Nirsevimab binding-site conservation in respiratory syncytial virus fusion glycoprotein worldwide between 1956 and 2021: an analysis of observational study sequencing data - 29/06/23

Doi : 10.1016/S1473-3099(23)00062-2

Deidre Wilkins, BSc ^a, Annefleur C Langedijk, MSc ^e, Robert Jan Lebbink, PhD ^f, Christopher Morehouse, MSc ^b, Michael E Abram, PhD ^a, Bahar Ahani, BSc ^b, Anastasia A Aksyuk, PhD ^a, Eugenio Baraldi, MD ^g,^h, Tyler Brady, MPH ^a, Albert Tian Chen, BEng ^i,^j, Hsin Chi, MD ^k, Eun Hwa Choi, MD ^l, Robert Cohen, MD ^m,ⁿ, Daria M Danilenko, PhD ^o, Vancheswaran Gopalakrishnan, PhD ^b, Anne Greenough, MD ^p,^q, Terho Heikkinen, MD ^q,^r,^s, Mitsuaki Hosoya, PhD ^t, Christian Keller, MD ^u, Elizabeth J Kelly, PhD ^a, Leyla Kragten-Tabatabaie, MD ^q,^v, Federico Martinón-Torres, PhD ^q,^w,^x,^y,^z, Abiel Homero Mascareñas de Los Santos, MD ^aa, Marta C Nunes, PhD ^q,^ab,^ac, María Angélica Palomino, MD ^ae, Jesse Papenburg, MD ^af, Jeffrey M Pernica, MD ^ag, Peter Richmond, MD ^ah, Renato T Stein, MD ^q,^ai, Kevin M Tuffy, MSc ^a, Charl Verwey, PhD ^ad, Mark T Esser, PhD ^c,⁎ , David E Tabor, PhD ^a, Louis J Bont, MD ^d,^q
on behalf of the
INFORM-RSV Study Group^{^†}
Members listed in appendix

Pascale Clement, Atul Gupta, Koichi Hashimoto, Kseniya Komissarova, Matt Laubscher, Magali Lumertz, Elena Priante, Irene Rivero-Calle, Ushma Wadia, Ki Wook Yun

^a Translational Medicine, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA

^b Bioinformatics, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA

^c Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA

^d Department of Paediatrics, University Medical Centre Utrecht, Utrecht, Netherlands

^e Division of Paediatric Infectious Diseases, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, Netherlands

^f Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, Netherlands

^g Woman’s and Child’s Health, Neonatal Intensive Care Unit, University of Padova, Padova, Italy

^h Institute of Pediatric Research, Città della Speranza, Padova, Italy

ⁱ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

^j Biological and Biomedical Sciences, Harvard University, Cambridge, MA, USA

^k Department of Paediatrics, MacKay Children’s Hospital, Taipei, Taiwan

^l Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, South Korea

^m Université Paris XII, Créteil, FranceAssociation Clinique et Thérapeutique Infantile du Val-de-Marne (ACTIV), Créteil, France

ⁿ Clinical Research Center, Centre Hospitalier Intercommunal de Créteil (CHIC), Créteil, France

^o Smorodintsev Research Institute of Influenza, Saint Petersburg, Russia

^p Department of Women and Children’s Health, King’s College London, London, UK

^q ReSViNET foundation, Zeist, Netherlands

^r Department of Pediatrics, University of Turku, Turku, Finland

^s Department of Pediatrics, Turku University Hospital, Turku, Finland

^t School of Medicine, Fukushima Medical University, Fukushima, Japan

^u University Hospital Giessen and Marburg, Marburg, Germany

^v Julius Clinical, Zeist, Netherlands

^w Translational Paediatrics and Infectious Diseases, Paediatrics Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain

^x Genetics, Vaccines and Infections Research Group (GENVIP), Instituto de Investigación Sanitaria de Santiago, University of Santiago de Compostela, Santiago de Compostela, Spain

^y Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain

^z Translational Pediatrics and Infectious Diseases Section, Pediatrics Department, Hospital Clínico Universitario de Santiago, Galicia, Spain

^aa Department of Pediatrics, Division of Infectious Diseases, Jose Eluterio Gonzalez Hospital Universitario, Monterrey, Mexico

^ab South African Medical Research Council, Vaccines and Infectious Diseases Analytics Research Unit, University of the Witwatersrand, Johannesburg, South Africa

^ac Department of Science and Technology, National Research Foundation, South African Research Chair Initiative in Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa

^ad 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

^ae Hospital Roberto del Río, Santiago, Chile

^af Department of Pediatrics, McGill University Health Centre, Montreal, QC, Canada

^ag Division of Infectious Diseases, McMaster University, Hamilton, ON, Canada

^ah Division of Pediatrics, School of Medicine, University of Western Australia, Perth, WA, Australia

^ai Pontificia Universidade Catolica de Rio Grande do Sul, Porto Alegre, Brazil

^* Correspondence to: Dr Mark T Esser, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA Vaccines & Immune Therapies BioPharmaceuticals R&D AstraZeneca Gaithersburg MD 20878 USA

Summary

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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Esquema

Introduction

Methods

Prospective RSV molecular epidemiology studies

Assignment of RSV subtypes and reference strains

RSV fusion protein amino-acid sequence variation analysis

Assessment of genetic variability in prospective molecular epidemiology studies

RSV microneutralisation susceptibility assay

Phylogenetic analysis of RSV, influenza, and SARS-CoV-2 viral fusion proteins

Statistical analysis

Role of the funding source

Results

Discussion

Data sharing

Exportación

Vol 23 - N° 7

P. 856-866 - juillet 2023 Regresar al número

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Nirsevimab binding-site conservation in respiratory syncytial virus fusion glycoprotein worldwide between 1956 and 2021: an analysis of observational study sequencing data - 29/06/23

Summary

Background

Methods

Findings

Interpretation

Funding

Esquema

Exportación citas

Fichero

Contenido

Mi cuenta

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Declaración CNIL