在接受尼塞韦单抗突破性感染后呼吸道合胞病毒的基因和表型特征：一项大型、多中心、观察性、真实世界研究。
Genotypic and phenotypic characterisation of respiratory syncytial virus after nirsevimab breakthrough infections: a large, multicentre, observational, real-world study.
作者信息
Fourati Slim, Reslan Alawiya, Bourret Jérome, Casalegno Jean-Sébastien, Rahou Yannis, Chollet Lionel, Pillet Sylvie, Tremeaux Pauline, Dossou Nefert Candace, Gault Elyanne, Salmona Maud, Imbert-Marcille Berthe-Marie, Mirand Audrey, Larrat Sylvie, Moisan Alice, Marot Stéphane, Schnuriger Aurélie, Veyrenche Nicolas, Engelmann Ilka, Handala Lynda, Henry Amandine, Stephan Valentin, Brichler Ségolène, Avettand-Fenoel Véronique, Zemali Nael, Lefeuvre Caroline, Pronier Charlotte, Deroche Luc, Jaffar-Bandjee Marie-Christine, Mouna Lina, Francois Catherine, Regueme Alexandre, Hartard Cédric, Rogez Sylvie, Gallais Floriane, Ly Arnaud, Rodriguez Christophe, Dos Santos Georges, Simon-Loriere Etienne, Schwartz Olivier, Buchrieser Julian, Pawlotsky Jean-MiIchel, Lemoine Frédéric, Audureau Etienne, Rameix-Welti Marie-Anne
机构信息
Department of Virology, Hôpitaux Universitaires Henri Mondor, AP-HP, Créteil, France; Université Paris-Est-Créteil, Créteil, France; INSERM U955, Team Viruses, Hepatology, Cancer, Créteil, France.
M3P, UMR 1173 (2I), INSERM, Université de Versailles St Quentin, Université Paris Saclay, Paris, France; M3P Centre National de Référence Virus des Infections Respiratoire Institut Pasteur Université Paris Cité, Paris, France.
出版信息
Lancet Infect Dis. 2025 Mar;25(3):301-311. doi: 10.1016/S1473-3099(24)00570-X. Epub 2024 Oct 14.
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.
背景
长效单克隆抗体尼塞韦单抗已被批准用于预防婴儿呼吸道合胞病毒（RSV）感染。在法国，2023 - 24季节期间，对1岁以下婴儿接种了超过21万剂单剂量疫苗。在这种情况下，逃逸变体的选择和传播可能令人担忧。在此，我们旨在对与突破性感染相关的RSV进行特征描述。
方法
我们在法国2023 - 24年RSV季节期间，对RSV感染婴儿（年龄<1岁）进行了一项多中心、全国性的观察性研究，这些婴儿在首个RSV季节之前接受或未接受尼塞韦单抗剂量。我们排除了尼塞韦单抗治疗信息不足或未获得家长同意的婴儿。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，以分析尼塞韦单抗结合位点Ø的变化。我们测试临床RSV分离株对尼塞韦单抗的中和作用。我们通过融合抑制试验分析F候选替代物。
结果
在695例RSV感染婴儿中，我们分析了545例（78%）全长RSV基因组序列：260例（48%）来自接受尼塞韦单抗治疗的突破性感染（236例[91%] RSV - A和24例[9%] RSV - B），285例（52%）来自未治疗的RSV感染婴儿（236例[83%] RSV - A和49例[17%] RSV - B）。对RSV - A的分析未发现已知与尼塞韦单抗耐药相关的位点Ø有任何替代。24例RSV - B突破性感染中有2例（8%）具有耐药相关替代：F:N208D（主要耐药相关替代）和新描述的F:I64M加F:K65R组合（次要耐药相关替代），两者在融合抑制试验中均诱导了高水平耐药。
解读
据我们所知，本研究是迄今为止关于尼塞韦单抗突破性感染的最大规模的基因型和表型监测研究。尽管该药物广泛使用，但尼塞韦单抗突破性变体仍然非常罕见。在RSV - B F蛋白中检测到耐药相关替代凸显了主动分子监测的重要性。
资金来源
法国国家艾滋病研究机构（ANRS）新兴传染病项目以及法国卫生与预防部。
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