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 demonstrate the independent convergent evolution of severe acute respiratory syndrome coronavirus (SARS-CoV-2), with its spike protein mutation L452R present in the delta (L452R), kappa (L452R), and lambda (L452Q) variants.

METHODS

Coronavirus disease 2019 (COVID-19) variants were detected in 1017 patients using whole-genome sequencing and were assessed for outcome and severity. The mechanistic effects of the epsilon versus non-epsilon variants were investigated using a multiomic approach including cellular response assays and paired cell and host transcriptomic and proteomic profiling.

RESULTS

We found that patients carrying the epsilon variant had increased mortality risk but not increased hospitalizations (P < .02). Cells infected with live epsilon compared with non-epsilon virus displayed increased sensitivity to neutralization antibodies in all patients but a slightly protective response in vaccinated individuals (P < .001). That the epsilon SARS-CoV-2 variant is more infectious but less virulent is supported mechanistically in the down-regulation of viral processing pathways seen by multiomic analyses. Importantly, this paired transcriptomics and proteomic profiling of host cellular response to live virus revealed an altered leukocyte response and metabolic messenger RNA 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 < .001) and an adjusted T-cell response in patients carrying the epsilon variant (P < .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 < .05).

CONCLUSIONS

While the epsilon variant is more infectious, by altering viral processing, we showed that patients with COVID-19 have adapted their innate immune response to this fitter variant. A protective T-cell response molecular signature is generated by this more transmissible variant in both vaccinated and unvaccinated patients.

Informations de copyright

© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Déclaration de conflit d'intérêts

Potential conflicts of interest. S. C. reports grants or contracts, unrelated to this work, from the Erika J Glazer Family Foundation. A. H. B. reports grants or contracts, unrelated to this work, from the National Institutes of Health (awards R01 HL133399 [29 March 2018 to 29 March 2022; principle investigator) and R01 DK124453 (1 April 2020 to 31 March 2024; coinvestigator); and Thermo-Brahms (15 December 2020 to 31 December 2022; FITRAPS study; coinvestigator). A. H. B. also reports the following patents: “Assays and methods of treatment relating to vitamin D insufficiency” (US patent US20140113885A1; never licensed; patent held by previous employer [Beth Israel Deaconess Medical Center] and Massachusetts General Hospital) and “Diagnosis, prognosis, and treatment of kidney disease” (US patent US9549964B2; never licensed; patent held by previous employer [Beth Israel Deaconess Medical Center]). S. C. J. reports grants or contracts unrelated to this work from CSL Behring, Hansa Biopharma, Regeneron, and CareDx; consulting fees, paid to the author, from CSL Behring, Regeneron, Hansa Biopharma, and Vera Therapeutics; stock options with CSL Behring; and 7 patents licensed by CSL Behring. E. V. reports consulting fees, paid to the author, from Thermo Fisher and Illumina. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.