Summary
Background The emergence of recombinant viruses is a threat to public health. Recombination of viral variants may combine variant-specific features that together catalyze viral escape from treatment or immunity. The selective advantages of recombinant SARS-CoV-2 isolates over their parental lineages remain unknown.
Methods Multi-method amplicon and metagenomic sequencing of a clinical swab and the in vitro grown virus allowed for high-confidence detection of a novel recombinant variant. Mutational, phylogeographic, and structural analyses determined features of the recombinant genome and spike protein. Neutralization assays using infectious as well as pseudotyped viruses and point mutants thereof defined the recombinant’s sensitivity to a panel of monoclonal antibodies and sera from vaccinated and/or convalescent individuals.
Results A novel Delta-Omicron SARS-CoV-2 recombinant was identified in an unvaccinated, immunosuppressed kidney transplant recipient treated with monoclonal antibody Sotrovimab. The recombination breakpoint is located in the spike N-terminal domain, adjacent to the Sotrovimab quaternary binding site, and results in a 5’-Delta AY.45 and a 3’-Omicron BA.1 mosaic spike protein. Delta and BA.1 are sensitive to Sotrovimab neutralization, whereas the Delta-Omicron recombinant is highly resistant to Sotrovimab, both with and without the RBD resistance mutation E340D.
Conclusions Recombination between circulating SARS-CoV-2 variants can functionally contribute to immune escape. It is critical to validate phenotypes of mosaic viruses and monitor immunosuppressed COVID-19 patients treated with monoclonal antibodies for the selection of recombinant and immune escape variants. (Funded by NYU, the National Institutes of Health, and others)
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of Interest Statement: The authors have declared that no conflict of interest exists.
The manuscript now contains new neutralization using in vitro grown recombinant virus and pseudoviruses with site directed mutagenesis; the data show that recombination itself is sufficient to confer resistance to Sotrovimab, and it is complemented by a rare E340D mutation in spike. We also determined that the phyleogeographic organ of the AY.45 Delta genome which is the 5' portion of the recombinant virus, lies in New York. Figures 3 and 4 are new and the Supplemental files are updated. There are new authors added who generated the neutralization data.
