US Severe Acute Respiratory Syndrome Coronavirus 2 Epsilon Variant: Highly Transmissible but With an Adjusted Muted Host T-Cell Response

Background The multiple mutations comprising the epsilon variant demonstrates the independent convergent evolution of SARS-CoV-2, with its spike protein mutation L452R present in the delta (L452R), kappa(L452R) and lambda (L452Q) variants. Methods COVID variants were detected in 1017 patients using whole genome sequencing and assessed for outcome and severity. The mechanistic effects of the episilon versus non epsilon variant were investigated using a multiomic approach including: cellular response assays and paired cell and host transcriptomic and proteomic profiling. Results We found patients carrying the epsilon variant had increased mortality but not increased hospitalizations (P < 0.02). Cells infected with live epsilon compared to non-epsilon virus displayed increased sensitivity to neutralization antibodies (NAb) in all patients but a slightly protective response in vaccinated individuals (P< 0.0001) Epsilon SARS-CoV-2 varient being more infectious but less virulent is supported mechanistically in the downregulation of viral processing pathways seen by multi-omic analyses. Importantly, this paired transcriptomics and proteomic profiling of host cellular response to live virus revealed an altered leukocyte response and metabolic mRNA processing with the epsilon variant. To ascertain host response to SARS-CoV-2 infection, primary COVID-19 positive nasopharyngeal samples were transcriptomically profiled and revealed a differential innate immune response (P < 2.0X10−12) and anadjusted T-cell response in the patients carrying the epsilon variant (P< 0.002). 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 epsilon variant (P < 0.05). Conclusions While the epsilon variant is more infectious via altering viral processing, we demonstrate that COVID-19 patients have adapted their innate immune response to this fitter variant. A protective T-cell response molecular signature is generated in both vaccinated and unvaccinated patients to this more transmissible variant.