Immunosuppression as a hub for SARS-CoV-2 mutational drift

Newly emerging SARS-CoV-2 variants of concern (VOCs) play a major role in the persistence of the coronavirus disease 2019 (COVID-19) pandemic. While these VOCs are characterized by extraordinary evolutionary leaps and evasion from previously acquired immunity, their origins remain mostly unknown. In this study, we paired electronic health records of individuals infected with SARS-CoV-2 to viral whole-genome sequences, to assess effects of host clinical parameters and immunity on the intra-host evolution of SARS-CoV-2. We found small, albeit significant differences in SARS-CoV-2 intra-host diversity, which depended on host parameters such as vaccination status and smoking. Viral genomes showed a significant difference in the early course of disease in only one of 31 immunosuppressed patients, a recently vaccinated woman aged in her 70s. We highlight the unusually mutated viral genome obtained from this woman, which harbored near-complete truncating of the accessory protein ORF3a. Our findings suggest only minor influence of host parameters on the SARS-CoV-2 intra-host evolutionary rate and trajectory, with even the majority of immunosuppressed persons carrying fairly unremarkable viral genomes. We hypothesize that major evolutionary steps, such as those observed in VOCs, are rare occurrences, even among immunodeficient hosts. HighlightsO_LIIntra-host viral diversity is modestly affected by host clinical parameters, such as vaccination status and smoking. C_LIO_LIThe emergence and fixation of high-impact SARS-CoV-2 mutations in immunosuppressed hosts are rare, and not exclusive to patients with prolonged viral shedding. C_LIO_LIWe identified a rare stop-gain mutation, leading to near-complete truncating of ORF3a, in an immunosuppressed woman recently vaccinated against COVID-19. C_LI