SARS-CoV-2 Spike-Specific CD4+ T Cell Response Is Conserved Against Variants of Concern, Including Omicron

Abstract

Although accumulating data have investigated the effect of SARS-CoV-2 mutations on antibody neutralizing activity, less is known about T cell immunity. In this work, we found that the ancestral (Wuhan strain) Spike protein can efficaciously reactivate CD4+ T cell memory in subjects with previous Alpha variant infection. This finding has practical implications, as in many countries only one vaccine dose is currently administered to individuals with previous COVID-19, independently of which SARS-CoV-2 variant was responsible of the infection. We also found that only a minority of Spike-specific CD4+ T cells targets regions mutated in Alpha, Beta and Delta variants, both after natural infection and vaccination. Finally, we found that the vast majority of Spike-specific CD4+ T cell memory response induced by natural infection or mRNA vaccination is conserved also against Omicron variant. This is of importance, as this newly emerged strain is responsible for a sudden rise in COVID-19 cases worldwide due to its increased transmissibility and ability to evade antibody neutralization. Collectively, these observations suggest that most of the memory CD4+ T cell response is conserved against SARS-CoV-2 variants of concern, providing an efficacious line of defense that can protect from the development of severe forms of COVID-19.

Keywords: CD4; SARS-CoV-2; T cells; cellular immunity; natural infection; vaccination; variants of concern (VOCs).

Figure 1

CD4+ T cell response to Spike in subjects with previous SARS-CoV-2 infection is minimally affected by mutations occurring in Alpha, Beta and Delta variants (A) Frequency of CD4+ T cells specific for Wuhan Spike protein in Wuhan strain- (15) or Alpha variant- (13) infected subjects. Mild COVID-19 patients are depicted in green, moderate in red, severe in blue, critical in gray. Representative FACS plots from one subject of each group are depicted in (B). (C) Frequency of CD4+ T cells specific for Wuhan Spike, Alpha variant reference or mutated pool, Beta variant reference or mutated pool, Delta variant reference or mutated pool in subjects with previous Wuhan strain SARS-CoV-2 infection. Representative FACS plots showing CD4+ T cells reactive to Alpha, Beta and Delta reference and mutated pools from three distinct patients are depicted in (D). Data in (A, C) are subtracted of background, unstimulated condition. Red lines in (A, C) represent mean values. Dashed line in (A) represents cut-off value. *p < 0.05; **p < 0.01, calculated with Wilcoxon-Signed Rank test.

Figure 2

CD4+ T cell response to Spike in vaccinated subjects is minimally affected by mutations occurring in Alpha, Beta and Delta variants. (A) Frequency of CD4+ T cells specific for Wuhan Spike protein in mRNA- (17) or viral vector- (9) vaccinated subjects. Representative FACS plot are depicted in (B). Frequency of CD4+ T cells specific for Wuhan Spike, Alpha variant reference or mutated pool (C), Beta variant reference or mutated pool (D), Delta variant reference or mutated pool (E) in 9, 6 and 10 mRNA-vaccinated subjects, respectively. (F) Frequency of CD4+ T cells specific for Wuhan Spike, Alpha variant reference or mutated pool, Beta variant reference or mutated pool in 9 subjects with viral vector vaccination. Data in (A, C–F) are subtracted of background, unstimulated condition. Red lines in (A, C–F) represent mean values. Dashed line in (A) represents cut-off value. *p < 0.05; **p < 0.01, calculated with Mann-Whitney test (A) or Wilcoxon-Signed Rank test (C–F).

Figure 3

Omicron variant does not significantly impair CD4+ T cell memory response to Spike following natural infection and mRNA vaccination. (A) Frequency of CD4+ T cells specific for Wuhan Spike, Omicron variant reference or mutated pool in 10 subjects with previous Wuhan strain SARS-CoV-2 infection. Representative FACS plot are depicted in (B). (C) Frequency of CD4+ T cells specific for Wuhan Spike, Omicron variant reference or mutated pool in mRNA-vaccinated subjects enrolled after dose 2 (n=11) or dose 3 (n=9) administration. Representative FACS plot are depicted in (D). Data in (A, C) are subtracted of background, unstimulated condition. Red lines in (A, C) represent mean value. *p < 0.05; **p < 0.01, calculated Wilcoxon-Signed Rank test.