New MoDC-Targeting TNF Fusion Proteins Enhance Cyclic Di-GMP Vaccine Adjuvanticity in Middle-Aged and Aged Mice

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.

Enhancing immunotherapy outcomes by targeted remodeling of the tumor microenvironment via combined cGAS-STING pathway strategies

“…The response to vaccine administration may decline with advancing age ( 135 , 136 ). Consequently, similar to many vaccines, the adjuvant potential of CDN vaccines is negatively affected by the aging process ( 137 ). Future animal research should explore the influence of mouse age on the efficacy of CDN vaccines and utilize mice that reflect the target age demographic, which may yield more precise experimental data for guiding clinical trials.…”

The Age of Cyclic Dinucleotide Vaccine Adjuvants

“…In 2020, Gogoi H et al reported that CDG (5 µg, i.n. )-induced high-affinity, durable antibodies, and Th1/Th17 responses were severely reduced in one-year-old (~equivalent age of 42.5-year-old in humans) and two-year-old (~equivalent age of 70-year-old in humans) C57BL/6J mice [95]. Aging decreases the response to vaccination [96][97][98][99].…”

The Promise and Challenges of Cyclic Dinucleotides as Molecular Adjuvants for Vaccine Development

“…Similarly, immunization of an H1N1 influenza vaccine with cGAMP and saponin (Quil-A) significantly improved the survival (by 80–100%) of vaccinated 20-month-old mice, whereas cGAMP alone showed no significant improvement [ 143 ]. In this regard, recent studies found that targeting MoDCs with TNF fusion proteins restored the c-di-GMP adjuvantivity in aged mice [ 144 ].…”