The BNT162b2 mRNA vaccine demonstrates reduced age-associated TH1 support in vitro and in vivo

mRNA vaccines demonstrate impaired immunogenicity and durability in vulnerable older populations. We hypothesized that human in vitro modeling and proteomics could elucidate age-specific mRNA vaccine actions. BNT162b2-stimulation changed the plasma proteome of blood samples from young (18-50Y) and older adult (≥60Y) participants, assessed by mass spectrometry, proximity extension assay, and multiplex. Young adult up-regulation (e.g., PSMC6, CPN1) contrasted reduced induction in older adults (e.g., TPM4, APOF, APOC2, CPN1, PI16). 30–85% lower TH1-polarizing cytokines and chemokines were induced in elderly blood (e.g., IFNγ, CXCL10). Analytes lower in older adult samples included human in vivo mRNA immunogenicity biomarkers (e.g., IFNγ, CXCL10, CCL4, IL-1RA). BNT162b2 also demonstrated reduced CD4+ TH1 responses in aged vs. young adult mice. Our study demonstrates the utility of human in vitro platforms modeling age-specific mRNA vaccine immunogenicity, highlights impaired support of TH1 polarization in older adults, and provides a rationale for precision mRNA vaccine adjuvantation to induce greater immunogenicity.