A third dose enhanced the number of responders to all variants and significantly increased CD8 T-cell responses, but the frequencies of Omicron-specific CD8 T-cells remained 70% of the responses specific to the vaccine strain.
Among a cohort of patients with multiple sclerosis (MS) treated with ocrelizumab (Ocrevus; Genentech), an anti-CD20 therapy, COVID-19 mRNA vaccination induced robust T-cell responses to both Delta and Omicron variants, suggesting a protective effect against severe COVID-19 infection. Furthermore, T-cell response rates increased after the third dose, demonstrating the importance of booster doses for this population.
Previous studies had showed that 2 doses of a COVID-19 mRNA vaccine induce suboptimal antibody responses but robust and functional T-cell responses against the vaccine strain. Senior author Christiane S. Eberhardt, MD, clinical vaccinologist, University of Geneva, and colleagues aimed to understand more about omicron-specific cytotoxic T-cell responses, mainly CD4 and CD8, in patients with MS on anti-CD20 therapy after they had received a third vaccine dose. To do so, the study authors sampled blood before and 1 month after the third dose.
This prospective study, conducted between March 2021 and Nov 2021, included 20 patients, 11 (55%) of whom were men, with a total median age of 45.8 years (IQR, 37.8-53.3). Specific T-cells were measured using the activation-induced marker assay. Peripheral blood mononuclear cells (PBMC) were stimulated with peptide pools covering the different spike proteins, and specific T-cells were identified by the expression of activation surface markers such as 4-1BB, CD69, and OX40.
In total, 16 patients received a third dose of mRNA-1273 (Moderna) and 4 received a third dose of BNT162b2 (Pfizer-BioNTech), with a median interval between the second and third dose of 26.7 weeks (IQR, 22.3-29.0). Prior to receiving the booster dose, 12, 10, and 9 patients, respectively, had cytotoxic T-cells that were specific for the vaccine strain and the Delta and Omicron variants.
Following the booster dose, the number of responders increased to 15 patients for the vaccine strain and to 14 for both variants each. The frequencies of specific CD8 T-cells were reduced for both variants compared with the vaccine strain before receiving a booster dose (Delta: 83% [95% CI, 73.6-114.5]; Omicron: 78.9% [95% CI, 59.4-100.0]) and after receiving a booster dose (Delta: 89.3% [95% CI, 57.6-100.0]; Omicron: 71.1% [95% CI, 41.6-96.2]). No difference was observed between levels of Delta-specific and Omicron-specific CD8 T-cells.
Detected responses on CD4 T-cells, which are known to provide help to B-cells, were observed in 9-10 patients before receiving the booster; this response increased after the booster dose for the vaccine strain in 15 patients and for Delta in 14 patients, but only slightly for Omicron in 11 patients. No significant changes were observed in the frequencies of specific CD4 T-cells after the booster, unlike the changes in CD8 T-cells. After reviewing blood samples, Delta and Omicron spike-specific CD4 T-cell responses were significantly reduced compared with the vaccine strain to 83.5% (95% CI, 69.4-105.6) for Delta and to 72.3% (95% CI, 53.4-82.7) for Omicron after the booster dose compared with 72.2% (95% CI, 67.4-90.5) and 62.5% (95% CI, 51.0-89.0), respectively, before the booster dose.
"Importantly, a third dose increased the frequency of cytotoxic CD8 T-cells, which are particularly important in viral defense, irrespective of the SARS-CoV-2 variant," Eberhardt et al wrote. "Yet both before and after the booster dose, their frequencies were lower against Omicron, similar to the moderate decrease observed in health individuals 5 to 6 months after 2 doses. This could indicate that the recognition of T-cells may be partially compromised as mutations accumulate in variants of concern."
Irrespective of strain, there was no significant correlation between antibody titers and CD4 or CD8 T-cells after receiving the booster dose. An exploratory analysis of memory phenotype showed that spike-specific CD4 and CD8 T-cells mostly had an effector phenotype independent of the variant, indicating their capacity to quickly respond in case of infection.