Abstract: Clinical Infectious Diseases MAJOR ARTICLE Rapid Selection of Sotrovimab Escape Variants in Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2) Omicron-Infected Immunocompromised Patients Smaranda Gliga,1,2,a Nadine Lübke,2,a, Alexander Killer,1,a Henning Gruell,3 Andreas Walker,2 Alexander T. Dilthey,4 Alexander Thielen,5 Carolin Lohr,1 Charlotte Flaßhove,1 Sarah Krieg,1 Joanna Ventura Pereira,1 Tobias Paul Seraphin,1 Alex Zaufel,1 Martin Däumer,5 Hans-Martin Orth,1 Torsten Feldt,1 Johannes G. Bode,1 Florian Klein,3,6 Jörg Timm,2 Tom Luedde,1,a and Björn-Erik Ole Jensen1,a 1 Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; 2Institute of Virology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; 3Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; 4Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; 5Institute of Immunology and Genetics, Kaiserslautern, Germany; and 6Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany 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. immunodeficiency; sotrovimab; SARS-CoV-2; Omicron; escape. During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, numerous studies showed that treatment options that directly target SARS-CoV-2 are most successful in the early phase of..