Emergence of SARS-CoV-2 Resistance with Monoclonal Antibody Therapy
et al., medRxiv, doi:10.1101/2021.09.03.21263105, NCT04518410, Sep 2021
25th treatment shown to reduce risk in
May 2021, now with p = 0.00049 from 22 studies, recognized in 11 countries.
Efficacy is variant dependent.
No treatment is 100% effective. Protocols
combine treatments.
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Analysis of ACTIV-2/A5401, showing the potential for rapid emergence of resistance during monoclonal antibody treatment, resulting in prolonged high level viral loads and clinical worsening. Treatment-emergent resistance mutations were more common after bamlanivimab 700mg (7% of 111 vs 0% of 112 participants, p=0.003).
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Liu et al., Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2, bioRxiv, doi:10.1101/2021.12.14.472719.
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Sheward et al., Variable loss of antibody potency against SARS-CoV-2 B.1.1.529 (Omicron), bioRxiv, doi:10.1101/2021.12.19.473354.
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Choudhary et al., 15 Sep 2021, preprint, 28 authors, trial NCT04518410 (history).
Emergence of SARS-CoV-2 Resistance with Monoclonal Antibody Therapy
doi:10.1101/2021.09.03.21263105
All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
Author contributions MCC, KC, RC, DMS, JZL conceptualized and performed the study, MCC, RD, JPF, JR, CC performed resistance analysis experiment; RMR, RK, ASP performed mathematical modeling; JD, AG performed viral load analysis; UP, SS performed serological analysis; CM, MH, JR performed statistical analysis.
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"abstract": "<jats:title>ABSTRACT</jats:title><jats:p>Resistance mutations to monoclonal antibody (mAb) therapy has been reported, but in the non-immunosuppressed population, it is unclear if <jats:italic>in vivo</jats:italic> 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.</jats:p>",
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Late treatment
is less effective
is less effective
