Document Type

Dissertation - Open Access

Award Date

2022

Degree Name

Doctor of Philosophy (PhD)

Department / School

Pharmaceutical Sciences

First Advisor

Hemachand Tummala

Keywords

Adjuvant, Influenza, Oral vaccine, Pigs, TLR4, Vaccine

Abstract

Vaccines are the most efficient and cost-effective method for preventing illnesses caused by infectious pathogens. Even though the great success of vaccines over decades, the development of safe and robust vaccines is still essential for emerging new pathogens, re-evolving old pathogens, and improving the insufficient protection given by existing vaccines. One of the most critical strategies for developing effective new vaccines is selecting and using a suitable adjuvant or immune stimulant. Immunologic adjuvants are essential for improving vaccine potency by enhancing the immune response of vaccine antigens. The amount of antigen could be spared with improved potency, especially during mass vaccinations in pandemics. In the past, our laboratory had discovered a plant-based novel toll-like-receptor-4 agonist (adjuvant), inulin acetate (InAc), and showed that a particulate delivery system using InAc is a potent vaccine delivery system that produces strong humoral and cell-mediated immunity, which was tested in mouse models. The study in this dissertation investigated the application of nanoparticles prepared with inulin acetate nanoparticles (InAc-NPs) for dual functionality: as a delivery system and vaccine adjuvant for enhancing mucosal and systemic immunity in mice and pigs. The rationale behind selecting InAc-NPs is their established ability to stimulate strong systemic immunity and a clear understanding of their activation mechanisms. In chapter II, we have established through subcutaneous vaccinations in swine for the first time that inulin acetate nanoparticles (InAc-NPs) could generate high levels of systemic antibodies (IgG) by using influenza antigens the extracellular domain of matrix protein 2 (M2e), and the influenza virus's surface membrane protein, Hemagglutinin (HA) protein. InAC-NPs, as a vaccine delivery system, protected the antigen from degradation during the storage and efficiently delivered it to swine macrophages (in-vitro). The antibodies induced by InAc-NPs have a strong affinity and avidity to bind to HA. These antibodies potentially prevent the virus from entering the host cell. The study introduced inulin acetate (InAc) as a vaccine adjuvant in swine for subcutaneous vaccine delivery. Chapter III, for the first time, established the efficacy of InAc-NPs as a vaccine delivery system in a mouse for oral vaccines using influenza peptide (Inf-A) as a model antigen. Importantly, InAc-NPs carrying the Inf-A produced higher mucosal and systemic antibodies than unadjuvanted antigens in mice. InAc-NPs activated mouse macrophages to secrete pro-inflammatory cytokines such as Interleukin-6 (IL-6) and macrophage activation marker nitric oxide (NO). In conclusion, we have demonstrated the capability of InAc-NPs as a robust vaccine delivery and adjuvant platform for parenteral and oral vaccines that offer strong systemic and mucosal immunity, which will have substantial implications in fighting several viral diseases in humans and animals (pigs) in future.

Number of Pages

115

Publisher

South Dakota State University

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Rights Statement

In Copyright