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.
Recommended Citation
Kim, Joo, "Novel Double-Layered Protein Nanoparticles Conjugating Truncated Flagellin Induces Improved Mucosal and Systemic Immune Responses Conferring Influenza Cross-protection." Dissertation, Georgia State University, 2024.
https://scholarworks.gsu.edu/biomedical_diss/19