Combinatorial Delivery of Dual and Triple TLR Agonists via Polymeric Pathogen-like Particles Synergistically Enhances Innate and Adaptive Immune Responses

• Type of Material: Article
• Authors: Ranjna Madan Lala, Emory University; Pallab Pradhan, Georgia Institute of Technology; Krishnendu Roy, Emory University
• Language: English
• Date: 2017-05-31
• Publisher: Nature Publishing Group: Open Access Journals - Option C
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2017
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-017-02804-y
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 7
• Issue: 1
• Start Page: 2530
• End Page: 2530
• Grant/Funding Information: This work was partially supported by the National Institutes of Health (NIH) through Grant U01AI124270 (PI: Roy), The Georgia Tech Foundation and the Georgia Research Alliance through an Immuno-Engineering seed grant, and through funding from the Carol Ann and David D. Flanagan Professorship as well as the Robert A. Milton Chair to K.R.
• Keywords: MONOPHOSPHORYL-LIPID-A; VACCINE ADJUVANT; BACTERIAL-DNA; Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; IN-VIVO; T-CELL RESPONSES; DENDRITIC CELLS; TOLL-LIKE RECEPTORS; SIGNAL-TRANSDUCTION; STRANDED-RNA; BIODEGRADABLE NANOPARTICLES
• Research Categories: Health Sciences, Immunology; Engineering, Biomedical

Abstract

Despite decades of research very few vaccine-adjuvants have received FDA approval. Two fundamental challenges plague clinical translation of vaccine-adjuvants: reducing acute toxicities that result from systemic diffusion of many soluble adjuvants, and delivering multiple adjuvants at the same time to mimic the synergistic immune-stimulation of pathogens, while being safe. In order to address these barriers, we evaluated combinations of four clinically relevant immune-agonists, specifically Toll-like receptor (TLR) ligands, using biodegradable, polymer microparticles. We tested them alone and in combinations of 2 or 3, for a total of 10 unique conditions. We evaluated primary bone-marrow-derived Dendritic Cell phenotypes and functionality, and identified several synergistic combinations. We picked a dual and a triple adjuvant combination, TLR4/TLR9 and TLR4/TLR7/TLR9, for further evaluation and found that both combinations promoted antigen cross-presentation in vitro. Studies in mice using the model antigen Ovalbumin, showed that both combinations enhanced lymph node germinal center and T follicular helper cell responses. The triple adjuvant combination showed increased antigen-specific antibody titer with an overall balanced Th1/Th2 response, while the dual combination promoted Th1-polarized IgG responses. Our results show how polymeric particulate-carriers can be adopted to safely deliver combinatorial adjuvants and selectively synergize specific types of immune responses for vaccine applications.