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
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 - 2023/7/1
Y1 - 2023/7/1
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 - http://www.scopus.com/inward/record.url?scp=85151344320&partnerID=8YFLogxK
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 -