1. 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).
- Author
-
Tuffy KM, Ahani B, Domachowske JB, Furuno K, Ji H, Madhi SA, Mankad VS, Hamrén UW, Villafana T, Wang Y, Kelly EJ, and Wilkins D
- Subjects
- Humans, Infant, Double-Blind Method, Male, Female, Infant, Newborn, Antibodies, Viral immunology, Child, Preschool, Antibodies, Neutralizing immunology, Antibodies, Neutralizing blood, Palivizumab therapeutic use, Palivizumab administration & dosage, Respiratory Syncytial Virus Infections prevention & control, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized administration & dosage, Antiviral Agents therapeutic use, Antiviral Agents administration & dosage, Respiratory Syncytial Virus, Human immunology, Respiratory Syncytial Virus, Human drug effects, Respiratory Syncytial Virus, Human genetics
- Abstract
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., Competing Interests: Declaration of competing interest Kevin M. Tuffy, Bahar Ahani, Hong Ji, Vaishali S. Mankad, Ulrika Wählby Hamrén, Tonya Villafana, Yingyi Wang and Deidre Wilkins are current employees of AstraZeneca and may hold AstraZeneca stock or stock options. Elizabeth J. Kelly is a former employee of AstraZeneca and a current employee of Sanofi and may hold stock or stock options for both institutions. Ulrika Wählby Hamrén, Tonya Villafana and Deidre Wilkins are named inventors on patents planned, issued or pending related to nirsevimab. Joseph B. Domachowske has received funding to their institution for the conduct of clinical trials from AstraZeneca, Merck and Regeneron, honoraria from Sanofi and has participated in advisory boards for GSK and Sanofi. Kenji Furuno has received honoraria from AstraZeneca and AbbVie. Shabir A. Madhi has received funding from AstraZeneca, Novavax, Providence, Gritstone and ImmunityBio for the conduct of clinical trials; institutional grants from the Bill and Malinda Gates Foundation, GSK, Pfizer and Minervax, honoraria from GSK and MSD and is a member of Data Safety Monitoring Boards for PATH and CAPRISA., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...
- Published
- 2024
- Full Text
- View/download PDF