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Document Type

Dissertation - University Access Only

Award Date

2013

Degree Name

Doctor of Philosophy (PhD)

Department / School

Pharmaceutical Sciences

First Advisor

Hemachand Tummala

Abstract

Vaccines often require addition of adjuvants to boost the potency and longevity of antigen specific immune responses. At present, there is a scarcity of safe vaccine adjuvants and delivery systems that can stimulate both cellular (Th1) and humoral (Th2) immune response. Such adjuvants are required for prevention or treatment of diseases like cancer and influenza. The main goal of this dissertation is to develop a novel and safe pathogen mimicking vaccine delivery system (PMVDS) that stimulates both Th1 and Th2 immune responses. The rationale behind developing PMVDS is that the immune system senses pathogens as foreign and particulate material containing multiple antigens, and generate strong immune response against the pathogens. Our preliminary results showed that soluble inulin particles mimic pathogens to stimulate immune cells and release proliferatory cytokines. With rational modification, we designed modified inulin particles and found them to be more potent in stimulating immune system and generating both Th1 and Th2 immune responses. In Chapter II, we evaluated the potential of antigen loaded soluble inulin microparticles (sIMs) as a vaccine adjuvant and delivery system. In-vivo immunization studies performed in mice showed ova loaded sIMs generated significantly higher IgG-1 antibody titers compared to the unadjuvanted ova or alum adjuvanted ova, indicating generation of Th2 type of immune response. However, mice immunized with ova encapsulated sIMs were not able to generate strong Th1 immune response (IgG-2a antibody) which is required for prevention or treatment of diseases like cancer and influenza. In Chapter III, we used Inulin Acetate (InAc), a modified hydrophobic derivative of inulin, and evaluated its potential to stimulate innate immune system. InAc microparticles were found to be efficient in activating innate immune system via TLR-4. Significantly higher Th1 (IgG-2a antibody titers, IFN-γ, and IL-2 cytokines) and Th2 (IgG-1 antibody titers, IL-4 and IL-10 cytokines) immune responses were generated in mice immunized with ova loaded InAc microparticles as compared to unadjuvated ova or alum adjuvanted ova. Further, in Chapter IV, our results demonstrated that melanoma self-antigens (gp100-trp2) loaded InAc microparticles activated antigen-specific CD8+ T cells and provided significant delay in tumor growth, when administered as a prophylactic or anticancer vaccine, as compared to the unadjuvanted antigens. In Chapter V, Influenza subunit antigens (HA and M2e) loaded InAc microparticles immunization showed 100 % protection in vaccinated mice after lethal challenge of influenza virus. In conclusion, we have developed a novel polymer based vaccine adjuvant and delivery system. The main innovation of the findings is that the polymer itself acts as a TLR-4 agonist which stimulates innate immune system. The developed vaccine formulation is more potent than commercially available alum, and more importantly activates both humoral and cellular immune responses.

Library of Congress Subject Headings

Vaccines.
Immunological adjuvants.

Description

Includes bibliographical references (pages 148-162).

Format

application/pdf

Number of Pages

176

Publisher

South Dakota State University

Rights

In Copyright - Educational Use Permitted
http://rightsstatements.org/vocab/InC-EDU/1.0/

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