<scp>Age‐related differences in mRNA</scp> vaccine immunogenicity and adjuvancy

Older people mount poorer adaptive immune responses to mRNA vaccines, leaving them more vulnerable to infection with SARS-CoV-2. To design better mRNA vaccines for older people, we need to understand how aging alters mechanisms of adjuvancy that shape immunogenicity. To first define age-related changes in immunogenicity, we vaccinated young (< 5 months old) and aged (> 18 months old) C57BL/6 mice with an mRNA vaccine encoding the SARS-CoV-2 spike protein. T cell responses were markedly reduced in aged mice at peak and memory timepoints, using intracellular cytokine staining or activation-induced marker assays. Spike and receptor-binding domain binding and neutralizing antibody titers were also markedly reduced in aged mice, consistent with deficits seen in older humans. To define age-related changes in adjuvancy mechanisms, we vaccinated young and aged mice with mRNA vaccines loaded with DiD lipid dye or mScarlet mRNA, then tracked dendritic cell (DC) numbers, phenotype, vaccine uptake, antigen expression, and activation, as well as local and systemic cytokine production. DC numbers in the draining lymph nodes (dLN) were dramatically reduced before and early after vaccination in aged compared to young mice, with delayed recruitment of DCs to the dLN. Vaccine uptake was not impacted by age, but the frequency of DCs expressing antigen increased with age and DC activation decreased with age. Aging accelerated the expression of some cytokines (IL-1α, IL-6), while delaying others (IFNγ, MCP-1) in dLNs and sera. This illustrates that aging impairs multiple adjuvancy mechanisms but mRNA vaccine strategies that address these age-related deficits could improve responses in older people.