Abstract
An Emergency Use Authorization was issued in the United States and in Europe for a monoclonal antibody monotherapy to prevent severe COVID-19 in high-risk patients. This study aimed to assess the risk of emergence of mutations following treatment with a single monoclonal antibody. Bamlanivimab was administered at a single dose of 700 mg in a one-hour IV injection in a referral center for the management of COVID-19 in France. Patients were closely monitored clinically and virologically with nasopharyngeal RT-PCR and viral whole genome sequencing. Six patients were treated for a nosocomial SARS-CoV-2 infection, all males, with a median age of 65 years and multiple comorbidities. All patients were infected with a B.1.1.7 variant, which was the most frequent variant in France at the time, and no patients had E484 mutations at baseline. Bamlanivimab was infused in the six patients within 4 days of the COVID-19 diagnosis. Four patients had a favorable outcome, one died of complications unrelated to COVID-19 or bamlanivimab, and one kidney transplant patient treated with belatacept died from severe COVID-19 more than 40 days after bamlanivimab administration. Virologically, four patients cleared nasopharyngeal viral shedding within one month after infusion, while two presented prolonged viral excretion for more than 40 days. The emergence of E484K mutants was observed in five out of six patients, and the last patient presented a Q496R mutation potentially associated with resistance. CONCLUSIONS: These results show a high risk of emergence of resistance mutants in COVID-19 patients treated with monoclonal antibody monotherapy.
Highlights
Preliminary data available in late 2020 has led several countries to give an emergency approval for the use of a monoclonal antibody monotherapy in the early phase of COVID-19 in high-risk patients [1]
We describe the selection of E484K mutations among five out of six patients at high risk of severe COVID-19 who were treated with bamlanivimab monotherapy
Since the beginning of this study, the Emergency Use Authorization (EUA) for bamlanivimab monotherapy have been revoked in the USA and in Europe due to the emergence of variants and the availability of combinations of monoclonal antibodies
Summary
Preliminary data available in late 2020 has led several countries to give an emergency approval for the use of a monoclonal antibody monotherapy in the early phase of COVID-19 in high-risk patients [1]. In an interim analysis from a phase two randomized, double-blind, placebo-controlled clinical trial involving 452 outpatients with recently diagnosed mild or moderate COVID-19, monoclonal anti-Spike antibody bamlanivimab appeared to accelerate the decline in viral load and provided encouraging results regarding clinical outcomes and COVID-19 related hospitalizations [2,3]. Following these and other results, an Emergency Use Authorization (EUA) to use bamlanivimab against SARS-CoV-2 was issued in November 2020 by the FDA for the early treatment (within 10 days of symptoms onset) of high-risk patients [4]. Bamlanivimab demonstrated a strongly decreased in vitro neutralization activity against SARS-CoV-2 variants harboring the E484K mutation [9,10]
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