Older individuals are both at increased risk of disease with infections and less likely to mount robust adaptive immunity to vaccines. Given this increased vulnerability, tailoring new mRNA vaccines specifically for the older immune system would be a significant advance. To design age-optimised mRNA vaccines, we first need to understand how current formulations perform in an aged setting. We therefore aimed to characterise how an mRNA vaccine performs in an aged mouse model.
We first validated that age-related differences in mRNA vaccine-induced adaptive responses are also seen in a mouse model. We vaccinated young (<5 months old (mo)) and aged (19 mo) C57BL/6 mice with an mRNA vaccine encoding the SARS-CoV-2 Spike protein at day 0 and day 21. Serum was harvested throughout the timecourse to track B cell responses, with this analysis still underway. T cell responses were assessed at peak (day 28) and memory (day 90) timepoints, using intracellular cytokine staining and activation-induced marker assays. Aged mice exhibited significantly lower antigen-specific CD8 and CD4 T cell responses with regard to nearly all markers assessed (IFNγ, TNF and IL-2 production, CD69+CD25+ CD8 T cells and CD154+OX40+ CD4 T cells), consistent with differences seen in older humans. Of note, aged mice had markedly higher background with all activation-induced markers assessed, consistent with previous observations of T cell hyperactivation in advanced age.
We then defined age-related differences in adjuvancy mechanisms that could impair adaptive responses. To track vaccine uptake and antigen expression by DCs, we vaccinated young and aged mice with mRNA vaccines, using either a fluorescently labelled lipid nanoparticle (LNP) or mRNA encoding a fluorescent protein. Draining lymph nodes were harvested 16 hours later, and uptake or expression were assessed using magnetic enrichment of DCs followed by flow cytometry. Serum was also harvested to track changes in innate immune activation, with this analysis still underway. Vaccine uptake by young and aged DCs was comparable (83.4% vs 87.3%) but intact antigen was significantly higher in aged DCs (12.33% vs 18.3%) and DC numbers were reduced in aged mice both prior to and after vaccination by at least 10-fold.
Our data both validates that aged mice are a viable model for mRNA vaccination and highlights age-related changes in adjuvancy (antigen retention, deficit in DC number) that may contribute to poorer adaptive immune responses in aged individuals. Strategies that circumvent these age-related deficits could improve vaccine outcomes for older individuals.