Summary

Introduction

Results

Discussion

STAR Methods

Acknowledgments

REFERENCES

Summary

     The SARS-CoV-2 Omicron variant (B.1.1.529) contains mutations that mediate escape from antibody responses, although the extent to which these substitutions in spike and non-spike proteins affect T cell recognition is unknown. In this study, we show that T cell responses in individuals with prior infection, vaccination, both prior infection and vaccination, and boosted vaccination are largely preserved to Omicron spike and non-spike proteins. However, we also identify a subset of individuals (∼۲۱%) with a >50% reduction in T cell reactivity to the Omicron spike. Evaluation of functional CD4+ and CD8+ memory T cell responses confirmed these findings and revealed that reduced recognition to Omicron spike is primarily observed within the CD8+ T cell compartment potentially due to escape from HLA binding. Booster vaccination enhanced T cell responses to Omicron spike. In contrast to neutralizing immunity, these findings suggest preservation of T cell responses to the Omicron variant, although with reduced reactivity in some individuals.

Introduction

     The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529), first identified in November 2021, has been the cause of a new surge of infections globally (Viana et al., 2021). With as many as 36 substitutions in the viral spike protein and 59 mutations in total throughout its genome, Omicron has been found to evade neutralization by infection- and vaccine-induced antibodies with unprecedented frequency (Garcia-Beltran et al., 2021a; Hoffmann et al., 2021) and escape neutralization by most therapeutic monoclonal antibodies (Ikemura et al., 2021; VanBlargan et al., 2021). Additional booster vaccine doses partially compensate for this effect (Garcia-Beltran et al., 2022; Hoffmann et al., 2021), but the durability of such protective antibody response remains to be determined. Thus, whether additional arms of the adaptive immune response, namely T cell responses, can augment protection against Omicron infection and disease are of considerable interest and have implications for predicting the course of future SARS-CoV-2 variants.

     In individuals with previous SARS-CoV-2 infection and vaccinees, robust T cell responses are quantitatively and qualitatively associated with milder outcomes (Moderbacher et al., 2020). Early induction of antigen-specific CD4+ T cells following vaccination is associated with coordinated generation of antibody and CD8+ T cell responses (Painter et al., 2021). Previous studies have also shown a key role for CD8+ T cells in mitigating COVID-19 disease severity and inducing long-term immune protection. Mild COVID-19 disease is associated with increased clonal expansion of CD8+ T cells in bronchoalveloar lavage fluid (Liao et al., 2020), robust CD8+ T cell reactivity to SARS-CoV-2 epitopes (Peng et al., 2020; Sekine et al., 2020), and rapid CD8+ T cell-mediated viral clearance (Tan et al., 2021). In addition, depletion of CD8+ T cells from convalescent macaques reduced protective immunity (McMahan et al., 2021). Given that T cells can target regions across the SARS-CoV-2 proteome and are not limited solely to the spike protein, it is perhaps not unexpected that prior SARS-CoV-2 variants were able to escape neutralizing antibody responses (Garcia-Beltran et al., 2021a), but not T cells (Geers et al., 2021). Thus, in light of the emergence of the Omicron variant, we sought to determine the extent to which mutations in the variant spike and nonspike proteins affect CD4+ and CD8+ T cell reactivities.

Results

     To assess the cross-reactivity of T cell responses to the Omicron variant, we studied anti-SARS-CoV-2 T cell responses in 76 ambulatory adult volunteers in Chelsea, Massachusetts sampled prior to vaccination, after primary series vaccination, and/or after receipt of additional “booster” doses. Study groups were stratified by prior infection (confirmed by anti-nucleocapsid antibody testing) and vaccination status (Table S1). In total, we studied 101 samples from 76 donors (Figure 1A). The median age was 45 years (range 37–۶۰ years), and 64% were female. Of the previously infected individuals, we included 11 unvaccinated, 12 vaccinated sampled after initial vaccination series, and 13 vaccinated and sampled after booster doses individuals. Among individuals without previous infection, we included 10 unvaccinated, 24 sampled after initial vaccination series, and 31 vaccinated and sampled after booster doses individuals. Samples were obtained at a median 220 (range 130–۲۸۶) days after primary series vaccination or 10 days (range 8–۵۴) after additional booster doses. The primary analysis of host, vaccine, and variant variables that affect T cell responses was by multivariate regression.