Year-long COVID-19 infection reveals within-host evolution of SARS-CoV-2 in a patient with B cell depletion

Nussenblatt, Veronique; Roder, Allison E; Das, Sanchita; de Wit, Emmie; Youn, Jung-Ho; Banakis, Stephanie; Mushegian, Alexandra; Mederos, Christopher; Wang, Wei; Chung, Matthew; Pérez-Pérez, Lizzette; Palmore, Tara; Brudno, Jennifer N.; Kochenderfer, James N.; Ghedin, Elodie

BACKGROUND: B-cell depleting therapies may lead to protracted disease and prolonged viral shedding in individuals infected with SARS-CoV-2. Viral persistence in the setting of immunosuppression raises concern for viral evolution. METHODS: Amplification of sub-genomic transcripts for the E gene (sgE) was done on nasopharyngeal samples over the course of 355 days in a patient infected with SARS-CoV-2 who had previously undergone CAR T cell therapy and had persistently positive SARS-CoV-2 nasopharyngeal swabs. Whole genome sequencing was performed on samples from the patient’s original presentation and 10 months later. RESULTS: Over the course of almost a year, the virus accumulated a unique in-frame deletion in the amino-terminal domain of the spike protein, and complete deletion of ORF7b and ORF8, the first report of its kind in an immunocompromised patient. Also, minority variants that were identified in the early samples—reflecting the heterogeneity of the initial infection—were found to be fixed late in the infection. Remdesivir and high-titer convalescent plasma treatment were given, and the infection was eventually cleared after 335 days of infection. CONCLUSIONS: The unique viral mutations found in this study highlight the importance of analysing viral evolution in protracted SARS-CoV-2 infection, especially in immunosuppressed hosts, and the implication of these mutations in the emergence of viral variants.