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

作者：Junkins Robert D; Gallovic Matthew D; Johnson Brandon M; Collier Michael A; Watkins Schulz Rebekah; Cheng Ning; David Clement N; McGee Charles E; Sempowski Gregory D; Shterev Ivo; McKinnon Karen; Bachelder Eric M; Ainslie Kristy M; Ting Jenny P Y^*

来源：Journal of Controlled Release, 2018, 270: 1-13.

DOI：10.1016/j.jconrel.2017.11.030

• STING
• cGAMP adjuvant
• Influenza vaccine
• Microparticle
• Acetalated dextran
• Electrospray

Most FDA-approved adjuvants for infectious agents boost humoral but not cellular immunity, and have poorly-understood mechanisms. Stimulator of interferon genes (STING, also known as MITA, MPYS, or ERIS) is an exciting adjuvant target due to its role in cyclic dinucleotide (CDN)-driven 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 the opportunity for improved formulations and bioactivity remains. In this study we evaluated the adjuvant activity of the potent STING agonist, CDN 3' 3'-cGAMP (cGAMP), encapsulated in acid-sensitive acetalated dextran (Ace-DEX) polymeric microparticles (MPs) which passively target antigen-presenting cells for intracellular release. This formulation was superior to all particle delivery systems evaluated and maintained its bioactivity following a sterilizing dose of gamma irradiation. Compared to soluble cGAMP, the Ace-DEX cGAMP MPs enhanced type-I interferon responses nearly 1000-fold in vitro and 50-fold in vivo, caused up to a 104-fold boost in antibody titers, increased Th1-associated responses, and expanded germinal center B cells and memory T cells. Furthermore, the encapsulated cGAMP elicited no observable toxicity in animals and achieved protective immunity against a lethal influenza challenge seven months post-immunization when using CDN adjuvant doses up to 100-fold lower than previous reports. For these reasons, Ace-DEX MP-encapsulated cGAMP represents a potent vaccine adjuvant of humoral and cellular immunity.

• 出版日期2018-1-28