Long-lasting cross-reactive and polyfunctional SARS-CoV-2 T cell responses in seniors are maintained after repeated vaccination and infections.

BACKGROUND

Understanding humoral and T cell responses to SARS-CoV-2 immunisations is important for informing seasonal COVID-19 vaccine recommendations in the elderly. Existing protection against emerging strains may vary based on vaccination and infection history. Using a longitudinal cohort of healthy seniors (65-80 years), we investigated the magnitude and quality of T cell and antibody responses after multiple SARS-CoV-2 vaccine doses and repeated infections.

METHODS

Samples were collected at six consecutive time points from Dec 2020 to May 2024, covering up to six doses of mRNA vaccines. Vaccination and infection records were retrieved from national health registries and questionnaires. Frequency and polyfunctionality of T cell responses and neutralising antibodies (NAbs) to the B.1 strain and several Omicron variants were determined, as well as anti-spike, -nucleocapsid, and -membrane protein IgG levels.

FINDINGS: After three vaccine doses, the quantity and quality of CD4 and CD8 spike-specific T cell responses remained stable throughout the study period spanning 2.5 years and up to three additional booster doses. About 60% of participants reported at least one infection over this time period. Samples from early 2022 showed cross-reactivity to emerging Omicron variants (XBB.1.5/BA.2.86) and CD4 T cell responses strongly correlated between newer SARS-CoV-2 strains and B.1. By contrast, NAb titres against B.1 remained high but were reduced against newer variants. Spike IgG levels plateaued over time while membrane protein IgG levels revealed unreported infections.

INTERPRETATION: The quality and quantity of spike-specific T cell responses were maintained over several years and three doses of the original B.1 vaccine generated good T cell cross-reactivity against future strains. This suggests that overall, healthy older adults have robust cellular protection against severe COVID-19. NAbs were more strain-specific with reduced neutralisation of newer variants, consistent with immune imprinting and antigenic drift, suggesting that updated vaccines may be necessary for vulnerable individuals.