Objectives: We characterized the molecular and mutational landscape of SARS-CoV-2 recombinant strains in Botswana.

Methods: We performed genomic, phylogenetic, and immunoinformatic analyses of 5254 near-complete genomes from 2020 to 2023. We assessed the presence of mutations of interested (MutOI) that may be associated with immune escape in silico.

Results: We observed a few recombinant strains in Botswana, with the majority being descendants of Omicron (XBB*), except for XV and XM. Most recombinant sequences corresponded to transmission clusters. Most recombination events occurred within the receptor-binding domain (RDB) of the spike (S) protein. We identified 16 MutOI among different proteins, with the majority occurring at a very low global prevalence (<4.8 × 10-⁵). We also observed S:Q474K, a MutOI in the RBD, that was predicted to escape human leukocyte antigen class I-mediated immune responses. Molecular surveillance is vital to inform early detection and response to potential variants with heightened immune and vaccine breakthrough properties.

Conclusions: These results underscore the need for continued molecular surveillance to map the evolutionary landscape of SARS-CoV-2.

Keywords: Africa; Botswana; COVID-19; Immune escape; Recombination; SARS-CoV-2.