherlands; South African Medical Research Council, Vaccines and Infectious Diseases Analytics Research Unit, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Technology, National Research Foundation, South African Research Chair Initiative in Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa.
  • 19. Hospital Roberto del Río, Santiago, Chile.
  • 20. Department of Pediatrics, McGill University Health Centre, Montreal, QC, Canada.
  • 21. Division of Infectious Diseases, McMaster University, Hamilton, ON, Canada.
  • 22. Division of Pediatrics, School of Medicine, University of Western Australia, Perth, WA, Australia.
  • 23. ReSViNET foundation, Zeist, Netherlands; Pontificia Universidade Catolica de Rio Grande do Sul, Porto Alegre, Brazil.
  • 24. Department of Paediatrics and Child Health, School of Clinical Medicine and South African Medical Research Council, Vaccines and Infectious Diseases Analytics Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
  • 25. Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA. Electronic address: [email protected].
  • 26. Department of Paediatrics, University Medical Centre Utrecht, Utrecht, Netherlands; ReSViNET foundation, Zeist, Netherlands.
PMID: 36940703 DOI: 10.1016/S1473-3099(23)00062-2
Abstract

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.

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