Author ORCID Identifier

https://orcid.org/ 0000-0001-9260-3957

Date of Award

5-2-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Sang-Moo Kang, PhD

Second Advisor

Bao-Zhong Wang, PhD

Third Advisor

Mukesh Kumar, PhD

Fourth Advisor

Ki-Hye Kim, PhD

Abstract

Seasonal influenza vaccination is ineffective in conferring cross-protection against antigenically different influenza viruses, particularly in the elderly population. The overarching goal of my dissertation research projects was to develop influenza vaccination strategies for inducing more effective cross-protection against influenza viruses.

Adjuvants are used to enhance vaccine-specific immune responses, but the efficacy comparison of different adjuvants remains to be determined. In chapter one, I investigated the comparative effects of adjuvants approved for human use on enhancing the immunogenicity and cross-protective efficacy of inactivated split influenza virus vaccination. The adjuvants studied include QS-21 (a saponin derived from the soap bark tree, Quillaja saponaria) plus monophosphoryl lipid (MPL) [QS-21+MPL], oligonucleotide CpG plus MPL (CpG+MPL), and Bacillus Calmette–Guérin Cell Wall Skeleton (BCG-CWS) adjuvant. The experimental outcomes demonstrated that QS-21+MPL adjuvant combination was most effective in inducing T helper type 1 (Th1) IgG antibody responses, whereas both CpG+MPL and QS-21+MPL combination adjuvants exhibited similar potency in enhancing vaccination responses leading to increased protection against influenza virus challenge in adult C57BL/6 and aged BALB/c mice.

In chapter two, I investigated whether VSA-1, an analog of licensed saponin QS-21, exhibits adjuvant properties on enhancing the immunogenicity and cross-protection by influenza split virus vaccination in C57BL/6 mice. The experimental outcomes demonstrated that a single dose of VSA-1 adjuvanted vaccination conferred higher efficacy of protection against challenge with homologous H1N1 virus than QS-21 and alum adjuvants. Prime-boost VSA-1 adjuvanted vaccination induced humoral and cellular immune responses and cross-protection against H5N1 virus. These findings provide evidence warranting further development of VSA-1 as a promising alternative adjuvant for QS-21 replacement.

Recent clinical studies have reported that repeat annual vaccination diminishes vaccine efficacy. In chapter three, I investigated the efficacy of cross-protection by heterologous prime-boost vaccination with inactivated influenza virus vaccines in BALB/c mice. The experimental outcomes of this study demonstrated that the heterologous prime-boost vaccination strategy induced cross-reactive virus- and hemagglutinin (HA) stalk-specific IgG antibodies and more effective cross-protection against antigenically different viruses than homologous vaccination with the same antigen in BALB/c mice. These research outcomes support the positive impacts of a heterologous prime-boost strategy on conferring more effective cross-protection.

DOI

https://doi.org/10.57709/28893730

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