Amphiphile-engineered DNA adjuvants stimulate strong type I IFN production in lymph nodes via cytosolic danger-sensing to induce potent cellular and humoral immunity in mice and non-human primates
Steinbuck, M. P.; Seenappa, L. M.; Zhan, W.; Palmer, E.; Jakubowski, A.; Cabana-Puig, X.; Jung, M. M.; McNeil, L. K.; Haqq, C. M.; Fitzgerald, K. A.; DeMuth, P. C.
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Adjuvants are immuno-activators capable of shaping the magnitude and quality of antigen-specific immune responses induced by subunit immunization. Presently, there is an acute need for effective adjuvants that safely induce durable and balanced humoral and cellular responses; the latter being indispensable for protection against intracellular pathogens and cancer. Here, we iteratively optimized a novel class of Amphiphile (AMP)-modified, immunostimulatory DNA-adjuvants designed for targeted delivery to lymph nodes and enhanced stimulation of cytosolic danger-sensing pathways to generate strong adaptive immunity. AMP-DNA adjuvants induced potent IFN-I-driven inflammatory environments in mouse and NHP lymph nodes that were dependent on TBK1 signaling, leading to significantly enhanced cytokine secretion by polyfunctional CD8+ and CD4+ T cells in multiple tissues, and strongly elevated TH1-associated and neutralizing antibody responses, without toxicity. These results demonstrate that AMP-engineering enables lymph node-targeted DNA-adjuvants to uniquely activate cytosolic immune-signaling to generate robust adaptive responses crucial for vaccine efficacy.
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