Development of Resistance-Associated Mutations After Sotrovimab Administration in High-risk Individuals Infected With the SARS-CoV-2 Omicron Variant

Abstract

The SARS-CoV-2 Omicron variant of concern is currently the dominant variant circulating globally. Sotrovimab is among the few monoclonal antibodies that has retained its neutralizing activity against Omicron/BA.1 and received Emergency Use Authorization for treatment of patients at risk for progression to severe disease. 1,2 However, concerns have been raised about the potential induction of spike protein resistance-associated viral mutations, especially in immunocompromised patients who are at risk for prolonged infection with SARS-CoV-2. 3 We investigated whether resistance-associated mutations developed after treatment with sotrovimab in high-risk patients infected with the SARS-CoV-2 Omicron variant.Methods | During the study period (January-February 2022), a single 500-mg dose of sotrovimab was recommended for use in ambulatory and hospitalized high-risk patients with SARS-CoV-2 infection. All patients treated at Amsterdam University Medical Centers in the Netherlands were eligible. The study was approved by the medical ethical committee for the Amsterdam University Medical Centers. Included patients provided written informed consent.Nasopharyngeal specimens were prospectively collected on days 0, 7, and 28 (at the discretion of the clinicians, additional specimens were collected 4 days before the sotrovimab infusion [4 days before day 0] to day 52). Specimens were se-

COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials

“…[15][16][17] Furthermore, escape mutations in the spike protein leading to acquired resistance during treatment with a single mAb have been repeatedly described in immunocompromised patients. 18,19 The rapid rise of variants with mutations in the spike protein has created a dilemma in mAb development, as pharmaceutical companies must weigh the high cost of their development against the short-lived utility of these agents 20 . Now that mAbs are proving less effective against mutant strains, CCP remains an important therapeutic option, especially for severely immunocompromised and other high-risk patients.…”

Broad SARS-CoV-2 Neutralization by Monoclonal and Bispecific Antibodies Derived from a Gamma-infected Individual

“…In addition, a substantial or complete loss in neutralizing activity has also been observed for most commercial therapeutic mAbs, with sotrovimab, bebtelovimab and the combination of tixagevimab with cilgavimab being the only antibodies still showing activity against Omicron BA.1, albeit with a 5 to 100-fold loss of potency. Moreover, sotrovimab and tixagevimab plus cilgavimab have been shown to lose efficacy against Omicron BA.2 and BA.4/5 [14][15][16][17][18][19][20] , and the emergence of resistance-associated mutations after sotrovimab administration have been recently reported 21,22 .…”

Delta-Omicron recombinant escapes therapeutic antibody neutralization

“…The recombinant virus sequence harbors one atypical spike mutation (E340D) not related to Delta or Omicron and rarely found in global SARS-CoV-2 sequences with a frequency of less than 3×10 −5 14,31 . Interestingly, E340 is in the middle of the Sotrovimab-binding epitope and is the primary site of resistance to Sotrovimab 27,32,33 . E340D is a conservative replacement without a change in charge, in contrast to the more abundant resistance mutations E340A/K 27,32 , yet we show that E340D can confer Sotrovimab resistance ( Figure 3 ).…”