Abstract
Cyclic dinucleotides (CDNs) are promising vaccine adjuvants inducing balanced, potent humoral, and cellular immune responses. How aging influences CDN efficacy is unclear. We examined the vaccine efficacy of 3′,5′-cyclic diguanylic acid (cyclic di-GMP, CDG), the founding member of CDNs, in 1-year-old (middle-aged) and 2-year-old (aged) C57BL/6J mice. We found that 1- and 2-year-old C57BL/6J mice are defective in CDG-induced memory T helper (Th)1 and Th17 responses and high-affinity serum immunoglobulin (Ig)G, mucosal IgA production. Next, we generated two novel tumor necrosis factor (TNF) fusion proteins that target soluble TNF (solTNF) and transmembrane TNF (tmTNF) to monocyte-derived dendritic cells (moDCs) to enhance CDG vaccine efficacy in 1- and 2-year-old mice. The moDC-targeting TNF fusion proteins restored CDG-induced memory Th1, Th17, and high-affinity IgG, IgA responses in the 1- and 2-year-old mice. Together, the data suggested that aging negatively impacts CDG vaccine adjuvanticity. MoDC-targeting TNF fusion proteins enhanced CDG adjuvanticity in the aging mice.
Highlights
The current COVID-19 pandemic has highlighted the vulnerability of aging populations to emerging pathogens where people 45 and older account for ∼97% of COVID-19 deaths [1]
As expected, neither transmembrane TNF (tmTNF)-Fc (IgG2A) nor soluble TNF (solTNF)-Fc (IgG2A) restored the memory T helper (Th) responses in the IRF4fl/flCD11ccre mice [28] as we previously demonstrated that R2D2 is required for CDG-induced cellular immunity [22]
A significant elevation in the IgA titer was observed in aged mice immunized with CDG/NP6CGG adjuvanted with solTNF-Fc (IgG2A) and tmTNF-Fc (IgG2A) as compared to the mice group immunized with only CDG/NP6CGG (p < 0.0001) (Figures 4G,H; Figure S4D)
Summary
The current COVID-19 pandemic has highlighted the vulnerability of aging populations to emerging pathogens where people 45 and older account for ∼97% of COVID-19 deaths [1]. Improving the efficacy of vaccines and immunotherapeutic agents in the aging population is critical to public health. While the efficacy of Prevnar R decreases with age [8] and is only ∼45% effective in adults 65 years or older [9], the Shingrix vaccine for shingles is 90% effective in people over 70. CDG was the founding member of CDNs and showed excellent vaccine efficacy in infectious diseases and immunotherapy [16,17,18]. We recently showed that CDG adjuvanticity is mediated by conventional DC2 (cDC2) and monocyte-derived DCs (moDCs) in vivo [22]. We examined CDG adjuvanticity in middle-aged and aged C57BL/6J mice. We further developed a mechanismguided moDC-targeting strategy to enhance CDG adjuvanticity in the middle-aged and aged mice
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