Abstract Background Clesrovimab is an investigational, long-acting monoclonal antibody (mAb) targeting site IV of the fusion protein for the prevention of RSV lower respiratory tract infection in infants. Methods This phase 2b/3 double-blind, randomized, placebo-controlled pivotal study enrolled healthy preterm and full-term infants birth to 1 year of age entering their first RSV season. Participants (pts) were randomized 2:1 to receive clesrovimab (105 mg IM) or placebo on day 1. Safety and tolerability were a primary endpoint. There were two hypothesis-tested endpoints: the efficacy of clesrovimab against RSV-associated medically attended lower respiratory tract infection (MALRI) through day 150 (primary) and against RSV-associated hospitalization through day 150 (secondary). The MALRI definition required ≥1 indicators of lower respiratory tract infection (LRI) or severity. To facilitate comparison across RSV mAb trials, a definition of RSV-associated MALRI that required ≥2 indicators of LRI/severity (≥1 indicator of LRI and ≥1 indicator of severity) was assessed post hoc. Results There were 3,632 pts randomized across 22 countries; >99% received study intervention. RSV-associated efficacy endpoints through day 150 and day 180 are shown in Table 1. Clesrovimab reduced the incidence of RSV-associated MALRI requiring ≥1 indicator of LRI/severity (60.4% [95% CI: 44.1, 71.9], p< 0.001) and ≥2 indicators of LRI/severity (88.0% [95% CI:76.1, 94.0]), RSV hospitalization (84.2% [95% CI: 66.6, 92.6], p< 0.001), and severe MALRI (91.7% [95% CI:62.9, 98.1]) through day 150 postdose compared to placebo. Efficacy increased with increasing RSV-associated disease severity and was similar from days 1-180 compared to days 1-150 across endpoints. The proportions of pts with adverse events (AEs), including injection-site and systemic AEs, drug-related AEs, and serious AEs were comparable between the clesrovimab and placebo groups (Table 2). There were no treatment-related deaths or deaths attributed to RSV disease. Conclusion A single dose of clesrovimab given before or during the first RSV season was efficacious in reducing RSV-associated MALRI and RSV-associated hospitalization in healthy preterm and full-term infants and was generally well tolerated with a safety profile comparable to placebo. Disclosures Heather J. Zar, PhD, MSD, Pfizer, AstraZeneca, Moderna (DSMB): Advisor/Consultant|MSD, Pfizer, AstraZeneca, Moderna (DSMB): Grant/Research Support|MSD, Pfizer, AstraZeneca, Moderna (DSMB): Honoraria|MSD, Pfizer, AstraZeneca, Moderna (DSMB): MSD Principal Investigator for the study and on MSD Advisory Board Eric Simoes, MD DCH, Pfizer, Sanofi, Merck, Icosavax, Enanta Cidara, Adiagio, Nuance, Shionogi, GIlead,: Advisor/Consultant|Pfizer, Sanofi, Merck, Icosavax, Enanta Cidara, Adiagio, Nuance, Shionogi, GIlead,: Grant/Research Support|Pfizer, Sanofi, Merck, Icosavax, Enanta Cidara, Adiagio, Nuance, Shionogi, GIlead,: Honoraria|Pfizer, Sanofi, Merck, Icosavax, Enanta Cidara, Adiagio, Nuance, Shionogi, GIlead,: MSD - PI for this study; DSMB Abbvie, Moderna, GSK Sabhir Madhi, MD, Pfizer, GSK, Medimmune, Merck & Co., Inc., Rahway, NJ, USA: Grant/Research Support|Pfizer, GSK, Medimmune, Merck & Co., Inc., Rahway, NJ, USA: Honoraria Octavio Ramilo, MD, Pfizer, Sanofi, Gates Foundation, NIH, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): Advisor/Consultant|Pfizer, Sanofi, Gates Foundation, NIH, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): Grant/Research Support|Pfizer, Sanofi, Gates Foundation, NIH, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): Honoraria|Pfizer, Sanofi, Gates Foundation, NIH, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): SAC member for MSD Shelly Senders, MD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Principal Investigator Julie S. Shepard, MD, MPH, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Principal Investigator Kamolwish Laoprasopwattana, MD, Merck & Co., Inc., Rahway, NJ, USA: Grant/Research Support|Merck & Co., Inc., Rahway, NJ, USA: MSD - PI for this study Jorge Piedrahita, MD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Principal Investigator Jose M. Novoa Pizarro, MD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): Principal Investigator for the study for MSD Sergio L. Vargas, MD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Principal Investigator Marc Dionne, MD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Principal Investigator Teresa Jackowska, MD, MSD Poland, Merck & Co., Inc, Rahway, NJ, USA: Advisor/Consultant|MSD Poland, Merck & Co., Inc, Rahway, NJ, USA: Grant/Research Support|MSD Poland, Merck & Co., Inc, Rahway, NJ, USA: Honoraria|MSD Poland, Merck & Co., Inc, Rahway, NJ, USA: MSD - PI for this study Enmei Liu, MD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Principal Investigator Yasunori Ishihara, MD, PhD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Principal Investigator Kazushige Ikeda, MD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Principal Investigator Ying Zhang, PhD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Employee|Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Stocks/Bonds (Public Company) Radha A. Railkar, PhD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, US (MSD): Employee|Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, US (MSD): Stocks/Bonds (Public Company) Jeannine Lutkiewicz, BS, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Employee|Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Stocks/Bonds (Public Company) Andrew W. Lee, MD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): Employee at the time of study|Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): Stocks/Bonds (Public Company) Andrea Guerra, MD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Employee|Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Stocks/Bonds (Public Company) Anushua Sinha, MD, MPH, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): Employee|Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): Stocks/Bonds (Public Company)