Emergence of SARS-CoV-2 Resistance with Monoclonal Antibody Therapy.

Abstract

Resistance mutations to monoclonal antibody (mAb) therapy has been reported, but in the non-immunosuppressed population, it is unclear if in vivo emergence of SARS-CoV-2 resistance mutations alters either viral replication dynamics or therapeutic efficacy. In ACTIV-2/A5401, non-hospitalized participants with symptomatic SARS-CoV-2 infection were randomized to bamlanivimab (700mg or 7000mg) or placebo. Treatment-emergent resistance mutations were significantly more likely detected after bamlanivimab 700mg treatment than placebo (7% of 111 vs 0% of 112 participants, P=0.003). There were no treatment-emergent resistance mutations among the 48 participants who received bamlanivimab 7000mg. Participants with emerging mAb resistant virus had significantly higher pre-treatment nasopharyngeal and anterior nasal viral load. Intensive respiratory tract viral sampling revealed the dynamic nature of SARS-CoV-2 evolution, with evidence of rapid and sustained viral rebound after emergence of resistance mutations, and worsened symptom severity. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest and associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment, resulting in prolonged high level respiratory tract viral loads and clinical worsening. Careful virologic assessment should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.

• Authors: Manish C Choudhary, Kara W Chew, Rinki Deo, James P Flynn, James Regan, Charles R Crain, Carlee Moser, Michael Hughes, Justin Ritz, Ruy M Ribeiro, Ruian Ke, Joan A Dragavon, Arzhang C Javan, Ajay Nirula, Paul Klekotka, Alexander L Greninger, Courtney V Fletcher, Eric S Daar, David A Wohl, Joseph J Eron, Judith S Currier, Urvi M Parikh, Scott F Sieg, Alan S Perelson, Robert W Coombs, Davey M Smith, Jonathan Z Li, ACTIV-2/A5401 Study Team
• Journal: medRxiv : the preprint server for health sciences (medRxiv) (Sep 15 2021) United States
• PMID: 34545376 (Publication Type: Preprint)