Date of Award

12-15-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Sang-Moo Kang

Second Advisor

Andrew Gewirtz

Third Advisor

Timothy Denning

Abstract

Adjuvants have been used for enhancing vaccine-specific immune responses, but the mechanisms of adjuvants and the roles of CD4 in adjuvant effects have been poorly understood. In a conventional model of vaccine adjuvant action mechanism, CD4+ T helper cells are known to play a critical role for adjuvants in improving vaccine efficacy. In this study, both licensed MF59 and monophosphoryl lipid (MPL)+Alum adjuvants were found to mediate IgG isotype-switched antibodies, memory responses, and protection against influenza virus in CD4 knockout (CD4KO) mice, which were comparable to those in wild type (WT) mice. Licensed oil-in-water emulsion MF59 adjuvanted influenza split vaccination was able to induce protective CD8+ T cells and long-lived IgG antibody-secreting cells in CD4KO mice. MF59 adjuvant mechanisms in CD4KO mice might be associated with uric acid, inflammatory cytokines, and recruitment of multiple immune cells at the injection site. Another licensed platform of MPL+ Alum adjuvant was also found to be effective in inducing IgG antibodies and protection, which appeared to be mediated by recruiting monocytes, neutrophils, dendritic cells in CD4KO mice. Additional studies in CD4-depleted WT mice and MHCIIKO mice suggest that MHCII+ antigen presenting cells contribute to providing alternative B cell help in CD4 deficient condition in the context of MPL+Alum adjuvanted vaccination. These findings suggest a new paradigm of CD4-independent adjuvant mechanisms, providing the rationales to improve vaccine efficacy in infants, elderly, and immune-compromised patients as well as in healthy adults.

Respiratory syncytial virus (RSV) is an important human pathogen, but there is no licensed RSV vaccine. RSV virus-like particle (VLP) vaccine conferred protection against RSV. RSV F and G VLP mixed with F-DNA (FdFG VLP) immunization induced low infiltrating cellularity, T helper type-1 immune responses, and no sign of eosinophilia in bronchoalveolar lavages upon RSV challenge, whereas alum adjuvanted formalin-inactivated RSV (FI-RSV) vaccination caused vaccine-enhanced eosinophilia. This study provides evidence that combination of recombinant RSV VLP and plasmid DNA vaccines may have a potential anti-RSV prophylactic vaccine inducing balanced innate and adaptive immune responses.

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