Omicron BA.1-specific T-cell responses in adults vaccinated with CoronaVac or BNT162b2 in Hong Kong: an observational cohort study

Abstract

Background: The primary aim of using vaccines in public health responses to SARS-CoV-2 variants of concern is to reduce incidence of severe disease, for which T-cell responses are essential. There is a paucity of data on vaccine-induced T-cell immunity to omicron (B.1.1.529). We aimed to compare SARS-CoV-2 omicron BA.1-specific T-cell responses in adults vaccinated with CoronaVac or BNT162b2.

Methods: For this observational cohort, we recruited adults (aged ≥18 years) from three vaccination centres in Hong Kong. We included participants from four cohorts (cohort 1: participants who received two doses of either BNT162b2 or CoronaVac, cohort 2: participants who received two doses and a booster, cohort 3: participants who received two doses and a booster and had a breakthrough omicron infection, and cohort 4: participants who had a previous non-omicron infection and subsequently received one dose of vaccine). People with confirmed history of COVID-19 at recruitment were excluded from cohort 1 and cohort 2. We collected blood samples before vaccination (for cohort 1 and 2), 1-month following vaccination (for all cohorts), and during convalescence for cohort 3 and 4) and determined the proportion of IFNγ⁺CD4⁺ and IFNγ⁺CD8⁺ T cells in peripheral blood against SARS-CoV-2 using flow cytometry with peptide pools of SARS-CoV-2 wild type or omicron BA.1. The primary outcome was proportion of CD4⁺ and CD8⁺ T cells against SARS-CoV-2 1 month after exposure (ie, vaccination or breakthrough infection).

Findings: Overall, between May 21, 2020, and Aug 31, 2021, we recruited 659 participants (231 [35%] men and 428 [65%] women). Of these participants, 428 were included in cohort 1 (214 [50%] received BNT162b2 and 214 [50%] received CoronaVac); 127 in cohort 2 (48 [38%] received all BNT162b2, 40 [31%] received all CoronaVac, and 39 [31%] received two CoronaVac and a booster with BNT162b2); 58 in cohort 3, and 46 in cohort 4 (16 [35%] received CoronaVac and 30 [65%] received BNT162b2). Vaccine-induced T-cell responses to the wild-type and omicron BA.1 variants were generally similar in adults receiving two doses of either CoronaVac (CD4⁺ cells p=0·33; CD8⁺ cells p=0·70) or BNT162b2 (CD4⁺ cells p=0·28; CD8⁺ cells p=1·0). Using a peptide pool of all structural proteins for stimulation, BNT162b2 induced a higher median frequency of omicron-specific CD4⁺ T cells in adults younger than 60 years (CD4⁺ cells 0·012% vs 0·010%, p=0·031; CD8⁺ cells 0·003% vs 0·000%, p=0·055) and omicron-specific CD8⁺ T cells in people aged 60 years or older (CD4⁺ cells 0·015% vs 0·006%, p=0·0070; CD8⁺ cells 0·007% vs 0·000%, p=0·035). A booster dose of either BNT162b2 or CoronaVac after two doses of CoronaVac boosted waning T-cell responses, but T-cell responses did not exceed those at 1 month after the second dose (CoronaVac CD4⁺ p=0·41, CD8⁺ p=0·79; BNT162b2 CD4⁺ p=0·70 CD8⁺ p=0·80).

Interpretation: The evidence that mRNA and inactivated vaccines based on the ancestral SARS-CoV-2 virus elicited T-cell responses to SARS-CoV-2 omicron variants might explain the high observed vaccine effectiveness against severe COVID-19 shown by both types of vaccine, despite great differences in neutralising antibody responses. The use of either vaccine can be considered if the primary aim is to reduce severity and death caused by the new omicron subvariants; however, BNT162b2 is preferable for adults older than 60 years.

Funding: The Health and Medical Research Fund Commissioned Research on the Novel Coronavirus Disease and S H Ho Foundation.

Figure 1

T-cell and antibody responses against SARS-CoV-2 in adults who received two doses of CoronaVac or BNT162b2 vaccines (cohort 1) Peripheral blood mononuclear cells collected 1 month after two doses of CoronaVac (n=214) or BNT162b2 (n=214) vaccines were stimulated with pooled spike or structural (ie, S/M/N/E) peptide pools. The proportions of CD4⁺ T cells that are IFNγ⁺ stimulated by spike peptide pools (A) and S/M/N/E peptide pools (B) and the proportions of IFNγ⁺CD8⁺ T cells stimulated by spike peptide pools (C) and S/M/N/E peptide pools (D) against wild-type or omicron BA.1 virus were measured by flow cytometry. The limit of detection following background (dimethyl sulfoxide) subtraction was 0·001, as indicated by the horizontal dashed lines. (E) The percentage of inhibition detected by the surrogate neutralisation test in the plasma of the two vaccine groups using the receptor-binding domain of the wild-type and omicron BA.1 virus. The positive threshold of the surrogate neutralisation test was 30%, as indicated by the horizontal dashed line. Whiskers indicate the minimum and maximum of the data. The upper and lower limits of the box indicate the IQR around the median. The cross represents the mean. Data within the same vaccine group were compared by the Friedman multicomparisons test followed by post-hoc pairwise Wilcoxon rank sum test paired with Benjamini-Hochberg correction. Wilcoxon rank-sum test was used to test between different subgroups. S/M/N/E=spike, membrane, nucleocapsid, and envelope proteins. *p value was generated by multiple linear regression model adjusting by age and gender.

Figure 2

T-cell responses against omicron BA.1 variant of SARS-CoV-2 in adults who received a booster dose of either CoronaVac or BNT162b2 (cohort 2) Peripheral blood mononuclear cells from 1 month after receiving the second vaccine dose and immediately before (excluding participants who received three doses of BNT162b2, due to availability of data) and 1 month after receiving a booster dose of either CoronaVac or BNT162b2 vaccine were stimulated with pooled spike or structural (S/M/N/E) peptides of omicron BA.1. n=39 for the CoronaVac–CoronaVac–BNT162b2 group, n=40 for the CoronaVac–CoronaVac–CoronaVac group, and n=48 for the BNT162b2–BNT162b2–BNT162b2 group. The proportions of IFNγ⁺CD4⁺ T cells stimulated with spike peptides (A) and S/M/N/E peptides (B) and the proportions of IFNγ⁺CD8⁺ T cells stimulated with spike peptides (C) and S/M/N/E peptides (D) were measured by flow cytometry. Whiskers indicate the minimum and maximum of the data. The upper and lower limits of the box indicate the IQR around the median. The cross represents the mean. The limit of detection following background (dimethyl sulfoxide) subtraction was 0·001, as indicated by the horizontal dashed lines. Data were compared by Friedman multicomparisons test followed by post-hoc pairwise Wilcoxon rank sum test paired with Benjamini-Hochberg correction (within each vaccine group at different timepoints) or Wilcoxon rank-sum test (between different vaccine strategies). S/M/N/E=spike, membrane, nucleocapsid, and envelope proteins.

Figure 3

T-cell responses from vaccinated adults after omicron breakthrough infection (cohort 3) or adults after convalescence from non-omicron infection who received one dose (cohort 4) Peripheral blood mononuclear cells were collected 1 month after people who had previously been vaccinated with a booster strategy had omicron breakthrough infection (n=58) or 1 month after people who had recovered from non-omicron SARS-CoV-2 infection received one dose of CoronaVac or BNT162b2 (n=46). Cells were stimulated with pooled spike or structural (S/M/N/E) peptides of either wild-type or omicron BA.1 virus. The proportions of IFNγ⁺CD4⁺ T cells stimulated with spike peptides in people with omicron breakthrough infection after booster vaccination (A) and people who received a vaccine after recovery from non-omicron infection (B), proportions of IFNγ⁺CD8⁺ T cells stimulated with spike peptides in people with omicron breakthrough infection after booster vaccination (C) and people who received a vaccine after recovery from non-omicron infection (D), proportions of IFNγ⁺CD4⁺ T cells stimulated with S/M/N/E peptides in people with omicron breakthrough infection after booster vaccination (E) and people who received a vaccine after recovery from non-omicron infection (F), and proportions of IFNγ⁺CD8⁺ T cells stimulated with S/M/N/E peptides in people with omicron breakthrough infection after booster vaccination (G) and people who received a vaccine after recovery from non-omicron infection (H) were measured by flow cytometry. Whiskers indicate the minimum and maximum of the data. The upper and lower limits of the box indicate the IQR around the median. The cross represents the mean. The limit of detection following background (dimethyl sulfoxide) subtraction was 0·001, as indicated by the horizontal dashed line. Data for wild-type and omicron virus were compared by Wilcoxon matched-pairs signed rank test. Wilcoxon rank-sum test was used to test between different subgroups. S/M/N/E=spike, membrane, nucleocapsid, and envelope proteins.

Figure 4

Memory phenotypes of the omicron-specific T cells from adults who received CoronaVac or BNT162b2 vaccine under different stimulation conditions The phenotype of IFNγ⁺CD4⁺ and IFNγ⁺CD8⁺ TEMs (CCR7^–CD45RA^–), TCMs (CCR7^–CD45RA^–), TEMRAs (CCR7^–CD45RA⁺), or TNs (CCR7⁺CD45RA⁺) responding to the omicron spike, membrane, nucleocapsid, and envelope peptide pool were determined from the peripheral blood mononuclear cells of participants after different vaccine combinations. Phenotypes characterised 1 month after two doses (A) or three doses of vaccine (B). (C) Phenotypes characterised 1 month after breakthrough omicron infection after previous booster vaccination. (D) Phenotypes characterised 1 month after the participants who had recovered from a non-omicron infection (n=46) received one dose of CoronaVac or BNT162b2. Bars represent the mean values and error bars represent 95% CI. Comparisons between vaccine groups were performed using the Wilcoxon rank-sum test. BB=BNT162b2–BNT162b2. BBB=BNT162b2–BNT162b2–BNT162b2. CC=CoronaVac–CoronaVac. CCB=CoronaVac–CoronaVac–BNT162b2. CCC=CoronaVac–CoronaVac–CoronaVac. TCM=central memory T cell. TEM=effector memory T cell. TEMRA=terminally differentiated effector memory T cell. TN=naive T cell.