Delayed CD4+T-cell response in older adults is associated with reduced immunogenicity and reactogenicity after COVID-19 mRNA vaccination

Abstract While the newly developed COVID-19 mRNA vaccines are highly effective, characteristics of the immune response after the vaccination and its association with the adverse effects, especially for an older population, remain elusive. In this study, we recruited a total of 216 SARS-CoV-2-naïve healthy donors of various ages (23–81 years) who received two doses of the BNT162b2 vaccine and assessed age-associated differences in vaccine-induced T-cell responses and adverse effects over 3 months. We observed that older adults (≥65 years) had fewer vaccine-induced Spike-specific CD4 +T cells, including CXCR3 +cTfh and Th1 cells, after the first dose, which correlated with their lower peak IgG levels and fewer systemic adverse effects after the second dose, compared with younger adults. Moreover, Spike-specific Th1 cells in older adults expressed higher levels of PD-1, a negative regulator of T-cell activation, which was associated with low Spike-specific CD8 +T-cell response. These data indicated that delayed induction of CD4 +T-cell response in older adults is linked to impaired humoral and cellular immunity and reduced systemic reactogenicity. Therefore, enhancing CD4 +T-cell response following the first dose is key to improving vaccine efficacy in older adults. This work was supported by the Japan Agency for Medical Research and Development (grant numbers JP21gm5010005, JP20fk0108454, and JP223fa627009; Y.H.), iPS Cell Research Fund (Y.H.), the COVID-19 Private Fund to the Shinya Yamanaka Laboratory, CiRA, Kyoto University (Y.H.), Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (grant number 19K23862; N.J.), Kansai Economic Federation (KANKEIREN; Y.H.), Sumitomo-Mitsui Trust Bank Fund for Covid-19 Research, Kyoto University (Y.H.), and Takeda Science Foundation (Y.H.).