A robust microparticle platform for a STING-targeted adjuvant that enhances both humoral and cellular immunity during vaccination

Abstract

Abstract Most FDA-approved adjuvants for infectious agents boost humoral but not cellular immunity, and have poorly-understood mechanisms. Stimulator of interferon genes (STING) is an exciting adjuvant target due to its role in anti-viral immunity; however, a major hindrance is STING’s cytosolic localization which requires intracellular delivery of its agonists. As a result, STING agonists administered in a soluble form have elicited suboptimal immune responses. Delivery of STING agonists via particle platforms has proven a more successful strategy, but has only been assessed at doses that are likely cost-prohibitive to clinical translation for vaccines against infectious diseases. Hence, alternative platforms for the intracellular delivery of STING-agonists are needed. We evaluated the adjuvant activity of a potent STING agonist, encapsulated in acid-sensitive acetalated dextran (Ace- DEX) polymeric microparticles (MPs) which target antigen-presenting cells for intracellular release. This formulation was superior to all particle delivery systems tested, achieved protective immunity in vivo at doses of STING agonist 50-fold lower than previous reports, and elicited no observable toxicity in animals. Compared to soluble agonist, the STING agonist Ace-DEX MPs enhanced type-I interferon responses up to 1000-fold in vitro and 50-fold in vivo, caused up to 104-fold increases in antibody titers, enhanced Th1-associated responses, and expanded germinal center B cells and memory T cells. It also provided protection against a lethal influenza challenge. Thus, Ace-DEX MP-encapsulated STING agonist represents a novel and feasible vaccine adjuvant of humoral and cellular immunity.