A new sublineage of the Omicron variant of SARS-CoV-2, labeled BA.1.23, has emerged through extensive intrahost evolution within an immunocompromised patient with diffuse B-cell lymphoma. Genomic sequencing of serial nasopharyngeal and anterior nares samples from the patient, referred to as P1, over a 12-week period revealed the accumulation of nine amino acid substitutions in the spike protein N-terminal domain (NTD), the receptor binding domain (RBD), and in the S1/S2 furin cleavage site (FCS). Two weeks after the first four mutations were detected, L167T and the FCS mutation P681Y were detected in addition to the four earlier mutations.
The SARS-CoV-2 substitution rate varied throughout the course of infection, with an initial period of three weeks without changes in the consensus sequence, followed by a rapid accumulation of substitutions from week 4 to week 12. On average, one substitution per week was observed during this period, corresponding to a rate of 52 substitutions per year, which is double the global average of 26-27 substitutions per year.
The presence of the same unique combination of mutations in five additional cases suggests limited local forward transmission of this novel Omicron subvariant, with three hematologic malignancy patients in the same healthcare system testing positive for the BA.1.23 variant. Patient P4 developed a persistent infection lasting for four weeks, with acquisition of an additional mutation in the spike RBD (S:V445A) within one week of the initial positive test, while patient P3 had a persistent infection lasting for over four months. In the 13 serially collected specimens from Patient P3, several new amino acid substitutions were identified throughout the viral genome.
The emergence of the BA.1.23 sublineage highlights the role of intrahost evolution in driving the development of viral variants. It also underscores the importance of continued genomic surveillance to monitor the emergence and spread of new variants and their potential impact on public health. Further research into the mechanisms driving the positive intrahost selection of spike protein changes due to competitive replication advantages could lead to new strategies for mitigating viral evolution and transmission. The findings also have implications for the ongoing COVID-19 vaccination efforts, suggesting the importance of developing and administering vaccines that can target a wide range of viral variants.
