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

Abstract

Background: Monoclonal antibodies (mAbs) that target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are predominantly less effective against Omicron variants. Immunocompromised patients often experience prolonged viral shedding, resulting in an increased risk of viral escape.

Methods: In an observational, prospective cohort, 57 patients infected with Omicron variants who received sotrovimab alone or in combination with remdesivir were followed. The study end points were a decrease in SARS-CoV-2 RNA <106 copies/mL in nasopharyngeal swabs at day 21 and the emergence of escape mutations at days 7, 14, and 21 after sotrovimab administration. All SARS-CoV-2 samples were analyzed using whole-genome sequencing. Individual variants within the quasispecies were subsequently quantified and further characterized using a pseudovirus neutralization assay.

Results: The majority of patients (43 of 57, 75.4%) were immunodeficient, predominantly due to immunosuppression after organ transplantation or hematologic malignancies. Infections by Omicron/BA.1 comprised 82.5%, while 17.5% were infected by Omicron/BA.2. Twenty-one days after sotrovimab administration, 12 of 43 (27.9%) immunodeficient patients had prolonged viral shedding compared with 1 of 14 (7.1%) immunocompetent patients (P = .011). Viral spike protein mutations, some specific for Omicron (e.g., P337S and/or E340D/V), emerged in 14 of 43 (32.6%) immunodeficient patients, substantially reducing sensitivity to sotrovimab in a pseudovirus neutralization assay. Combination therapy with remdesivir significantly reduced emergence 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 for dedicated clinical trials in this patient population.

Keywords: Omicron; SARS-CoV-2; escape; immunodeficiency; sotrovimab.

Figure 1.

Patients with persistent viral replication (≥10⁶ copies/mL) after sotrovimab administration. A, Prolonged viral shedding by day 21 after the first positive SARS-CoV-2 PCR test according to immunocompetence. B, Prolonged viral shedding by day 21 after sotrovimab administration in immunocompetent patients and patients with immunodeficiency. Numbers at risk are patients with a viral load ≥10⁶ copies/mL; censored are patients lost to follow-up (1 patient was first lost to follow-up on day 28 and was included in numbers at risk). Abbreviations: PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2.

Prevalence and evolution of escape mutations in the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after sotrovimab treatment. Detected amino acid exchanges in the spike protein at positions 337 and 340 on day 0, day 7, and day 14 after sotrovimab administration. The frequency of reads in % is indicated by the color scale. The determined patient-related SARS-CoV-2 variant is shown. Only patients with detected mutations after sotrovimab treatment are indicated. Patients selecting a spike protein mutation after day 14 are not included in this figure (patient 51).

Figure 3.

Neutralization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike mutants by sotrovimab. A, SARS-CoV-2 variant-specific pseudoviruses harboring mutations that emerged after sotrovimab treatment were analyzed in sotrovimab neutralization assays. All samples were tested in duplicate. Symbols and bars indicate mean and standard deviation, respectively. The determined IC₅₀ values are shown in (B). Abbreviation: IC₅₀, half maximal inhibitory concentration.