Efficacy of Nirsevimab Over 6 Months: A 180-Day Endpoint Analysis from the HARMONIE Study, a Randomized Phase IIIb Trial

Background: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) and hospitalizations in infants worldwide.The primary analyses of HARMONIE showed that nirsevimab reduced infant RSV LRTI hospitalizations through the RSV season.This analysis aims to evaluate nirsevimab's efficacy through 180 days post-dosing, a period exceeding the typical 5-month RSV season. Methods: HARMONIE is an ongoing Phase IIIb, open-label, randomized, parallel 2-arm study conducted in France, Germany, and the UK. Infants ≤12 months old, born at ≥29 weeks gestational age, were randomized 1:1 to receive a single dose of nirsevimab or standard care (without RSV prophylaxis) before or during their first RSV season. Two key secondary endpoints were the incidence of RSV LRTI hospitalization through 180 days post-dosing/randomization and the incidence of hospitalizations for all-cause LRTI through the same period.  Findings: 8057 participants were randomized, 4038 to the nirsevimab group and 4019 to the standard care group.Through 180 days post-dosing/randomization, twelve infants (0.3%) in the nirsevimab group and 68 (1.7%) in the standard care group were hospitalized for RSV-associated LRTI, corresponding to a nirsevimab efficacy of 82.7% (95% confidence interval [CI], 67.8 to 91.5; P<0.0001). For all-cause LRTI through 180 days, 82 infants (2.0%) in the nirsevimab group and 138 (3.4%) in the standard care group were hospitalized, corresponding to an efficacy of 41.9% (95% CI, 23.1 to 56.3; P<0.0001). Nirsevimab was well tolerated and no apparent safety concerns were raised. Interpretations: Nirsevimab demonstrated a significant beneficial efficacy at 180 days post dose, offering consistent and sustained protection against RSV LRTI hospitalization in infants for at least 6 months. This provides global health systems greater flexibility when implementing nirsevimab, marking a significant benefit in the ongoing effort to reduce the burden of infant RSV. (Funded by Sanofi and AstraZeneca; HARMONIE Trial Registration: ClinicalTrials.gov number, NCT05437510). Funding: The trial was funded by AstraZeneca and Sanofi. Declaration of Interest: N.C.Vassilouthis, M. Roberts, M.Carreno, P.Bourron, L.Marcellon, K.Mari, C.Moreau are employed by Sanofi and have stock and/or share options. Pierre Tissieres, Drs Knuf, Cathie, Flamein, Collins, Royal, Alasdair, H.C.Hill, F.Kaiser, D.Pinquier have declared tp not receiving any funding for the present manuscript. Drs Hill, Alasdair and Knuf have declare no conflict of interests. F.Kaiser received a contract from Sanofi as investigator in HARMONIE, fees paid to institution Dr Drysdale received feeds paid to institution from Sanofi to run the present study; travel grant from Sanofi (October 2022); consulting or investigator roles for Janssen, AstraZeneca, Pfizer, Moderna, Valneva, MSD, iLiAD, MundiPharma, Sanofi; and is a member of the UK DHSC JCVI MHRA PMEAG. Pr Faust received funding for HARMONIE from Sanofi, paid to the institution; grants or contracts from Pfizer, Sanofi, GSK, Johnson & Johnson, Merck, AstraZeneca, Valneva, Moderna, BioNTech as clinical trial investigator on behalf of institution; honoraria for symposium participation paid to institution from Moderna, Pfizer and Novavax; honoraria for ad-boards participation paid to institution from AstraZeneca, MedImmune, Sanofi, Pfizer, Seqirus, Merck, Johnson & Johnson and MSD; and was the chair of UK NICE Sepsis (2014-2016) and Lyme Disease (2016-2018) Guidelines R.Cohen has received consulting fees from Pfizer, Sanofi, MSD, GSK, Viatris; Symposia honoraria from Pfizer, MSD, GSK, Sanofi; Payment for expert testimony from Pfizer and MSD; Travel grants from Pfizer, MSD, Sanofi, GSK; Honoraria for participation to ad-board from Pfizer, Sanofi, MSD and GSK. Dr Pinquier received consulting fees from Sanofi, GSK, MSD, Pfizer; Symposia honoraria from AstraZeneca, GSK, MSD, Pfizer and Sanofi; Travel grant from Sanofi, Pfizer, MSD; Honoraria for ad- board presence from Sanofi, Pfizer and GSK. Dr Royal received a grant to the NIHR CRN East Midlands (where he is employed as the primary care specialty lead for the organization); Honoraria for ad-board presence from Sanofi; for involvement in HARMONIE from Sanofi. Dr Flamein was invited by Sanofi to ESPID 2023 Dr Collins received grants or contracts from Pfizer, MSD, Moderna, Infex, Sanofi; consulting fees from Sanofi; travel grant from Sanofi (ESPID); payment or honoraria for lectures and presentations from Sanofi and Pfizer; honoraria for ad-board participation from OVG; and has leadership in RTI conference committee, TPI scientific committee and Liverpool CRF committee. Dr Cathie received grants or contracts from Pfizer, Sanofi, GSK, Janssen, Merck, Iliad, MedImmune, AstraZeneca and Valneva as clinical trial investigator on behalf of institution; Consulting fees on behalf of institution from Sanofi. Pierre Tissieres received grants and consulting contract from Baxter; Consulting fees from Sedana, Sanofi, Thermo Fisher and Viatris; Honoraria for symposium presentation from Thermo Fisher, Baxter and BioMerieux. Ethical Approval: The trial protocol (provided in supplementary appendix) and any amendments were approved by the appropriate independent ethics committee or institutional review board at each participating site and by the relevant regulatory agencies in each country in accordance with local regulations. Consent was given by the parents or legally acceptable representatives of all the infants before any trial procedures were performed.