Emergence of SARS-CoV-2 escape mutations during Bamlanivimab therapy in a phase II randomized clinical trial

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  • Choudhary, Manish C.
    • Other Affiliation: Harvard Medical School
  • Chew, Kara W.
    • Other Affiliation: University of California, Los Angeles
  • Deo, Rinki
    • Other Affiliation: Harvard Medical School
  • Flynn, James P.
    • Other Affiliation: Harvard Medical School
  • Regan, James
    • Other Affiliation: Harvard Medical School
  • Crain, Charles R.
    • Other Affiliation: Harvard Medical School
  • Moser, Carlee
    • Other Affiliation: Harvard T.H. Chan School of Public Health
  • Hughes, Michael D.
    • Other Affiliation: Harvard T.H. Chan School of Public Health
  • Ritz, Justin
    • Other Affiliation: Harvard T.H. Chan School of Public Health
  • Ribeiro, Ruy M.
    • Other Affiliation: Los Alamos National Laboratory
  • Ke, Ruian
    • Other Affiliation: Los Alamos National Laboratory
  • Dragavon, Joan A.
    • Other Affiliation: University of Washington
  • Javan, Arzhang Cyrus
    • Other Affiliation: National Institutes of Health
  • Nirula, Ajay
    • Other Affiliation: Lilly Research Laboratories
  • Klekotka, Paul
    • Other Affiliation: Lilly Research Laboratories
  • Greninger, Alexander L.
    • Other Affiliation: University of Washington
  • Fletcher, Courtney V.
    • Other Affiliation: University of Nebraska Medical Center
  • Daar, Eric S.
    • Other Affiliation: Harbor-UCLA Medical Center
  • Wohl, David A.
    • Other Affiliation: Department of Medicine
  • Eron, Joseph J.
    • Other Affiliation: Department of Medicine
  • Currier, Judith S.
    • Other Affiliation: University of California, Los Angeles
  • Parikh, Urvi M.
    • Other Affiliation: University of Pittsburgh
  • Sieg, Scott F.
    • Other Affiliation: Case Western Reserve University
  • Perelson, Alan S.
    • Other Affiliation: Los Alamos National Laboratory
  • Coombs, Robert W.
    • Other Affiliation: University of Washington
  • Smith, Davey M.
    • Other Affiliation: University of California, San Diego
  • Li, Jonathan Z.
    • Other Affiliation: Harvard Medical School
  • ACTIV-2/A5401 Study Team
Abstract
  • SARS-CoV-2 mutations that cause resistance to monoclonal antibody (mAb) therapy have been reported. However, it remains unclear whether in vivo emergence of SARS-CoV-2 resistance mutations alters viral replication dynamics or therapeutic efficacy in the immune-competent population. As part of the ACTIV-2/A5401 randomized clinical trial (NCT04518410), non-hospitalized participants with symptomatic SARS-CoV-2 infection were given bamlanivimab (700 mg or 7,000 mg) or placebo treatment. Here¸ we report that treatment-emergent resistance mutations [detected through targeted Spike (S) gene next-generation sequencing] were significantly more likely to be detected after bamlanivimab 700 mg treatment compared with the placebo group (7% of 111 vs 0% of 112 participants, P = 0.003). No treatment-emergent resistance mutations among the 48 participants who received 7,000 mg bamlanivimab were recorded. Participants in which emerging mAb resistant virus mutations were identified showed significantly higher pretreatment nasopharyngeal and anterior nasal viral loads. Daily respiratory tract viral sampling through study day 14 showed the dynamic nature of in vivo SARS-CoV-2 infection and indicated a rapid and sustained viral rebound after the emergence of resistance mutations. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest that are associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment that results in prolonged high-level respiratory tract viral loads. Assessment of viral resistance should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.
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Identifier
Resource type
  • Article
Journal title
  • Nature Microbiology
Journal volume
  • 7
Journal issue
  • 11
Language
  • English
ISSN
  • 2058-5276

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