Defense Date

8-20-2024

Graduation Date

Winter 12-20-2024

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Pharmaceutics

School

School of Pharmacy

Committee Chair

Wilson Meng

Committee Member

Kerry Empey

Committee Member

Devika Manickam

Committee Member

Ellen Gawalt

Committee Member

Ira Buckner

Committee Member

Lauren O'Donnell

Keywords

PLGA, Nanoparticles, Pharmacokinetics, Vaccine, Adjuvant, Modeling

Abstract

Vaccination remains a critical public health imperative to prevent infectious disease. Despite success in minimizing and eradicating certain diseases, vaccination remains an unoptimized intervention both for emergent and existing pathogens. To enhance vaccine outcomes, extending the timeframe of immunogenic antigen exposure to the immune system improves cellular and humoral adaptive responses. Promoting long-term exposure is most effectively achieved through formulation strategies which increase antigen availability to the lymph nodes, where the mechanisms of adaptation occur. To meet this need, we propose the use of polymeric biotinylated nanoparticles (bNPs) to deliver antigen to the lymph nodes through surface loading. bNPs provide bi-functionality as both antigen carrier and adjuvant. bNPs were found to have self-adjuvant properties, evidenced by bNP induced IL-1β, IL-18, and IL-12 production in vitro in APCs, thereby licensing the cells to generate Th1-type helper T cell responses. Cytokine production was reduced in avidin pre-coated bNPs (but not with other proteins) suggesting that the pro-inflammatory response is specific to exposed biotin on the surface of bNPs. To evaluate the kinetics of bNP and antigen lymph node occupancy, streptavidin, which can be loaded directly onto the bNP surface, was used as a model antigen. Antigen exposure in vivo was significantly improved through surface loading onto bNPs, and we developed a working kinetic model to account for the retention of both particles and antigen in draining lymph nodes. We observed enhanced T cell responses and antigen-specific B cell response in vivo when antigen was delivered on the particle surface. Finally, bNPs were evaluated for their ability to protect against clinically relevant Respiratory Syncitial Virus (RSV) in mice. Through intranasal delivery of an RSV prefusion protein, bNPs improved markers of the immune response such as Th1 relevant cytokine expression (IL-12), critical to providing protection against RSV in children. Overall, despite opportunities for further optimization and modification of the bNP system, the work presented in this dissertation supports the hypothesis of utilizing a biotinylated nanoparticle as a vaccine carrier, and advances the field of nanoparticle-based vaccines.

Language

English

Additional Citations

(1) Hartmeier, P. R.; Ostrowski, S. M.; Busch, E. E.; Empey, K. M.; Meng, W. S. Lymphatic distribution considerations for subunit vaccine design and development. Vaccine 2024, 42 (10), 2519-2529. DOI: 10.1016/j.vaccine.2024.03.033 From NLM Medline.

(1) Hartmeier, P. R.; Kosanovich, J. L.; Velankar, K. Y.; Ostrowski, S. M.; Busch, E. E.; Lipp, M. A.; Empey, K. M.; Meng, W. S. Modeling the Kinetics of Lymph Node Retention and Exposure of a Cargo Protein Delivered by Biotin-Functionalized Nanoparticles. Acta Biomater 2023. DOI: 10.1016/j.actbio.2023.08.048 From NLM.

(1) Hartmeier, P. R.; Kosanovich, J. L.; Velankar, K. Y.; Armen-Luke, J.; Lipp, M. A.; Gawalt, E. S.; Giannoukakis, N.; Empey, K. M.; Meng, W. S. Immune Cells Activating Biotin-Decorated PLGA Protein Carrier. Molecular Pharmaceutics 2022.

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