Background

Nirsevimab, a long-acting monoclonal antibody, has been approved for the prevention of respiratory syncytial virus (RSV) infection in infants. In France, more than 210 000 single doses were administered in infants younger than 1 year during the 2023–24 season. In this context, the selection and spread of escape variants might be a concern. Here, we aimed to characterise RSV associated with breakthrough infection.

Methods

We did a multicentre, national, observational study in France during the 2023–24 RSV season in RSV-infected infants (aged <1 year) who either received or did not receive a dose of nirsevimab before their first RSV season. We excluded infants with insufficient information about nirsevimab treatment or without parental consent. We used respiratory samples collected in each laboratory for full-length RSV RNA sequencing to analyse changes in the nirsevimab binding site Ø. We tested clinical RSV isolates for neutralisation by nirsevimab. We analysed F candidate substitutions by fusion-inhibition assay.

Findings

Of the 695 RSV infected infants, we analysed 545 (78%) full-length RSV genome sequences: 260 (48%) from nirsevimab-treated breakthrough infections (236 [91%] RSV-A and 24 [9%] RSV-B) and 285 (52%) from untreated RSV-infected infants (236 [83%] RSV-A and 49 [17%] RSV-B). Analysis of RSV-A did not reveal any substitution in site Ø known to be associated with resistance to nirsevimab. Two (8%) of 24 RSV-B breakthrough infections had resistance-associated substitutions: F:N208D (dominant resistance-associated substitution) and a newly described F:I64M plus F:K65R combination (minority resistance-associated substitution), both of which induced high levels of resistance in the fusion-inhibition assay.

Interpretation

This study is, to the best of our knowledge, the largest genotypic and phenotypic surveillance study of nirsevimab breakthrough infections to date. Nirsevimab breakthrough variants remain very rare despite the drug's widespread use. The detection of resistance-associated substitutions in the RSV-B F protein highlights the importance of active molecular surveillance.

Funding

ANRS Maladies Infectieuses Emergentes and the French Ministry of Health and Prevention.

中文翻译：

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nirsevimab 突破性感染后呼吸道合胞病毒的基因型和表型特征：一项大型、多中心、观察性、真实世界研究

 背景

Nirsevimab 是一种长效单克隆抗体，已被批准用于预防婴儿呼吸道合胞病毒 （RSV） 感染。在法国，在 2023-24 赛季期间，对 1 岁以下婴儿接种了超过 210 000 剂单剂疫苗。在这种情况下，逃逸变体的选择和传播可能是一个问题。在这里，我们旨在表征与突破性感染相关的 RSV。

 方法

我们在 2023-24 年 RSV 季节在法国进行了一项多中心、全国、观察性研究，对象是 RSV 感染婴儿（年龄 <1 岁），这些婴儿在第一个 RSV 季节之前接受或未接受一剂 nirsevimab。我们排除了关于 nirsevimab 治疗信息不足或未经父母同意的婴儿。我们使用每个实验室收集的呼吸道样本进行全长 RSV RNA 测序，以分析 nirsevimab 结合位点 Ø 的变化。我们测试了临床 RSV 分离株对 nirsevimab 的中和作用。我们通过融合抑制试验分析了 F 候选取代。

 发现

在 695 名 RSV 感染婴儿中，我们分析了 545 个 （78%） 全长 RSV 基因组序列：260 个 （48%） 来自 nirsevimab 治疗的突破性感染 （236 个 [91%] RSV-A 和 24 个 [9%] RSV-B） 和 285 个 （52%） 来自未经治疗的 RSV 感染婴儿 （236 个 [83%] RSV-A 和 49 个 [17%] RSV-B）。RSV-A 的分析未发现已知与 nirsevimab 耐药性相关的位点 Ø 中的任何替换。24 例 RSV-B 突破性感染中有 2 例 （8%） 具有耐药相关替代：F：N208D （显性耐药相关替代） 和新描述的 F：I64M 加 F：K65R 组合 （少数耐药相关替代），这两者都在融合抑制测定中诱导了高水平的耐药。

 解释

据我们所知，这项研究是迄今为止最大的 nirsevimab 突破性感染的基因型和表型监测研究。尽管 Nirsevimab 药物被广泛使用，但该药物的突破性变体仍然非常罕见。RSV-B F 蛋白中耐药相关替换的检测突出了主动分子监测的重要性。

 资金

ANRS 疾病感染紧急和法国卫生与预防部。