IMMUNE RESPONSE VARIABILITY FOLLOWING VACCINATION IN DIFFERENT AGE GROUPS

Abstract

Life course variability of immune responses is crucial for vaccine efficacy, but conventional vaccines targeted to young adults are often less effective in children and the elderly. We adopted a problem-based research strategy of meta-analysis, transcriptomic analysis, and mathematical modeling to investigate the life course variability of age-associated immune responses to vaccination using data from 147 studies and 48,372 individuals. Biexponential decay evaluation revealed that the half-life of antibody persistence declines from 9.9 years in young adults to 2.0 years in the oldest-old, and the rapid decay rate constant λ₁ increases from 0.09 to 0.25 year⁻¹.. Meta-analysis showed seroconversion failure odds ratios of 2.89 for influenza and 3.45 for hepatitis B vaccines in the elderly compared to young adults and no age difference for the AS01-adjuvanted varicella zoster vaccine with an adjuvant age-response index of 1.72. Weighted gene co-expression network analysis revealed B-cell signaling modules are negatively correlated with age and have significant age interaction and are likely less effective in the elderly. The mixed-effects model showed naive CD4⁺ T-cell numbers and plasma blast numbers 7 days after the vaccination are strong predictors of seroconversion. Ordinary differential equation modeling of memory T-cell generation showed a reduction in the numbers of naive T-cell precursor cells with age and a reduction in the half-life of memory T-cells from 8.9 to 2.1 months. Non-linear regression of vaccine efficacy against infection revealed decay constants γ of 0.042 year⁻¹ for influenza, compared to 0.005 year⁻¹ for the varicella zoster vaccine containing the adjuvant AS03. Our findings show that age-related immune alterations such as fast antibody decay, reprogramming of gene expression from B-cell to inflammatory modules, and a diminished naive T-cell repertoire all contribute to vaccine efficacy loss at the extremes of age. Personalized vaccination strategies using adjuvants and predictive biomarkers and targeting the root causes of immunosenescence and immune bias in babies and toddlers are needed to increase vaccine efficacy across the lifespan.