Document Type

Dissertation - Open Access

Award Date

2019

Degree Name

Doctor of Philosophy (PhD)

Department / School

Pharmaceutical Sciences

First Advisor

Hemachand Tummala

Abstract

Many serious infections for which there are no existing vaccines, enter by a mucosal route such as HIV, influenza, and tuberculosis, etc. Therefore, designing safe and effective mucosal vaccines that elicit robust immune response at mucosal sites is still a major challenge without a safe mucosal adjuvant. Previously, our laboratory had discovered inulin acetate as a novel toll-like-receptor-4 agonist (adjuvant). The study in this dissertation explored the application of nanoparticles prepared with inulin acetate (InAc-NPs) as a vaccine adjuvant and delivery system for enhancing mucosal immunity. The rationale behind selecting InAc-NPs is their proven ability to activate strong systemic immunity along with an extensive understanding of their mechanisms of activation. In chapter-II, we have clearly established, through intranasal vaccinations in mice, that InAc-NPs could generate strong systemic and mucosal antibodies (IgG1, IgG2a, sIgA) and cytokine response that represents both humoral and cellular immunity. InAc-NPs efficiently delivered the antigen into macrophages as well as activated them to release inflammatory cytokines such as TNF-α, which have been attributed for robust immune response in mice. In chapter-III, the efficacy of InAc-NPs as a vaccine adjuvant in swine model was established for the first time along with the safety profile in mice. InAc-NPs are proficient in stimulation of swine PBMCs to secrete cytokines such as IL-6, IL12, and IFN-. Importantly, InAc-NPs carrying the influenza peptide (M2e) produced higher mucosal and systemic antibodies compared to unadjuvanted antigen in pigs. The study, for the first time, showed InAc as a vaccine adjuvant in pigs that will have significant implications in swine industry and human health. In chapter-IV, InAc-NPs were explored as a delivery system to carry TLR7 agonist C-563 to its target site in the phagosomes/endosomes of antigen presenting cells. InAc-NPs loaded with C563 provided a unique dual adjuvant and/or a delivery system for vaccines that require robust immune response such as cancer or influenza vaccines. In conclusion, we have demonstrated the ability of InAc-NPs as a robust vaccine adjuvant and a delivery platform that provides strong systemic and mucosal immunity, which will have significant implications in fighting challenging diseases such as HIV, influenza, cancer, and tuberculosis.

Library of Congress Subject Headings

Mucous membrane -- Immunology.
Vaccines.
Vaccination.
Immunological adjuvants.
Nanotechnology.

Format

application/pdf

Number of Pages

141

Publisher

South Dakota State University

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Rights Statement

In Copyright