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

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 s...

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Autores principales:	Ranjna Madan-Lala, Pallab Pradhan, Krishnendu Roy
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f599358cdd0c4d71a5068c2a8070d416
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spelling	oai:doaj.org-article:f599358cdd0c4d71a5068c2a8070d4162021-12-02T15:05:16ZCombinatorial Delivery of Dual and Triple TLR Agonists via Polymeric Pathogen-like Particles Synergistically Enhances Innate and Adaptive Immune Responses10.1038/s41598-017-02804-y2045-2322https://doaj.org/article/f599358cdd0c4d71a5068c2a8070d4162017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02804-yhttps://doaj.org/toc/2045-2322Abstract 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.Ranjna Madan-LalaPallab PradhanKrishnendu RoyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ranjna Madan-Lala Pallab Pradhan Krishnendu Roy Combinatorial Delivery of Dual and Triple TLR Agonists via Polymeric Pathogen-like Particles Synergistically Enhances Innate and Adaptive Immune Responses
description	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.
format	article
author	Ranjna Madan-Lala Pallab Pradhan Krishnendu Roy
author_facet	Ranjna Madan-Lala Pallab Pradhan Krishnendu Roy
author_sort	Ranjna Madan-Lala
title	Combinatorial Delivery of Dual and Triple TLR Agonists via Polymeric Pathogen-like Particles Synergistically Enhances Innate and Adaptive Immune Responses
title_short	Combinatorial Delivery of Dual and Triple TLR Agonists via Polymeric Pathogen-like Particles Synergistically Enhances Innate and Adaptive Immune Responses
title_full	Combinatorial Delivery of Dual and Triple TLR Agonists via Polymeric Pathogen-like Particles Synergistically Enhances Innate and Adaptive Immune Responses
title_fullStr	Combinatorial Delivery of Dual and Triple TLR Agonists via Polymeric Pathogen-like Particles Synergistically Enhances Innate and Adaptive Immune Responses
title_full_unstemmed	Combinatorial Delivery of Dual and Triple TLR Agonists via Polymeric Pathogen-like Particles Synergistically Enhances Innate and Adaptive Immune Responses
title_sort	combinatorial delivery of dual and triple tlr agonists via polymeric pathogen-like particles synergistically enhances innate and adaptive immune responses
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f599358cdd0c4d71a5068c2a8070d416
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Combinatorial Delivery of Dual and Triple TLR Agonists via Polymeric Pathogen-like Particles Synergistically Enhances Innate and Adaptive Immune Responses

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