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

Authors :
Junkins RD
Gallovic MD
Johnson BM
Collier MA
Watkins-Schulz R
Cheng N
David CN
McGee CE
Sempowski GD
Shterev I
McKinnon K
Bachelder EM
Ainslie KM
Ting JP
Source :
Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2018 Jan 28; Vol. 270, pp. 1-13. Date of Electronic Publication: 2017 Nov 21.
Publication Year :
2018

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 <superscript>4</superscript> -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.<br /> (Copyright © 2017 Elsevier B.V. All rights reserved.)

Details

Language :
English
ISSN :
1873-4995
Volume :
270
Database :
MEDLINE
Journal :
Journal of controlled release : official journal of the Controlled Release Society
Publication Type :
Academic Journal
Accession number :
29170142
Full Text :
https://doi.org/10.1016/j.jconrel.2017.11.030