University of North Carolina at Chapel Hill Graduate School
Doi
Abstract
Dengue viruses (DENV1-4) cause 390 million annual infections across the globe. Primary DENV infection elicits an antibody response that is thought to provide lifelong protection against re-infection with the same serotype. A protective antibody response provided by vaccination would be the best tool available to prevent DENV related disease but the currently licensed DENV vaccine had variable efficacy. We still have large knowledge gaps that need to be addressed surrounding qualities of protective antibodies. My thesis defines three properties of the protective antibody response to DENV infection and vaccination. Isolation and characterization of potently neutralizing monoclonal antibodies identified the majority of these antibodies bind across multiple DENV E-proteins (quaternary epitopes) on the virion surface. For my thesis, I defined the epitope of a potently neutralizing antibody to the closely related Zika virus (ZIKV) and used its structure to guide questions about the mechanism of potent neutralization. I identify that targeting a quaternary epitope is essential for potent neutralization. Recently, a DENV vaccine that induced neutralizing antibodies did not demonstrate protection in DENV naïve individuals. To understand qualities of a protective neutralizing antibody response, I compared the antibody response elicited by WT DENV infection to the antibody response elicited in DENV vaccinated individuals who subsequently experience infection. I observed a specific fraction of the neutralizing antibody response correlated with protection. While antibody response to primary infection protects against clinically significant disease, it is unclear if the antibody response provides sterilizing immunity as rare, homotypic reinfections are reported. To understand if antibody response to primary infection provides sterilizing immunity, I used a unbalanced DENV vaccine as a human challenge model. The majority of individuals respond to the vaccine, regardless of DENV serostatus. My results help guide future development of DENV vaccines to achieve a protective, balanced vaccine.Doctor of Philosoph
