Rapid Selection of Sotrovimab Escape Variants in Severe Acute Respiratory Syndrome Coronavirus 2 Omicron-Infected Immunocompromised Patients

Abstract

Background Monoclonal antibodies (mAb) targeting SARS-CoV-2 are predominantly less effective against Omicron variants. Immunocompromised patients often experience prolonged viral shedding and are therefore at increased risk for viral escape mutations, when mAbs are used as monotherapy. Methods In an observational, prospective cohort, 57 patients infected with Omicron variants receiving sotrovimab alone or in combination with remdesivir were followed. The study endpoints were a decrease in SARS-CoV-2-RNA <106 copies/ml in nasopharyngeal swabs at day 21 and the emergence of resistance mutations at days 7, 14, and 21 after sotrovimab administration. All SARS-CoV-2 samples were analyzed by whole-genome sequencing, individual variants within the quasispecies were subsequently quantified and further characterized by a pseudovirus neutralization assay. Results 47/57 patients (82.5%) were infected with Omicron/BA.1 and 10/57 (17.5%) with Omicron/BA.2. The vast majority of patients (43/57, 75.4%) were immunodeficient, predominantly due to immunosuppression after organ transplantation or hematologic malignancies. 21 days after sotrovimab administration, 12/43 (27.9%) of immunodeficient patients had prolonged viral shedding compared to 1/14 (7.1%) immunocompetent patients (p = 0.011). Longitudinal sequencing revealed that 14/43 (32.6%) immunodeficient patients had in part Omicron-specific viral spike protein mutations (e.g., P337S and/or E340D/V) that substantially reduced susceptibility to sotrovimab in a pseudovirus neutralization assay. Combination therapy with remdesivir significantly reduced the selection of escape variants. Conclusions Immunocompromised patients face a considerable risk of prolonged viral shedding and emergence of escape mutations after early therapy with sotrovimab. These findings underscore the importance of careful monitoring and the need to conduct dedicated clinical trials for this patient population.

SARS-CoV-2 evolution during persistent infection in a CAR-T recipient shows an escape to both sotrovimab and T-cell responses

“…Whole viral genome sequencing revealed Spike mutations (L5F, Y145D, E340A, L582F, F855L, and L938F) after receiving sotrovimab, as shown in Supplementary Table 2 (GISAID accession EPI_ISL_16849243, EPI_ISL_16849243, EPI_ISL_16849245). Notably, S:E340A confers immune escape to sotrovimab [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] . We also observed an overall reduction in the number of S epitopes that could be presented by the patient's HLA alleles, as depicted in Supplementary Materials.…”

HIV and COVID-19 Co-Infection: Epidemiology, Clinical Characteristics, and Treatment

“…In vitro studies, however, demonstrated that sotrovimab had lost activity against the BA.2 strain almost completely [ 90 ]. Even worse, it has been demonstrated that in immunocompromised patients undergoing treatment with sotrovimab, treatment failure was associated with emerging spike mutations conferring resistance to sotrovimab [ 115 ]. On the other hand, two case reports suggested that the use of sotrovimab as an adjunctive to remdesivir therapy in severely immunocompromised AIDS patients showed a dramatic improvement in symptoms and rapid viral clearance [ 116 , 117 ].…”

Tixagevimab/Cilgavimab in SARS-CoV-2 Prophylaxis and Therapy: A Comprehensive Review of Clinical Experience

“… Green, orange and red indicate no, mild/moderate, and severe reduction in potency in vitro. Data composition as per [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. …”

“…At the moment, genomic epidemiology has identified Omicron as the only variant of concern. In this context, the susceptibility of circulating SARS-CoV-2 variants i.e., Omicron BA.2, BA.4, BA.5, and its subvariants, i.e., BA.2.75.2, BA.4.6, and BQ.1.1, against anti-SARS-CoV-2 antibodies remains variable [ 8 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ] (see Table 1 ). Sotrovimab [ 14 , 15 , 16 , 17 ], Casirivimab/Imdevimab [ 18 ], and Bamlanivimab/Etesevimab [ 18 , 19 ], although effective against the previous variants, i.e., alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2, non-AY.1/AY.2), and Omicron (B.1.1.529/BA.1 and BA.1.1), they seem to be inactive against the present ones (BA.2, BA.4, BA.5).…”

“…In this context, the susceptibility of circulating SARS-CoV-2 variants i.e., Omicron BA.2, BA.4, BA.5, and its subvariants, i.e., BA.2.75.2, BA.4.6, and BQ.1.1, against anti-SARS-CoV-2 antibodies remains variable [ 8 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ] (see Table 1 ). Sotrovimab [ 14 , 15 , 16 , 17 ], Casirivimab/Imdevimab [ 18 ], and Bamlanivimab/Etesevimab [ 18 , 19 ], although effective against the previous variants, i.e., alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2, non-AY.1/AY.2), and Omicron (B.1.1.529/BA.1 and BA.1.1), they seem to be inactive against the present ones (BA.2, BA.4, BA.5). On the contrary, Bebtelovimab and Tixagevimab/Cilgavimab, remain active in vitro against the circulating subtypes (BA.2, BA.4, BA.5) and are expected to retain their clinical activity in the future, even though the duration of their activity remains poorly defined in some cases [ 11 , 20 , 21 ].…”