Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

Vaccination is historically the most effective tool for preventing infectious disease but current vaccine strategies fail to generate robust immunity to major infectious diseases such as HIV and malaria. Therefore, newer vaccine approaches are needed. Vaccines generated from viral, adenovirus based, vectors (AdVs) have proven highly immunogenic in multiple disease models. However, the clinical use of many AdVs is limited by the presence of pre-existing antibodies in human populations, which prevent expression of antigenic genes during immunization with AdVs based on common adenovirus (Ad) serotypes, such as HAdV-5C. Immunization with rare serotype based AdVs, such as HAdV-28D, are not affected by pre- existing immunity; however, these rare AdVs stimulate high levels of type I interferon (IFN), which suppress antigenic gene expression and hence, preclude antigen-specific immunity. We suggest that there is a way to prevent these rare AdVs from stimulating IFN. This would allow for the generation of Ads that can bypass neutralization from preexisting antibodies but also elicit appropriate immune responses that are sufficient for durable immunization.

We sought to identify and characterize serotype-specific properties of AdVs that contribute to the ability of these vectors to induce potent vaccine immunity. As high levels of type I IFN are known to negatively impact the ability of rare serotype-vectors to express antigenic genes and stimulate antigen-specific immune responses, we focused our studies on determining how different AdV serotypes stimulate unique innate immune responses that vary in type I IFN production. We found that AdV serotypes differentially interact with a serum protein,

Gas6, that is known to negatively regulate innate immunity during viral infection. Our studies show that adenoviruses interact with Gas6 in manner that is mediated by interactions between the Gas6 Gla domain and the HAdV-5C fiber protein shaft domain. Further, we demonstrate that Gas6 reduces the IFN response stimulated by HAdV-5C and enhances HAdV-5C encoded transgene expression. Our studies suggest that Gas6-fiber interactions contribute to AdV immunogenicity. We reason that rare-serotype based AdVs engineered to include Gas6 binding motifs will more effectively deliver DNA-based vaccines.

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