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

Abstract

The highly mutated SARS-CoV-2 Omicron (B.1.1.529) variant has been shown to evade a substantial fraction of neutralizing antibody responses elicited by current vaccines that encode the WA1/2020 spike protein¹. Cellular immune responses, particularly CD8⁺ T cell responses, probably contribute to protection against severe SARS-CoV-2 infection^2-6. Here we show that cellular immunity induced by current vaccines against SARS-CoV-2 is highly conserved to the SARS-CoV-2 Omicron spike protein. Individuals who received the Ad26.COV2.S or BNT162b2 vaccines demonstrated durable spike-specific CD8⁺ and CD4⁺ T cell responses, which showed extensive cross-reactivity against both the Delta and the Omicron variants, including in central and effector memory cellular subpopulations. Median Omicron spike-specific CD8⁺ T cell responses were 82-84% of the WA1/2020 spike-specific CD8⁺ T cell responses. These data provide immunological context for the observation that current vaccines still show robust protection against severe disease with the SARS-CoV-2 Omicron variant despite the substantially reduced neutralizing antibody responses^7,8.

Fig. 1. Humoral immune responses to Omicron.

Antibody responses at months 1 and 8 following final vaccination with Ad26.COV2.S (n = 20) or BNT162b2 (n = 27). a, Neutralizing antibody (NAb) titres by a luciferase-based pseudovirus neutralization assay. b, Receptor-binding domain (RBD)-specific binding antibody titres by ELISA. Responses were measured against the SARS-CoV-2 WA1/2020 (WA), B.1.617.2 (Delta), B.1.351 (Beta) and B.1.1.529 (Omicron) variants. Medians (red bars) are depicted and numerically shown.

Fig. 2. Cellular immune responses to Omicron.

T cell responses at months 1 and 8 following final vaccination with Ad26.COV2.S (n = 20) or BNT162b2 (n = 27). a, b, Pooled peptide spike-specific IFNγ CD8⁺ T cell responses (a) and CD4⁺ T cell responses (b) by intracellular cytokine staining assays. Responses were measured against the SARS-CoV-2 WA1/2020, B.1.617.2 (Delta) and B.1.1.529 (Omicron) variants. Responses in five unvaccinated, uninfected individuals are also shown. Media backgrounds were subtracted from the specific values. Medians (red bars) are depicted and numerically shown.

Fig. 3. Correlations of variant-specific and WA1/2020-specific cellular immune responses.

a, Ratio of Omicron to WA1/2020 CD8⁺ (top) and CD4⁺ (bottom) T cell responses in individual participants. b, c, Correlations of log Delta-specific and Omicron-specific to log WA1/2020-specific CD8⁺ T cell responses (b) and CD4⁺ T cell responses (c) by intracellular cytokine staining assays. Two-sided unadjusted P and R values for linear regression correlations are shown, and lines of best fit and slopes are depicted.

Fig. 4. Cellular immune memory subpopulations to Omicron.

Pooled peptide spike-specific IFNγ CD8⁺ and CD4⁺ central memory (CD45RA⁻CD27⁺) and effector memory (CD45RA⁻CD27⁻) T cell responses by intracellular cytokine staining assays at months 1 and 8 following final vaccination with Ad26.COV2.S (n = 20). Responses were measured against the SARS-CoV-2 WA1/2020, B.1.617.2 (Delta) and B.1.1.529 (Omicron) variants. Medians (red bars) are depicted and numerically shown.

Extended Data Fig. 1. Nucleocapsid antibody responses.

Nucleocapsid antibody responses at month 8 following final vaccination with Ad26.COV2.S (N = 20) or BNT162b2 (N = 27) by meso-scale discovery (MSD) electrochemoluminscent assay. SARS-CoV-2 convalescent and pre-pandemic samples were included as positive and negative controls, respectively. Relative light units are shown.

Extended Data Fig. 2. ELISA reactivity against WA1/2020, Beta, Delta, and Omicron RBD proteins.

Positive and negative control standards were assessed by ELISA against WA1/2020, Beta, Delta, and Omicron RBD proteins. The positive control standards were known to have 2-3 fold lower antibody titers to Omicron.

Extended Data Fig. 3. Cellular immune responses to Omicron by ELISPOT assays.

Spike-specific IFN-γ ELISPOT assays at month 1 and 8 following final vaccination with Ad26.COV2.S (N = 20) or BNT162b2 (N = 27). Responses were measured against the SARS-CoV-2 WA1/2020, B.1.617.2 (Delta), and B.1.1.529 (Omicron) variants. Medians (red bars) are depicted and numerically shown.

Extended Data Fig. 4. Representative CD8+ T cell responses by flow cytometry.

Representative of 47 samples is shown.

Extended Data Fig. 5. Representative CD4+ T cell responses by flow cytometry.

Representative of 47 samples is shown.

Extended Data Fig. 6. Cellular immune responses to Omicron by intracellular cytokine staining assays.

Spike-specific IFN-γ, TNF-α, and IL-2 CD8+ and CD4+ T cell responses by intracellular cytokine staining assays at month 8 following final vaccination with Ad26.COV2.S (N = 20). Responses were measured against the SARS-CoV-2 WA1/2020, B.1.617.2 (Delta), and B.1.1.529 (Omicron) variants. Medians (red bars) are depicted and numerically shown.