The mRNA vaccine BNT162b2 demonstrates impaired T1 immunogenicity in human elders and aged mice .

mRNA vaccines have been key to addressing the SARS-CoV-2 pandemic but have impaired immunogenicity and durability in vulnerable older populations. We evaluated the mRNA vaccine BNT162b2 in human whole blood assays with supernatants from adult (18-50 years) and elder (≥60 years) participants measured by mass spectrometry and proximity extension assay proteomics. BNT162b2 induced increased expression of soluble proteins in adult blood (e.g., C1S, PSMC6, CPN1), but demonstrated reduced proteins in elder blood (e.g., TPM4, APOF, APOC2, CPN1, and PI16), including 30-85% lower induction of T1-polarizing cytokines and chemokines (e.g., IFNγ, and CXCL10). Elder T1 impairment was validated in mice and associated with impaired humoral and cellular immunogenicity. Our study demonstrates the utility of a human platform to model age-specific mRNA vaccine activity, highlights impaired T1 immunogenicity in older adults, and provides rationale for developing enhanced mRNA vaccines with greater immunogenicity in vulnerable populations.