Biomedical Sciences ETDs

Publication Date

5-1-2014

Abstract

Virus-like particles (VLPs) comprised of viral structural proteins that self-assemble into particles resembling the native virion represent a relatively novel vaccine development strategy. Both safe and immunogenic, VLPs can be used as vaccines against the virus from which they are derived, but can also be used to present heterologous epitopes from other pathogens to the immune system. Both techniques result in high-titer antibody responses against the target epitope. Indeed, vaccines of VLPs are already available, including the two vaccines targeting Human Papillomavirus (HPV). These vaccines are very effective at preventing infection by the HPV types included in their formulation; high-risk HPV types that are associated with the development of cervical cancer. The elicited antibody response, however, largely does not protect against the other high-risk HPV types. Herein we report the results of studies aimed at developing a next-generation HPV vaccine using bacteriophage VLPs displaying epitopes from the minor capsid protein of HPV L2 that have been found to induce cross-protective antibodies. We first displayed a variety of N-terminal L2 epitopes on PP7 and Qβ VLPs and measured the elicited homologous protection in mice. Finding a type-specific neutralizing epitope, we were able to considerably broaden the observed cross-neutralization by immunizing with a consensus sequence of this epitope drawn from the high-risk HPV types. We also explored displaying a L2 epitope from two different HPV types on one VLP. We were able to construct assembled VLPs that displayed both targets on their surface. We observed that immunization with these hybrid VLPs elicited a more-cross neutralizing response than vaccination with VLPs displaying one target alone. Finally, we investigated the display of two molecular adjuvants on the surface of VLPs. Hypothesizing an increase in the speed and intensity of antibody response, we displayed both the complement receptor 2-minimum binding region, p28, and the monomer component of flagella, flagellin, at low levels on the surface of VLPs. We found, however, that displaying p28 in this way did not increase antibody titers.

Keywords

virus-like particles, human papillomavirus, vaccines

Sponsors

Infectious Diseases and Inflammation Program T-32 Training Grant (AI007538-14), Sexually Transmitted Infections Cooperative Research Center NIH grant(U19 AI084081)

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Chackerian, Bryce

First Committee Member (Chair)

Peabody, David

Second Committee Member

Ozbun, Michelle

Third Committee Member

Hjelle, Brian

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