SARS-CoV-2 Delta Variant: Resistance Mutations after Sotrovimab Use

Last Updated on April 11, 2022 by Joseph Gut – thasso

April 10, 2022 – Sotrovimab, sold under the brand name Xevudy, is a monoclonal antibody that was available under emergency use authorization (EUA) from the FDA and similar urgency authorisations from several drug regulatory agencies worldwide for the treatment of patients who are at risk for progression of Covid-19 disease to severe or fatal disease status. Sotrovimab is thought to neutralize all sarbecoviruses, including SARS-CoV-2, by binding to a highly conserved epitope within the receptor-binding domain. However, the use   of SARS-CoV-2–specific monoclonal antibodies to target a single viral epitope warrants caution because of the risk of rapid development of mutations that confer resistance after exposure to such antibodies.

In effect, in March 2022, Australian virologists observed that sotrovimab may cause a drug-resistant mutation, as they describe in a very recent report to the New England Journal of Medicine (NEJM) showing that apparently mutations at viral genome positions S:E340K/A/V and S:P337L/T  have been associated with a reduction by a factor of 100 to 297 in neutralization by Sotrovimab.

Thus, in their study, the researchers reviewed the first 100 consecutive patients who received Sotrovimab at health care facilities in the Western Sydney Local Health District in New South Wales, Australia, during the B.1.617.2 (delta) variant outbreak between August and November 2021. They identified 8 patients (R001 through R008) with reverse transcriptase–polymerase-chain-reaction (RT-PCR) assays that were persistently positive for SARS-CoV-2 and for whom respiratory tract specimens obtained before and after the use of Sotrovimab were available.

Genomic analysis showed that 4 of these 8 patients (R001 through R004) acquired previously defined receptor-binding domain mutations within 6 to 13 days after they received Sotrovimab. Mutations in S:E340 developed in all 4 patients, findings that are concordant with those in the Covid-19 Monoclonal Antibody Efficacy Trial–Intent to Care Early (COMET-ICE). Cultures obtained from these patients remained positive for 23, 24, 12, and 15 days, respectively, after they received Sotrovimab. Read frequencies of S:E340K/A/V mutations increased over the course of infection; the proportion of the viral population carrying S:E340K/A/V exceeded 75% by day 7 in Patient R002, by day 13 in Patient R003, and by day 37 in Patient R004. In addition, a minority variant developed in Patient R002 at position P337L after fixation of the S:E340K mutation. A retrospective review of 11,841 SARS-CoV-2 genomes in the Global Initiative on Sharing All Influenza Data database (a site for compiling sequence data on viruses) and reported in New South Wales, Australia, identified 4 additional patients with S:E340 mutations. In 1 patient, the SARS-CoV-2 genome was detected 5 days after Sotrovimab treatment, and in another it was detected 11 days after treatment.

Overall, these data show the persistence of viable SARS-CoV-2 in patients after Sotrovimab infusions and the rapid development of spike gene mutations associated with high-level Sotrovimab resistance in vitro. These findings underscore the importance of stewardship of monoclonal antibodies, particularly because Sotrovimab is one of the few monoclonal antibodies with retained activity against the B.1.1.529 (Omicron) variant. Postmarketing genomic surveillance of patients who receive monoclonal antibodies for the treatment of SARS-CoV-2 infection is prudent in order to minimize the risk of both, treatment failure and the transmission of potentially resistant SARS-CoV-2 variants in health care settings and the community, given that SARS-CoV-2 may be isolated up to 24 days after Sotrovimab treatment.

Overall. and simply speaking: We don’t known everything yet about this particular virus, and we should, at all levels, remain alert. In any direction.

See here a presentation on Sotrovinab: