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

INFORM-RSV Study Group

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

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

INFORM-RSV Study Group

Women & Children's Health

Statistical Innovation Group
UMC University Medical Center Utrecht
University of Padua
Città della Speranza
Broad Institute of MIT and Harvard
Harvard University
MacKay Children's Hospital
Seoul National University
Île-de-France
Centre Hospitalier Intercommunal de Créteil
Smorodintsev Research Institute of Influenza
Department of Women and Children's Health
King's College London
ReSViNET Foundation
University of Turku
Turku University Hospital
Fukushima Medical University
University Hospital Marburg
Julius Clinical
University Clinical Hospital of Santiago
Santiago de Compostela University
Centro de Investigación Biomédica en Red de Enfermedades Respiratorias
Jose Eluterio Gonzalez Hospital Universitario
University of the Witwatersrand
Hospital Roberto del Río
McGill University
McMaster University
University of Western Australia
Pontificia Universidade Catolica do Rio Grande do Sul
School of Pathology

Research output: Contribution to journal › Article › peer-review

104 Citations (Scopus)

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.

Original language	English
Pages (from-to)	856-866
Number of pages	11
Journal	The Lancet infectious diseases
Volume	23
Issue number	7
DOIs	https://doi.org/10.1016/S1473-3099(23)00062-2
Publication status	Published - Jul 2023

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1016/S1473-3099(23)00062-2

Cite this

@article{4ec3a7ba3eba461d8d56f3f5a2130eb1,

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

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.",

author = "Deidre Wilkins and Langedijk, \{Annefleur C.\} and Lebbink, \{Robert Jan\} and Christopher Morehouse and Abram, \{Michael E.\} and Bahar Ahani and Aksyuk, \{Anastasia A.\} and Eugenio Baraldi and Tyler Brady and Chen, \{Albert Tian\} and Hsin Chi and Choi, \{Eun Hwa\} and Robert Cohen and Danilenko, \{Daria M.\} and Vancheswaran Gopalakrishnan and Anne Greenough and Terho Heikkinen and Mitsuaki Hosoya and Christian Keller and Kelly, \{Elizabeth J.\} and Leyla Kragten-Tabatabaie and Federico Martin{\'o}n-Torres and \{de Los Santos\}, \{Abiel Homero Mascare{\~n}as\} and Nunes, \{Marta C.\} and Palomino, \{Mar{\'i}a Ang{\'e}lica\} and Jesse Papenburg and Pernica, \{Jeffrey M.\} and Peter Richmond and Stein, \{Renato T.\} and Tuffy, \{Kevin M.\} and Charl Verwey and Esser, \{Mark T.\} and Tabor, \{David E.\} and Bont, \{Louis J.\} and Pascale Clement and Atul Gupta and Koichi Hashimoto and Kseniya Komissarova and Matt Laubscher and Magali Lumertz and Elena Priante and Irene Rivero-Calle and Ushma Wadia and Yun, \{Ki Wook\} and \{INFORM-RSV Study Group\}",

note = "Funding Information: This work was supported by AstraZeneca and Sanofi. The OUTSMART-RSV and INFORM-RSV studies received funding from AstraZeneca. 16–18 Sample collection and logistical support for OUTSMART-RSV was provided by IQVIA, a contract research organisation. Sample collection and logistical support for INFORM-RSV was provided by Julius Clinical, an academic research organisation. IQVIA's and Julius Clinical's support for these studies was funded by AstraZeneca. The sequencing portion of the South African pilot study was supported by AstraZeneca. 20 The authors thank the study participants and their families and the investigators and research staff from INFORM-RSV, OUTSMART-RSV, and the South African pilot study laboratories who contributed data to this analysis. The authors acknowledge Rebecca A Bachmann of AstraZeneca (Cambridge, UK) for facilitating author discussion and providing strategic advice and critical review of the manuscript. Medical writing support was provided by Craig O'Hare of Ashfield MedComms, an Inizio company (Macclesfield, UK), which was in accordance with Good Publication Practice 2022 guidelines and funded by AstraZeneca and Sanofi. Funding Information: This work was supported by AstraZeneca and Sanofi. The OUTSMART-RSV and INFORM-RSV studies received funding from AstraZeneca. 16–18 Sample collection and logistical support for OUTSMART-RSV was provided by IQVIA, a contract research organisation. Sample collection and logistical support for INFORM-RSV was provided by Julius Clinical, an academic research organisation. IQVIA's and Julius Clinical's support for these studies was funded by AstraZeneca. The sequencing portion of the South African pilot study was supported by AstraZeneca. 20 The authors thank the study participants and their families and the investigators and research staff from INFORM-RSV, OUTSMART-RSV, and the South African pilot study laboratories who contributed data to this analysis. The authors acknowledge Rebecca A Bachmann of AstraZeneca (Cambridge, UK) for facilitating author discussion and providing strategic advice and critical review of the manuscript. Medical writing support was provided by Craig O'Hare of Ashfield MedComms, an Inizio company (Macclesfield, UK), which was in accordance with Good Publication Practice 2022 guidelines and funded by AstraZeneca and Sanofi. Publisher Copyright: {\textcopyright} 2023 Elsevier Ltd",

year = "2023",

month = jul,

doi = "10.1016/S1473-3099(23)00062-2",

language = "English",

volume = "23",

pages = "856--866",

journal = "The Lancet infectious diseases",

issn = "1473-3099",

publisher = "Elsevier",

number = "7",

}

TY - JOUR

T1 - Nirsevimab binding-site conservation in respiratory syncytial virus fusion glycoprotein worldwide between 1956 and 2021

T2 - an analysis of observational study sequencing data

AU - Wilkins, Deidre

AU - Langedijk, Annefleur C.

AU - Lebbink, Robert Jan

AU - Morehouse, Christopher

AU - Abram, Michael E.

AU - Ahani, Bahar

AU - Aksyuk, Anastasia A.

AU - Baraldi, Eugenio

AU - Brady, Tyler

AU - Chen, Albert Tian

AU - Chi, Hsin

AU - Choi, Eun Hwa

AU - Cohen, Robert

AU - Danilenko, Daria M.

AU - Gopalakrishnan, Vancheswaran

AU - Greenough, Anne

AU - Heikkinen, Terho

AU - Hosoya, Mitsuaki

AU - Keller, Christian

AU - Kelly, Elizabeth J.

AU - Kragten-Tabatabaie, Leyla

AU - Martinón-Torres, Federico

AU - de Los Santos, Abiel Homero Mascareñas

AU - Nunes, Marta C.

AU - Palomino, María Angélica

AU - Papenburg, Jesse

AU - Pernica, Jeffrey M.

AU - Richmond, Peter

AU - Stein, Renato T.

AU - Tuffy, Kevin M.

AU - Verwey, Charl

AU - Esser, Mark T.

AU - Tabor, David E.

AU - Bont, Louis J.

AU - Clement, Pascale

AU - Gupta, Atul

AU - Hashimoto, Koichi

AU - Komissarova, Kseniya

AU - Laubscher, Matt

AU - Lumertz, Magali

AU - Priante, Elena

AU - Rivero-Calle, Irene

AU - Wadia, Ushma

AU - Yun, Ki Wook

AU - INFORM-RSV Study Group

N1 - Funding Information: This work was supported by AstraZeneca and Sanofi. The OUTSMART-RSV and INFORM-RSV studies received funding from AstraZeneca. 16–18 Sample collection and logistical support for OUTSMART-RSV was provided by IQVIA, a contract research organisation. Sample collection and logistical support for INFORM-RSV was provided by Julius Clinical, an academic research organisation. IQVIA's and Julius Clinical's support for these studies was funded by AstraZeneca. The sequencing portion of the South African pilot study was supported by AstraZeneca. 20 The authors thank the study participants and their families and the investigators and research staff from INFORM-RSV, OUTSMART-RSV, and the South African pilot study laboratories who contributed data to this analysis. The authors acknowledge Rebecca A Bachmann of AstraZeneca (Cambridge, UK) for facilitating author discussion and providing strategic advice and critical review of the manuscript. Medical writing support was provided by Craig O'Hare of Ashfield MedComms, an Inizio company (Macclesfield, UK), which was in accordance with Good Publication Practice 2022 guidelines and funded by AstraZeneca and Sanofi. Funding Information: This work was supported by AstraZeneca and Sanofi. The OUTSMART-RSV and INFORM-RSV studies received funding from AstraZeneca. 16–18 Sample collection and logistical support for OUTSMART-RSV was provided by IQVIA, a contract research organisation. Sample collection and logistical support for INFORM-RSV was provided by Julius Clinical, an academic research organisation. IQVIA's and Julius Clinical's support for these studies was funded by AstraZeneca. The sequencing portion of the South African pilot study was supported by AstraZeneca. 20 The authors thank the study participants and their families and the investigators and research staff from INFORM-RSV, OUTSMART-RSV, and the South African pilot study laboratories who contributed data to this analysis. The authors acknowledge Rebecca A Bachmann of AstraZeneca (Cambridge, UK) for facilitating author discussion and providing strategic advice and critical review of the manuscript. Medical writing support was provided by Craig O'Hare of Ashfield MedComms, an Inizio company (Macclesfield, UK), which was in accordance with Good Publication Practice 2022 guidelines and funded by AstraZeneca and Sanofi. Publisher Copyright: © 2023 Elsevier Ltd

PY - 2023/7

Y1 - 2023/7

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85151344320

U2 - 10.1016/S1473-3099(23)00062-2

DO - 10.1016/S1473-3099(23)00062-2

M3 - Article

C2 - 36940703

AN - SCOPUS:85151344320

SN - 1473-3099

VL - 23

SP - 856

EP - 866

JO - The Lancet infectious diseases

JF - The Lancet infectious diseases

IS - 7

ER -

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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