从医学上脆弱的儿童中分离出的呼吸道合胞病毒株的分子和表型特征：尼司特韦单抗（MEDLEY）的 2/3 期随机、双盲、帕利珠单抗对照试验的探索性分析。
Molecular and phenotypic characteristics of respiratory syncytial virus isolates recovered from medically vulnerable children: An exploratory analysis of a phase 2/3 randomized, double-blind, palivizumab-controlled trial of nirsevimab (MEDLEY).
机构信息
Translational Medicine, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
Bioinformatics, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
出版信息
Vaccine. 2024 Oct 24;42(24):126276. doi: 10.1016/j.vaccine.2024.126276. Epub 2024 Sep 5.
BACKGROUND
Nirsevimab is an extended half-life monoclonal antibody (mAb) licensed for the prevention of respiratory syncytial virus (RSV)-associated lower respiratory tract disease in neonates, infants and medically vulnerable children. We characterized RSV isolates recovered from participants enrolled in MEDLEY: a randomized, palivizumab-controlled phase 2/3 trial of nirsevimab in infants born preterm and/or with congenital heart disease or chronic lung disease of prematurity.
METHODS
Participants were assessed in two RSV seasons (Season 1 and 2). Season 1 participants were randomized (2:1) to receive a single dose of nirsevimab (50 mg if weight <5 kg or 100 mg if weight ≥5 kg in Season 1; 200 mg in Season 2) followed by four monthly doses of placebo, or five once-monthly doses of palivizumab (15 mg/kg weight per dose). Season 2 participants continued nirsevimab and placebo (nirsevimab/nirsevimab) or were re-randomized (1:1) to switch to nirsevimab (palivizumab/nirsevimab) or continue palivizumab (palivizumab/palivizumab). Cases of RSV infection were identified by central testing of nasal swabs from participants seeking medical attention for respiratory illnesses. Nirsevimab and palivizumab binding site substitutions were assessed via microneutralization assay.
RESULTS
Twenty-five cases of confirmed RSV infection were observed during the trial and sequenced: 12 in nirsevimab recipients and 10 in palivizumab recipients during Season 1, and 1 case in each Season 2 group. Molecular sequencing of RSV A (n = 14) isolates detected no nirsevimab binding site substitutions, and 3 palivizumab neutralization-resistant substitutions (Lys272Met, Lys272Thr, Ser275Leu). The nirsevimab binding site Ile206Met:Gln209Arg and Ile206Met:Gln209Arg:Ser211Asn substitutions were the only anti-RSV mAb binding site substitutions detected among RSV B isolates (n = 11). Nirsevimab neutralized all nirsevimab and palivizumab binding site substitutions in RSV A and B isolates recovered from MEDLEY participants.
CONCLUSION
No binding site substitution detected during MEDLEY affected RSV susceptibility to nirsevimab neutralization.
背景
尼赛珠单抗是一种半衰期延长的单克隆抗体（mAb），已获得许可，可用于预防呼吸道合胞病毒（RSV）相关的下呼吸道疾病，适用于新生儿、婴儿和医学上易感染的儿童。我们对参加 MEDLEY 研究的参与者中分离出的 RSV 株进行了特征描述：这是一项尼赛珠单抗在早产儿和/或患有先天性心脏病或早产儿慢性肺疾病的婴儿中进行的随机、帕利珠单抗对照的 2/3 期试验。
方法
参与者在两个 RSV 季节（第 1 季和第 2 季）进行评估。第 1 季参与者按 2:1 随机分配接受单剂量尼赛珠单抗（50mg，如果体重<5kg；如果体重≥5kg，在第 1 季则为 100mg；在第 2 季则为 200mg），随后接受 4 剂每月一次的安慰剂，或 5 剂每月一次的帕利珠单抗（每次 15mg/kg 体重）。第 2 季参与者继续接受尼赛珠单抗和安慰剂（尼赛珠单抗/尼赛珠单抗），或重新随机分配（1:1）为转为尼赛珠单抗（帕利珠单抗/尼赛珠单抗）或继续帕利珠单抗（帕利珠单抗/帕利珠单抗）。通过对因呼吸疾病寻求医疗关注的参与者的鼻拭子进行中心检测，确定 RSV 感染病例。通过微量中和试验评估尼赛珠单抗和帕利珠单抗的结合部位取代情况。
结果
在试验期间观察到 25 例确诊 RSV 感染病例，并对其进行了测序：第 1 季中，尼赛珠单抗组 12 例，帕利珠单抗组 10 例，第 2 季每组各 1 例。对 RSV A（n=14）分离株的分子测序未检测到尼赛珠单抗结合部位取代，检测到 3 个帕利珠单抗中和耐药取代（Lys272Met、Lys272Thr、Ser275Leu）。在 RSV B 分离株（n=11）中仅检测到尼赛珠单抗结合部位 Ile206Met：Gln209Arg 和 Ile206Met：Gln209Arg：Ser211Asn 取代，这些取代是抗 RSV mAb 结合部位取代。尼赛珠单抗中和了 MEDLEY 参与者中分离出的 RSV A 和 B 株中的所有尼赛珠单抗和帕利珠单抗结合部位取代。
结论
在 MEDLEY 期间未检测到影响 RSV 对尼赛珠单抗中和敏感性的结合部位取代。
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