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BNT162b2-induced memory T cells respond to the Omicron variant with preserved polyfunctionality - Nature.com

BNT162b2-induced memory T cells respond to the Omicron variant with preserved polyfunctionality - Nature.com

BNT162b2-induced memory T cells respond to the Omicron variant with preserved polyfunctionality - Nature.com
May 16, 2022 13 mins, 47 secs

The Omicron variant (B.1.1.529) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) extensively escapes neutralizing antibodies elicited by SARS-CoV-2 infection or vaccination.

In the present study, we investigated whether BNT162b2 messenger RNA vaccine-induced memory T cells functionally respond to the Omicron spike protein.

Vaccine-induced memory T cells exhibited substantial responses to the Omicron spike protein, with no difference between healthcare workers with two versus three vaccine doses.

In individuals with prior infection, two-dose vaccination robustly boosted memory T cells that responded to the Omicron spike protein and the SARS-CoV-2 wild-type (lineage B) spike protein.

Importantly, polyfunctionality was preserved in vaccine-induced memory T cells responding to the Omicron spike protein.

The present findings indicate that BNT162b2-induced memory T cells substantially respond to the Omicron variant with preserved polyfunctionality.

Since the COVID-19 pandemic began, several variants of concern (VOCs) have emerged, including the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Omicron (B.1.1.529) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants2.

The Omicron variant carries over 30 mutations in its spike protein and infects host cells more efficiently than other variants3,4; thus, it has rapidly replaced other variants and is the dominant SARS-CoV-2 strain worldwide3.

The high number of mutations in the Omicron spike protein prompted concerns that this variant might escape from the immunity elicited by COVID-19 vaccination or natural infection5.

In fact, recent studies demonstrate that the Omicron variant extensively escapes the neutralizing activities of antibodies present in COVID-19 convalescent or vaccinated individuals6,7,8,9,10,11.

Although a third-dose booster vaccination significantly increases neutralizing activities against the Omicron variant7,10,12,13,14,15,16, this variant frequently causes breakthrough infections among individuals immunized with COVID-19 vaccines17,18.

In the present study, we investigated whether COVID-19 vaccine-induced memory T cells functionally respond to the Omicron spike protein by analysing samples from BNT162b2-vaccinated healthcare workers (HCWs) and individuals with prior SARS-CoV-2 infection.

We report that BNT162b2-induced memory T cells substantially respond to the Omicron variant with preserved polyfunctionality.

We performed intracellular cytokine staining (ICS) assays for interferon-γ (IFN-γ), interleukin-2 (IL-2) and tumour necrosis factor (TNF) in peripheral blood mononuclear cells (PBMCs) that were stimulated using overlapping peptide (OLP) pools for the spike protein of the SARS-CoV-2 wild-type (WT) (lineage B) strain and the Omicron variant (Fig. 1a).

We compared the frequency of IFN-γ-producing CD4+ T cells against the WT spike protein versus the Omicron spike protein and found that the average frequency against the Omicron spike protein was 22% (P < 0.001) and 10% (P < 0.05) lower in PBMCs from HCWs with 2 and 3 doses of the vaccine, respectively (Fig. 1b, left).

Nevertheless, BNT162b2-induced memory CD4+ T cells maintained substantial responses to the Omicron spike protein.

The frequency of TNF-producing CD4+ T cells against the Omicron spike protein, compared to the WT spike protein, was decreased by 14% (P < 0.005) and 6% (non-significant) in the two- and three-dose vaccinated groups, respectively (Fig. 1b, middle).

Similarly, the frequency of IL-2-producing CD4+ T cells against the Omicron spike protein, compared to the WT spike protein, was decreased by 21% (P < 0.001) in the two-dose vaccinated group and by 3% (non-significant) in the three-dose vaccinated group (Fig. 1b, right).

ICS was performed to examine the frequency of CD4+ or CD8+ T cells responding to the WT and Omicron spike proteins.

a,d, Representative flow cytometry plots showing cytokine-producing cells among CD4+ (a) or CD8+ (d) T cells.

b,c,e,f, The frequency of cytokine-producing CD4+ (b,c) or CD8+ (e,f) T cells against the WT and Omicron spike proteins in HCWs with 2 (n = 20) or 3 (n = 20) doses of the BNT162b2 vaccine (b,e) and in COVID-19-recovered individuals with 2 BNT162b2 vaccine doses (n = 20) (c,f).

The percentage numbers in each graph indicate the mean decrease in the frequency of cytokine-producing cells against the Omicron spike protein compared to the WT spike protein.

P values were calculated with a two-tailed, matched-pairs Wilcoxon signed-rank test (WT versus Omicron) or two-tailed, unpaired Mann–Whitney U-test.

Two-dose BNT162b2 vaccination significantly increased the frequency of IFN-γ-producing CD4+ T cells against both the WT and Omicron spike protein (Fig. 1c, left).

The frequency of IFN-γ-producing CD4+ T cells against the Omicron spike protein, compared to against the WT spike protein, was reduced by 26% (P < 0.01) before vaccination, 5% (non-significant) at 1 month after the second vaccination and 9% (P < 0.05) at 3 months after the second vaccination.

Similarly, against the Omicron spike protein compared to the WT spike protein, the frequency of TNF-producing CD4+ T cells decreased by 19% (P < 0.05), 7% (non-significant) and 19% (P < 0.01) at the 3 time points (Fig. 1c, middle); the frequency of IL-2-producing CD4+ T cells decreased by 3% (non-significant), 8% (P < 0.05) and 11% (P < 0.005) at the 3 time points (Fig. 1c, right).

These findings indicated that vaccine-induced memory T cells substantially responded to the Omicron spike protein.

The observed CD8+ T cell responses were relatively weak and IL-2-producing cells were not detected among CD8+ T cells (Fig. 1d).

Therefore, we analysed IFN-γ and TNF production from CD8+ T cells and found that memory CD8+ T cells exhibited substantial responses to the Omicron spike protein.

Both the IFN-γ and TNF responses were non-significantly decreased against the Omicron spike protein compared to the WT spike protein (Fig. 1e,f) and did not significantly differ between the two- and three-dose vaccinated groups (Fig. 1e).

Vaccination induced significantly increased responses against both WT and Omicron spike protein among individuals with prior infection (Fig. 1f).

Our results showed that the geometric MFI did not differ between T cells responding to the WT versus Omicron spike protein in the CD4+ or CD8+ T cell population (Extended Data Fig. 1).

Our analysis of CD4+ T cells from HCWs revealed an IFN-γ+ response against the WT spike protein in 90% (18 of 20) of two-dose vaccinated donors and 60% (12 of 20) of three-dose vaccinated donors (Fig. 2a, left).

The corresponding percentages of IFN-γ+ responses against the Omicron spike protein were reduced to 80% (16 of 20 two-dose vaccinated donors) and 55% (11 of 20 three-dose vaccinated donors); however, these percentages did not notably differ from the percentages of positive responders against the WT spike protein.

Similar results were observed in analyses of TNF- or IL-2-producing CD4+ T cells (Fig. 2a, middle and right).

a–d, The percentage of positive responders was determined on the basis of the percentage of cells positive for each cytokine in the CD4+ (a,b) or CD8+ (c,d) T cell population in HCWs with 2 (n = 20) or 3 (n = 20) doses of the BNT162b2 vaccine (a,c) and in COVID-19-recovered individuals with 2 BNT162b2 vaccine doses (n = 20) (b,d).

In individuals with prior infection, a two-dose BNT162b2 vaccination increased the percentage of IFN-γ+ responders to 100% against both WT and Omicron spike protein and these responses were maintained for 3 months (Fig. 2b, left).

Similar results were obtained in analyses of TNF- or IL-2-producing CD4+ T cells (Fig. 2b, middle and right).

In our analysis of CD8+ T cell responses, the percentages of positive responders were relatively low compared to our analysis of CD4+ T cell responses.

However, the percentages of IFN-γ+ or TNF+ responders did not notably differ between CD8+ T cell responses against the WT versus Omicron spike protein in HCWs (Fig. 2c) or in individuals with prior infection (Fig. 2d).

We also calculated the ratio of the frequency of cytokine-producing T cells against the Omicron spike protein to the frequency of cytokine-producing T cells against the WT spike protein for each cytokine in each individual.

These findings indicate that although BNT162b2-induced memory T cells generally exhibited a substantial response to the Omicron spike protein, they could not respond to the Omicron spike protein in certain individuals.

a,b, The ratio of the frequency of cytokine-producing T cells against the Omicron spike protein to the frequency of cytokine-producing T cells against the WT spike protein was determined for each cytokine in each individual.

CD4+ (a) and CD8+ (b) T cells were analysed in HCWs with two or three doses of the BNT162b2 vaccine and in COVID-19-recovered individuals with two BNT162b2 vaccine doses.

Positive responders for each cytokine against the WT spike protein were included in this analysis.

We further focused on the polyfunctionality of the memory T cells that responded to the WT or Omicron spike protein.

Polyfunctional T cells, which simultaneously exert several effector functions, play a crucial role in host protection during viral infection22,23,24,25.

Representative flow cytometry dot plots showed that a proportion of CD4+ T cells simultaneously produced IFN-γ, TNF and IL-2 in response to both WT and Omicron spike protein OLPs (Fig. 4a).

We additionally analysed polyfunctional (triple-positive or double-positive) CD4+ T cells from two- and three-dose vaccinated HCWs.

Against the Omicron spike protein compared to the WT spike, the average percentage of polyfunctional cells decreased by 8% (P < 0.05) in two-dose vaccinated donors and 2% (non-significant) in three-dose vaccinated donors (Fig. 4c).

In our analysis of polyfunctionality using every possible combination of functions, we observed no significant difference between CD4+ T cells responding to the WT versus Omicron spike protein (Fig. 4d).

a, Representative flow cytometry plots showing polyfunctional cells among CD4+ T cells.

c, Percentage of polyfunctional T cells among any cytokine-producing CD4+ T cells from HCWs with 2 (n = 18) or 3 (n = 12) doses of the BNT162b2 vaccine.

e, Percentage of polyfunctional T cells among any cytokine-producing CD4+ T cells from COVID-19-recovered individuals with 2 doses of the BNT162b2 vaccine (n = 18 for pre-vaccine; n = 20 for 1 month post 2× vaccine; n = 20 for 1 month post 2× vaccine).

f, Pie graphs representing the fraction of cells positive for a given number of functions among CD4+ T cells with any type of function before vaccination and one month after the second vaccination.

CD4+ T cell IFN-γ responders against the WT spike protein were included in this analysis.

P values were calculated with a two-tailed, matched-pairs Wilcoxon signed-rank test (WT versus Omicron) or two-tailed, unpaired Mann–Whitney U-test.

In individuals with prior infection, two-dose BNT162b2 vaccination significantly increased the percentage of polyfunctional cells against both the WT and Omicron spike protein (Fig. 4e).

At all three time points, the percentage of polyfunctional cells did not significantly differ between CD4+ T cells responding to the WT versus Omicron spike protein.

Polyfunctionality analysis using pie graphs confirmed that two-dose vaccination was associated with a significant increase in the percentage of polyfunctional cells against both the WT and Omicron spike protein (Fig. 4f).

In our analysis of polyfunctionality using every possible combination of functions, we found no significant difference between the CD4+ T cells responding to the WT versus Omicron spike protein (Fig. 4g).

We also analysed the polyfunctionality of BNT162b2-induced memory CD8+ T cells.

In the HCW groups with two and three doses of the vaccine, the percentage of polyfunctional cells was not significantly decreased against the Omicron spike protein compared to the WT spike (Fig. 5a).

In our analysis of polyfunctionality using every possible combination of functions, we observed no significant difference between CD8+ T cells responding to the WT versus Omicron spike protein (Fig. 5b).

In individuals with prior infection, at all three time points, the percentage of polyfunctional cells did not significantly differ between CD8+ T cells responding to WT versus Omicron spike protein (Fig. 5c).

The pie graphs also confirmed that the polyfunctional responses did not significantly differ against WT versus Omicron spike protein (Fig. 5d); when we analysed polyfunctionality using every possible combination of functions, we again found no significant difference between CD8+ T cells responding to the WT versus Omicron spike protein (Fig. 5e).

Taken together, these results demonstrate that BNT162b2-induced memory CD4+ and CD8+ T cells exhibit preserved polyfunctionality against the Omicron spike protein.

a, Percentage of polyfunctional T cells among any cytokine-producing CD8+ T cells from HCWs with two or three doses of the BNT162b2 vaccine.

c, Percentage of polyfunctional T cells among any cytokine-producing CD8+ T cells from COVID-19-recovered individuals with two doses of the BNT162b2 vaccine.

d, Pie graphs representing the fraction of cells positive for a given number of functions among CD8+ T cells with any type of functions before vaccination and one month after the second vaccination.

CD8+ T cell IFN-γ responders against the WT spike protein were included in this analysis.

P values were calculated with a two-tailed, matched-pairs Wilcoxon signed-rank test (WT versus Omicron) or two-tailed, unpaired Mann–Whitney U-test.

Since its emergence, the Omicron variant has shown remarkable ability to escape the neutralizing activities of antibodies present in individuals convalescing from COVID-19 or vaccinated individuals6,7,8.

However, our current study demonstrates that memory T cells elicited by BNT162b2 vaccination substantially respond to the Omicron variant with polyfunctionality.

This finding is in line with recent reports of relatively preserved responses of infection- or vaccine-induced memory T cells against the Omicron variant26,27,28,29,30.

Notably, it has also been demonstrated that T cell epitopes in SARS-CoV-2 proteins are substantially conserved in the spike and non-spike proteins of the Omicron variant31.

The other SARS-CoV-2 VOCs, including the Alpha, Beta, Gamma and Delta variants, also rarely escape the memory T cell responses elicited by COVID-19 vaccination or natural infection32,33,34,35,36, although they can considerably evade the neutralizing activities of antibodies induced by vaccination or infection1.

These findings indicate that vaccine-induced memory T cells may recognize and respond to a broad range of variants even if nAbs cannot neutralize them.

The host-protective roles of T cells have been demonstrated in patients and animal models with SARS-CoV-2 infection.

In a macaque model, depletion of CD8+ T cells in convalescent animals partially abrogated host protection against SARS-CoV-2 rechallenge37.

Collectively, these data indicate that T cells contribute to host protection against SARS-CoV-2, particularly when nAb activity is suboptimal and insufficient, for example, because of waning nAbs and emerging variants36.

Our present results demonstrate that BNT162b2-induced memory T cells substantially respond to the Omicron variant with preserved polyfunctionality.

These findings suggest that memory T cells exert effector functions against the Omicron variant during breakthrough infections in individuals immunized with COVID-19 vaccines.

Cryopreserved PBMCs were thawed, rested overnight at 37 °C and cultured in the presence of OLP pools (1 μg ml−1 for each peptide; Peptides & Elephants GmbH) for the spike protein of the WT strain (NM908947) or Omicron variant (hCoV-19/South Africa/CERI-KRISP-K032284/2021; EPI_ISL_6699770 in GISAID) and anti-human CD28 and CD49d monoclonal antibodies (mAbs) (1 μg ml−1 for each; BD Biosciences) for 6 h at 37 °C.

We calculated the percentage of positive responders based on the percentage of cells positive for each cytokine in the CD4+ or CD8+ T cell population.

SARS-CoV-2 Omicron variant replication in human bronchus and lung ex vivo.

Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity.

Heavily mutated Omicron variant puts scientists on alert.

Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2.

Considerable escape of SARS-CoV-2 Omicron to antibody neutralization.

The Omicron variant is highly resistant against antibody-mediated neutralization: implications for control of the COVID-19 pandemic.

mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variantK

mRNA-1273 and BNT162b2 mRNA vaccines have reduced neutralizing activity against the SARS-CoV-2 omicron variant.

Activity of convalescent and vaccine serum against SARS-CoV-2 Omicron.

Neutralizing antibodies to SARS-CoV-2 Omicron variant after third mRNA vaccination in health care workers and elderly subjects.

Neutralisation sensitivity of the SARS-CoV-2 omicron (B.1.1.529) variant: a cross-sectional study.

Association between 3 doses of mRNA COVID-19 vaccine and symptomatic infection caused by the SARS-CoV-2 Omicron and Delta variants.

mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant.

Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study.

Breakthrough infections with SARS-CoV-2 omicron despite mRNA vaccine booster dose.

HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cellsJ

Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses.

Ancestral SARS-CoV-2-specific T cells cross-recognize the Omicron variantC

T cell reactivity to the SARS-CoV-2 Omicron variant is preserved in most but not all individuals.

SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron.

T cell responses to SARS-CoV-2 spike cross-recognize Omicron.

Vaccines elicit highly conserved cellular immunity to SARS-CoV-2 Omicron.

T cell epitopes in SARS-CoV-2 proteins are substantially conserved in the Omicron variant.

SARS-CoV-2 mRNA vaccines induce broad CD4+ T cell responses that recognize SARS-CoV-2 variants and HCoV-NL63.

Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals.

CD8+ T cells contribute to survival in patients with COVID-19 and hematologic cancer

The geometric mean fluorescence intensity (gMFI) was determined for each cytokine among cytokine-producing cells

BNT162b2-induced memory T cells respond to the Omicron variant with preserved polyfunctionality

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