Translational Medicine, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
Division of Paediatric Infectious Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, Netherlands.
Lancet Infect Dis. 2023 Jul;23(7):856-866. doi: 10.1016/S1473-3099(23)00062-2. Epub 2023 Mar 17.
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.
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.
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.
The nirsevimab binding site was highly conserved between 1956 and 2021. Nirsevimab escape variants were rare and have not increased over time.
AstraZeneca and Sanofi.
尼瑞斯单抗是一种针对呼吸道合胞病毒（RSV）融合蛋白的延长半衰期单克隆抗体，旨在为婴儿提供整个 RSV 季节的保护。先前的研究表明，尼瑞斯单抗的结合位点高度保守。然而，对最近（即 2015-2021 年）RSV 季节潜在逃逸变异的地理时空演变的研究很少。在这里，我们检查了前瞻性 RSV 监测数据，以评估 RSV A 和 B 的地理时空流行率，并对 2015 年至 2021 年间确定的尼瑞斯单抗结合位点取代的功能特征进行了评估。
我们从三个前瞻性 RSV 分子监测研究（美国的 OUTSMART-RSV、全球的 INFORM-RSV 和南非的试点研究）评估了 2015 年至 2021 年期间 RSV A 和 B 以及尼瑞斯单抗结合位点保守性的地理时空流行率。在 RSV 微量中和敏感性测定中评估了尼瑞斯单抗结合位点取代。我们通过评估 1956 年至 2021 年期间相对于其他呼吸道病毒包膜糖蛋白的 RSV 融合蛋白序列多样性，从 NCBI GenBank 中发布的 RSV 融合蛋白序列来评估我们的发现。
我们从三个监测研究（2015-2021 年）中确定了 5675 个 RSV A 和 RSV B 融合蛋白序列（2875 个 RSV A 和 2800 个 RSV B）。在 2015 年至 2021 年期间，尼瑞斯单抗结合位点的几乎所有（25 [100%] RSV A 融合蛋白的 25 个位置和 22 [88%] RSV B 融合蛋白的 25 个位置）氨基酸都高度保守。2016 年至 2021 年期间，一种高度流行的（即，>40.0%的所有序列）尼瑞斯单抗结合位点 Ile206Met:Gln209Arg RSV B 多态性出现。尼瑞斯单抗中和了一组多样化的重组 RSV 病毒，包括含有结合位点取代的新变体。2015 年至 2021 年间，尼瑞斯单抗中和的 RSV B 变体的检测频率较低（即，流行率<1.0%）。我们使用了 NCBI GenBank 中 1956 年至 2021 年期间发表的 3626 个 RSV 融合蛋白序列（2024 个 RSV 和 1602 个 RSV B），以表明 RSV 融合蛋白的遗传多样性低于流感血凝素和 SARS-CoV-2 刺突蛋白。
尼瑞斯单抗的结合位点在 1956 年至 2021 年期间高度保守。尼瑞斯单抗逃逸变异很少，而且随着时间的推移并没有增加。
阿斯利康和赛诺菲。
