Pre‐Existing Th1 Immunity Outperforms Age in Predicting Antibody Responses to SARS‐CoV‐2 Inactivated Vaccines

Challenging the focus on age, this study finds pre‐existing T helper 1 cells are the key biomarker for predicting antibody response to SARS‐CoV‐2 inactivated vaccines. In both mice and humans, high responders exhibited elevated baseline T helper 1 cells, which correlated with robust humoral immunity, offering crucial guidance for improving vaccine design. Abstract Understanding and enhancing vaccine‐induced immune responses in the elderly population is critical, as they face elevated risks of severe COVID‐19. This work systematically delineates age‐associated alterations in innate and adaptive immunity and their impact on responses to SARS‐CoV‐2 inactivated vaccination. Compared to young mice, aged mice exhibited polarized bystander Th1 CD4+T cell populations (31.68 ± 5.62% versus 3.31 ± 0.48%) with distinct transcriptomic signatures, which augmented humoral immunity in aged mice. In human cohorts, post‐vaccination antigen‐specific antibody titers are comparable across different age groups. Stratified analysis based on antibody concentration reveals that high‐responder individuals possess elevated pre‐existing Th1 cells at baseline, which exhibit a modest positive correlation with post‐vaccination antibody titers (r = 0.423, p = 0.001). Therefore, compared to age‐based stratification, baseline Th1 cells serve as a superior predictive biomarker for antibody generation following SARS‐CoV‐2 inactivated vaccination. Collectively, these findings unveil novel mechanisms underlying Th1‐mediated vaccine immunogenicity, offering pivotal insights for developing next‐generation vaccines with optimized protective efficacy. Challenging the focus on age, this study finds pre-existing T helper 1 cells are the key biomarker for predicting antibody response to SARS-CoV-2 inactivated vaccines. In both mice and humans, high responders exhibited elevated baseline T helper 1 cells, which correlated with robust humoral immunity, offering crucial guidance for improving vaccine design. Abstract Understanding and enhancing vaccine-induced immune responses in the elderly population is critical, as they face elevated risks of severe COVID-19. This work systematically delineates age-associated alterations in innate and adaptive immunity and their impact on responses to SARS-CoV-2 inactivated vaccination. Compared to young mice, aged mice exhibited polarized bystander Th1 CD4 + T cell populations (31.68 ± 5.62% versus 3.31 ± 0.48%) with distinct transcriptomic signatures, which augmented humoral immunity in aged mice. In human cohorts, post-vaccination antigen-specific antibody titers are comparable across different age groups. Stratified analysis based on antibody concentration reveals that high-responder individuals possess elevated pre-existing Th1 cells at baseline, which exhibit a modest positive correlation with post-vaccination antibody titers (r = 0.423, p = 0.001). Therefore, compared to age-based stratification, baseline Th1 cells serve as a superior predictive biomarker for antibody generation following SARS-CoV-2 inactivated vaccination. Collectively, these findings unveil novel mechanisms underlying Th1-mediated vaccine immunogenicity, offering pivotal insights for developing next-generation vaccines with optimized protective efficacy. Advanced Science, EarlyView.