Functional Assessment of US SARS-CoV-2 L452R Epsilon Variant

The multiple mutations comprising the epsilon variant demonstrates the independent convergent evolution of SARS-CoV-2 with its spike protein mutation L452R also present in the delta variant. Cells infected with live viral samples of the epsilon viral variant compared to non-epsilon variant displayed increased sensitivity to neutralization antibodies (NAb) suggesting an intact humoral response (P< 1.0 e-4). The ability for SARS-CoV2 to become more infectious but less virulent is supported mechanistically in the downregulation of viral processing pathways seen by multiomic analyses. Importantly, this paired transcriptomics and proteomic profiling of cellular response to live virus revealed an altered leukocyte response and metabolic mRNA processing in cells upon live viral infection of the epsilon variant. To ascertain host response to SARS-CoV-2 infection, primary COVID-19 positive nasopharyngeal samples were transcriptomically profiled a differential innate immune response (P<2.0 e-12) but, a relatively unaltered T cell response in the patients carrying the epsilon variant (P< 2.0 e-3). In fact, patients infected with SARS-CoV-2 and those vaccinated with the BNT162b2 vaccine have comparable CD4+/CD8+ T-cell immune responses to the B.1.429 variant (P<5 e-2). The epsilon variant alters viral processing response in infected cells, and the host innate immune response in COVID-19 positive nasopharyngeal swabs, but generates a protective host T cell response molecular signature in both vaccinated and unvaccinated patients.