Date of Award
Fall 12-16-2024
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical Sciences
First Advisor
Sang-Moo Kang, Ph.D.
Second Advisor
Mukesh Kumar, Ph.D.
Third Advisor
Baozhong Wang, Ph.D.
Abstract
Conventional hemagglutinin (HA) based inactivated influenza vaccines provide insufficient cross-protection against antigenically distant influenza strains, especially in older adults. The major goal of my dissertation research projects was to study influenza vaccination strategies to improve cross-protection by inducing extra immunity to neuraminidase (NA) and M2 ion channel ectodomain (M2e) proteins.
In chapter one, to address the issue of poor influenza vaccine efficacy in the elderly population, I employed a supplementation vaccination strategy, where I combined bivalent inactivated split vaccines (H1N1+H3N2) with a virus-like particle (VLP) expressing consensus NA (N1+ N2 + B NA) plus M2e repeat (5xM2e of human, swine and avian M2e sequences), referred as NA-M2e here, in 17-month-old-mice by a 2-dose immunication regimen. Vaccination with split plus NA-M2e induced protective IgG antibodies towards T-helper type 1 and effector T cell responses in aged mice, conferring enhanced protection against homologous and heterologous viruses compared to split vaccine . These findings suggest a promising strategy to overcome aging-related declines in vaccine efficacy and improve immune responses and vaccine efficacy in the elderly.
In chapter two, I investigated the protection efficacy of split plus NA-M2e vaccination in young adult mice and the adjuvant effects of supplementing NA-M2e on improving the immunogenicity and efficacy of split vaccine. Vaccination with combined split and NA-M2e was more effective in conferring enhanced cross-protection than either vaccine alone in young adult mice. Injection of NA-M2e VLP and combined split and NA-M2e VLP vaccines resulted in recruiting more activated monocytes, macrophages, and dendritic cell subsets in the lymphoid tissues within a day. Young adult mice, when co-immunized with split plus NA-M2e vaccines, could induce stronger humoral and cellular immune responses compared to their aged counterparts. These findings suggest the combination of split plus NA-M2e vaccines is more effective in conferring the high efficacy of homo and cross-protection, probably via activating both innate and adaptive immune responses.
Most approved vaccines provide robust systemic immunity via intramuscular immunization (IM) but not effective mucosal immunity in protecting against respiratory pathogens. In Chapter 3, I investigated the immunogenicity and efficacy of NA-M2e VLP vaccine after delivery via the intranasal route versus intramuscular route. Intranasal immunization with NA-M2e induced comparable systemic IgG antibodies, elevated IgA antibodies, and increased populations of effector T cells, memory B cells, and antigen-presenting cells in the mucosal site compared to intramuscular immunization in mice. Intranasal delivery of NA-M2e VLP vaccine induced more effective cross-protection against antigenically variant influenza strains than intramuscular injection. These findings suggest that intranasal delivery of NA-M2e vaccine can be an effective route in inducing humoral and cellular immune responses at local mucosal sites, contributing to cross-protection.
Recommended Citation
Raha, Jannatul, "Vaccination Approaches to Enhance Cross-Protection against Influenza by Inducing Immunity to Neuraminidase and M2e." Dissertation, Georgia State University, 2024.
https://scholarworks.gsu.edu/biomedical_diss/22