Abstract: nature communications Article https://doi.org/10.1038/s41467-022-32551-2 Antiviral and clinical activity of bamlanivimab in a randomized trial of nonhospitalized adults with COVID-19 Received: 4 May 2022 Check for updates 1234567890():,; 1234567890():,; Accepted: 4 August 2022 Kara W. Chew 1 , Carlee Moser 2, Eric S. Daar3, David A. Wohl 4, Jonathan Z. Li 5, Robert W. Coombs 6,7, Justin Ritz 2, Mark Giganti2, Arzhang Cyrus Javan8, Yijia Li5,14, Manish C. Choudhary5, Rinki Deo5, Carlos Malvestutto9, Paul Klekotka10, Karen Price10, Ajay Nirula10, William Fischer4, Veenu Bala11,15, Ruy M. Ribeiro 12, Alan S. Perelson 12, Courtney V. Fletcher 11, Joseph J. Eron 4, Judith S. Currier 1, ACTIV-2/A5401 Study Team, Michael D. Hughes2,16 & Davey M. Smith 13,16 Anti-SARS-CoV-2 monoclonal antibodies are mainstay COVID-19 therapeutics. Safety, antiviral, and clinical efficacy of bamlanivimab were evaluated in the randomized controlled trial ACTIV-2/A5401. Non-hospitalized adults were randomized 1:1 within 10 days of COVID-19 symptoms to bamlanivimab or blinded-placebo in two dose-cohorts (7000 mg, n = 94; 700 mg, n = 223). No differences in bamlanivimab vs placebo were observed in the primary outcomes: proportion with undetectable nasopharyngeal SARS-CoV-2 RNA at days 3, 7, 14, 21, and 28 (risk ratio = 0.82–1.05 for 7000 mg [p(overall) = 0.88] and 0.81–1.21 for 700 mg [p(overall) = 0.49]), time to symptom improvement (median 21 vs 18.5 days [p = 0.97], 7000 mg; 24 vs 20.5 days [p = 0.08], 700 mg), or grade 3+ adverse events. However, bamlanivimab was associated with lower day 3 nasopharyngeal viral levels and faster reductions in inflammatory markers and viral decay by modeling. This study provides evidence of faster reductions in nasopharyngeal SARS-CoV-2 RNA levels but not shorter symptom durations in non-hospitalized adults with early variants of SARS-CoV-2. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Coronavirus disease 2019 (COVID-19), continues to exert an enormous global public health and economic toll, and in the U.S. case-fatality rates exceed estimates for the 1918 influenza pandemic1. Anti-SARS-CoV-2 monoclonal antibody (mAb)-based therapies have shown sufficient clinical efficacy to receive emergency 1 Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA. 2Harvard T.H. Chan School of Public Health, Boston, MA, USA. 3Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA. 4Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. 5Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 6 Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA. 7Department of Medicine, University of Washington, Seattle, WA, USA. 8National Institutes of Health, Bethesda, MD, USA. 9Ohio State University Wexner Medical Center, Columbus, OH, USA. 10Eli Lilly and Company, San Diego, CA, USA. 11UNMC Center for Drug Discovery, University of Nebraska Medical Center, Omaha, NE, USA. 12Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA. 13Department of Medicine, University of California, San Diego, La Jolla, CA, USA. 14Present address: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. 15Present address: Clinical Pharmacology & Pharmacometrics, Jounce..