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

Abstract

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 10-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.

Combination of STING Pathway Agonist With Saponin Is an Effective Adjuvant in Immunosenescent Mice

“…Remarkably, the combination-adjuvanted vaccine provided 100% protection in the aged mice after a single vaccination. Our data also demonstrate that the cGAMP/Quil-A combination is effective as an adjuvant when co-delivered with the vaccine by either intradermal or systemic routes of administration, which is consistent with recently reported results for 3 ′ 3-cGAMP-loaded microparticles (56). Other adjuvant combinations and delivery vehicles containing STING agonists have been previously reported including use of aluminum hydroxide (57) and encapsulation in lipid nanoparticles (58) or microparticles (59,60).…”

Preparation and Characterization of an Oral Vaccine Formulation Using Electrosprayed Chitosan Microparticles

“…Moreover, the morphology and particle size can be adjusted through varying the process parameters and the choice of the materials and thereby electrospray has been reported as a versatile method, also for producing chitosan particles (15,19,20). Previously, electrospray has been used to produce a vaccine formulation with microparticles of acetylated dextran encapsulating a subunit antigen, and this process resulted in an increased protection of the antigen (18,21). Furthermore modified chitosan has been used for coating of calcium-alginate particles where the model subunit antigen ovalbumin (OVA) was encapsulated by the method of electrospraying (22,23).…”

Agonists and inhibitors of the STING pathway: Potential agents for immunotherapy

“…The 2′,3′‐cGAMP‐loaded PC7A NPs efficiently inhibited the replication of HIV RNA and generated a long‐lasting antiretroviral response in human peripheral blood mononuclear cells, with free cGAMP as a control. Other polymers, such as dextran microparticles and poly (beta‐amino ester) (PBAE) NPs, were also employed to deliver CDNs and achieved prominent effects.…”