Journal Article

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)

Mankad, Vaishali S., Wang, Yingyi, Domachowske, Joseph B., Ahani, Bahar, Furuno, Kenji, Ji, Hong, Tuffy, Kevin M., Kelly, Elizabeth J., Madhi, Shabir A., Wilkins, Deidre, Hamrén, Ulrika Wählby, Villafana, Tonya

2024

Overview

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. 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. 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. No binding site substitution detected during MEDLEY affected RSV susceptibility to nirsevimab neutralization. •Nirsevimab and palivizumab are mAbs used to prevent severe pediatric RSV disease.•Ongoing evolution necessitates the surveillance of mAb epitopes in circulating RSVs.•We present an exploratory analysis of RSV variants identified in the MEDLEY study.•Nirsevimab neutralized all RSVs with substitutions in anti-RSV mAb binding sites.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Allergy and Immunology / Amino acids / Anti-RSV F protein monoclonal antibody / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - therapeutic use / Antibodies, Neutralizing - blood / Antibodies, Neutralizing - immunology / Antibodies, Viral - immunology / Antiviral Agents - administration & dosage / Antiviral Agents - therapeutic use / Binding sites / Cardiovascular diseases / Child, Preschool / Disease control / Double-Blind Method / Female / Gestational age / half life / Heart diseases / Hospitalization / Humans / Infant / Infant, Newborn / Infants / Infections / Intervention / Lung diseases / Male / Monoclonal antibodies / Neonates / Neutralization / Newborn babies / Nirsevimab / nose / Palivizumab / Palivizumab - administration & dosage / Palivizumab - therapeutic use / phenotype / Placebos / Premature babies / premature birth / Proteins / Respiratory diseases / Respiratory syncytial virus / Respiratory Syncytial Virus Infections - prevention & control / Respiratory Syncytial Virus, Human - drug effects / Respiratory Syncytial Virus, Human - genetics / Respiratory Syncytial Virus, Human - immunology / Respiratory tract / Respiratory tract diseases / RSV immunization / Seasons / vaccines / Weight