SARS-CoV-2 infection and vaccination-induced T cells cross-recognize Omicron

In a recent study posted to the Nature In Review* preprint server, researchers performed a comprehensive, in-depth comparison of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell epitope repertoire following natural infection of coronavirus disease 2019 (COVID-19) compared to messenger ribonucleic acid (mRNA) vaccinations.

Study: SARS-CoV-2 specific T cells induced by both SARS-CoV-2 infection and mRNA vaccination broadly cross-recognize omicron. Image Credit: Kateryna Kon / Shutterstock

Background

Although the SARS-CoV-2 Omicron variant has higher infectivity and immune evasion induced by previous infection or vaccination, the severity of COVID-19 in convalescent and vaccinated individuals is lower, indicating the protection by previously primed SARS-CoV-2-specific T cells cross-recognition of Omicron. However, comparative in-depths studies regarding the SARS-CoV-2-specific T cell epitope repertoire targeted by vaccination compared to infection-induced T cell responses are lacking.

About the study

In the present study, the researchers analyzed SARS-CoV-2-specific T cell responses in 19 individuals who recovered from SARS-CoV-2 infection, 16 participants who received two doses of Pfizer/BioNTech mRNA vaccine, and seven individuals who were mRNA booster vaccinated.

The team initially mapped the overall SARS-CoV-2-specific CD8+ T cell response. Further, they evaluated a set of 43 previously described immunodominant SARS-CoV-2-specific CD8+ T cell epitopes restricted by common human leukocyte antigen (HLA) class I alleles in epitope-specific T cell cultures after cytokine staining.

The CD8+ T cell responses in convalescents versus vaccinees were analyzed using overlapping peptides spanning the whole spike protein and an in-silico analysis. Further, the CD4+ T cell responses and the effect of boosting convalescents and two-dose vaccinated individuals were determined using overlapping spike peptides spanning the whole spike protein.

Finally, the researchers analyzed T cell response targeting highly conserved selective sweep regions in SARS-CoV-2 among convalescents compared to vaccinated individuals.

Results

The results demonstrated that convalescent individuals had CD8+ T cell responses against most of the epitopes of all SARS-CoV-2 proteins; however, spike (S)-specific responses were not dominant. In contrast, the SARS-CoV-2 vaccinees had CD8+ T cells responses targeted against the S epitopes. Some of the CD8+ T cells responses were also directed towards non-S epitopes such as HLA-B*07/N, for which T cells have previously shown cross-recognition against common cold coronaviruses. In the SARS-CoV-2 vaccinees, individual S-specific CD8+ T cells epitopes were targeted the most and had a broad range of S-specific CD8+ T cell repertoire compared to convalescent individuals.

Boosted vaccine- and infection-induced spike-specific CD8+ and CD4+ T cell responses. Number, location and percentages of spike-specific CD8+ and CD4+ T cell responses to overlapping peptides (OLP) that are detectable in SARS-CoV-2 vaccinees after the 2nd versus after the 3rd dose (A) of Pfizer/BioNTech mRNA vaccine (measured 2-4 weeks after vaccination) and in SARS-CoV-2 convalescents who subsequently received a single dose (B) of Pfizer/BioNTech mRNA boost vaccination (measured 2 weeks after vaccination) are depicted. Targeted epitopes with sequence variations in omicron are marked in red. statistical analysis was performed with paired t test.

The comparison between corresponding viral sequences of the SARS-CoV-2 ancestral and Omicron variants showed that viral variation affected only a single CD8+ T cell epitope.

SARS-CoV-2-vaccinated individuals had significantly broader S-specific CD8+ T cell responses repertoire than the convalescents. While several HLA class I alleles restricted five or more S-specific CD8+ T cell epitopes in SARS-CoV-2 vaccinees, no HLA class I allele restricted more than two S-specific CD8+ T cell epitopes in convalescents. In addition, vaccinated individuals showed a higher number of S-specific CD8+ T cell responses per individual compared to those who had SARS-CoV-2 previously.

In contrast to CD8+ T cell responses, vaccinees showed a more limited repertoire of targeted S-specific CD4+ T cell response epitopes than the SARS-CoV-2 convalescent individuals. Further, fewer S-specific CD4+ T cell epitopes were restricted by single HLA class II alleles, and fewer CD4+ T cell responses were detectable per individual in SARS-CoV-2-vaccinated individuals compared to convalescent individuals. Individual and population-based CD4+ T cell epitopes showed limited S-specific CD4+ T cell repertoire in SARS-CoV-2 vaccinees. High conservation between SARS-CoV-2 ancestral and Omicron variants was observed among the fewer targeted S-specific CD4+ T cell epitopes in SARS-CoV-2 vaccinees, as well as convalescent individuals.

Following mRNA booster vaccination, the participants had a similarly broad and cross-reactive S-specific CD8+ T cell repertoire and similarly limited; however, cross-reactive S-specific CD4+ T cell repertoire to that of SARS-CoV-2 convalescents and the two-dose mRNA vaccinated individuals. Convalescents had a broader S-specific CD8+ T cell repertoire after mRNA booster vaccination, whereas CD4+ T cell repertoire was similar before and after booster vaccination. The identified CD8+ and CD4+ T cell responses targeted epitopes were conserved in Omicron.

Highly conserved selective sweep regions in SARS-CoV-2 mediate per definition an evolutionary advantage in T cell responses in convalescents and vaccinees. The four different selective sweep regions that have been described to date exhibited a high degree of amino acid homology among the already evolved SARS-CoV-2 variants of concern (VOCs). Furthermore, vaccinated individuals demonstrated S-specific CD8+ T cell responses targeting epitopes within the highly conserved selective sweep regions compared to SARS-CoV-2 convalescents. However, a similar highly conserved selective sweep region targeted S-specific CD4+ T cell response was not evident after vaccination.

Conclusions

The study findings indicated that while convalescents target a wide range of SARS-CoV-2-specific CD8+ T cell epitopes over the complete SARS-CoV-2 proteome, S-specific CD8+ T cell responses were not dominant. Opposite to the CD4+ T cell response, vaccinees had CD8+ T cell responses targeted to a broader repertoire of highly conserved S-specific CD8+ T cell epitopes resulting in high cross-recognition potential. The mRNA booster vaccination in convalescents broadened S-specific CD8+ T cell response. Further, the CD8+ and CD4+ T cell responses in the SARS-CoV-2 convalescent and vaccinated individuals target epitopes that are highly conserved within ancestral SARS-CoV-2, Omicron, and possibly in future emerging SARS-CoV-2 VOCs.

Overall, the study findings underscore the significance of mRNA booster vaccine-induced S-specific CD8+ T cell responses in mitigating emerging SARS-CoV-2 VOCs, including Omicron, as well as the importance of mRNA booster vaccination in SARS-CoV-2 convalescent individuals.

*Important notice

Research Square and Nature In Review publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information