Author

Joo KimFollow

Date of Award

Winter 12-18-2024

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Baozhong Wang, Ph.D.

Second Advisor

Sang-Moo Kang, Ph.D.

Third Advisor

Timothy Denning, Ph.D.

Abstract

Influenza remains a persistent global health challenge. One of the weaknesses of current seasonal flu vaccines is their limited efficacy against drifted influenza strains. Our study focused on developing a novel self-adjuvanted double-layered protein nanoparticle vaccine that will be intranasally delivered and cross-protective. These nanoparticles consisted of an influenza nucleoprotein (NP) core encapsulated by hemagglutinin (HA) and a truncated form of bacterial flagellin (tFliC). Immunizations with these double-layered nanoparticles that included tFliC as a mucosal adjuvant, which activates toll-like receptor 5 (TLR5), induced significant mucosal and systemic immune responses, conferring cross-protection against influenza in mice. Compared to traditional vaccines, the double-layered nanoparticles induced higher levels of antigen-specific IgA and IgG in mucosal samples and serum and robust T-cell responses. In addition, the nanoparticles demonstrated robust immune responses in pre-infected mice, demonstrating that prior exposure to a heterologous influenza strain synergizes the vaccine's efficacy. To further optimize the vaccine's effectiveness, we employed a slow delivery method for the prime dose, spreading the administration over several days. This strategy markedly enhanced germinal center reactions and T-cell activation in lung-draining lymph nodes, resulting in superior protective efficacy against homologous and heterologous H3N2 influenza challenges. Our results demonstrate that the tFliC-adjuvanted, double-layered protein nanoparticles can be developed into a highly effective universal influenza vaccine. This novel intranasal vaccine formulation provides robust and broad protection and highlights a promising approach to improving influenza vaccine efficacy through simplified intranasal immunization, such as nasal drops.

Available for download on Friday, October 24, 2025

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