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

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.Across a broad spectrum of viral infections, host immune pressure 1,2 and antiviral therapy 3-5 can select for viral escape mutations. The detection and characterization of antiviral resistance mutations have been critical for the selection of appropriate antiviral therapies and the advancement of our understanding of viral adaptation against evolutionary pressures 6 . Monoclonal antibody (mAb) therapy has been one of key treatment options for non-hospitalized persons with early SARS-CoV-2 infections and mild to moderate COVID-19 7,8 . Bamlanivimab was the first mAb to receive US Food and Drug Administration (FDA) emergency use authorization (EUA) after it was demonstrated that treatment with

Modeling the emergence of viral resistance for SARS-CoV-2 during treatment with an anti-spike monoclonal antibody

“…S1, Supplementary Material). This is unlikely since the viral peak is usually around the time of symptom onset and BAM was initiated a median of 4.5 days post symptom onset in these participants (Choudhary., 2022). Essentially, this simple model tries to preserve target cells to allow the resistant virus to grow by preventing the viral load from increasing rapidly after infection.…”

“…Data. We analyzed data from the cohort of individuals with SARS-CoV-2 infection and symptoms consistent with COVID-19 who were given a single infusion of 700 mg BAM in a phase 2 randomized, placebo-controlled trial (ACTIV-2/A5401 study) described in detail previously (Chew et al, 2022;Choudhary et al, 2022). Viral load and mutant frequency data were obtained from anterior nasal swabs collected by the participants daily from the time of the BAM infusion to day 14 and at days 21 and 28.…”

“…No original data was generated for the paper. The viral loads and the primary resistance mutation frequencies from anterior nasal swabs for the study subjects are all available in the Extended Data section of Choudhary et al (2022).…”

“…One concerning observation during treatment of SARS-CoV-2 infection with mAbs is the emergence of viral resistance and concomitant viral rebound. In the case of BAM treatment, after the initial peak in the viral load, viral rebounds of up to 3-4 orders of magnitude consisting mostly of resistant virus have been observed in small subsets of patients in multiple studies (Choudhary et al, 2022; Jensen et al, 2021; Peiffer-Smadja et al, 2021). During rebound, infectious viruses are culturable, implying virus may be able to be transmitted and infect others (Boucau et al, 2022a).…”

The evolution of SARS-CoV-2

“…Experimental results indicate the emergence of resistance mutations in the SARS-CoV-2 spike protein after in vitro passaging in the presence of SARS-CoV-2-specific monoclonal antibodies 202,203 . SARS-CoV-2 in individuals treated with monoclonal antibody monotherapy following the emergence of resistance mutations showed a dynamic evolution characterized by immune escape, altered replication kinetics, an extended period of elevated viral loads and rebound of clinical symptoms 204 . Meanwhile, in patients with mild or moderate COVID-19, resistance to monoclonal antibodies such as bamlanivimab was substantially reduced when given as a combination with etesevimab 205 .…”