Biomedical Sciences ETDs

Author

Zoe Hunter

Publication Date

5-1-2011

Abstract

Many viral structural proteins are capable of spontaneously self-assembling into structures that resemble virus particles. These structures, called virus-like particles (VLPs), have multivalent, highly repetitive structures which are capable of inducing robust and enduring immune responses, and, therefore, can serve as the basis for effective vaccines. VLPs can be used as stand-alone vaccines targeting the viruses from which they are derived and also as platforms for presenting heterologous antigens; their ability to evoke strong antibody responses against even poorly immunogenic targets makes them an attractive model for future vaccine and drug delivery vehicle designs. Our lab developed display technologies that allow us to modify VLPs so they can present essentially any potential target antigen on its surface. These technologies have led to the development of several VLP-based vaccines that target molecules derived from microbial and self-antigens. We have previously shown that when given intramuscularly, these vaccines consistently induce high-titer serum antibodies. Here we present data showing that VLP-based vaccines are compatible with mucosal deliveries to both the genital and respiratory tracts. Specifically, we displayed peptides from the HPV16 L2 coat protein on the bacteriophage VLP platform PP7, and used a second bacteriophage VLP platform, Qβ, to target two domains of the cellular HIV coreceptor CCR5 involved in HIV binding. Vaccines targeting both the viral and self-antigens were successful at inducing mucosal and systemic immune responses, represented by the presence of IgA- and IgG-specific antibodies. The induction of both mucosal and systemic immune responses presents a particular advantage for preventing infection by pathogens transmitted at mucosal surfaces. Indeed, we determined that the L2 mucosal vaccine was successful at preventing genital pseudoviral infection in a mouse model of HPV infection. As a demonstration of the VLPs ability to evoke strong antibody responses against a self - and therefore weakly immunogenic - molecule, we also present data indicating that immunization of macaques with our CCR5 vaccine results in the maintenance of undetectable viral loads in some animals, indicating protection from infection following a high-dose challenge with SIV. Our results provide a general method for the induction of a broad, comprehensive immune response using VLPs as vaccine platforms.

Keywords

virus-like particles, CCR5, mucosal immunity, vaccine, HPV16 L2

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)

Ozbun, Michelle

Second Committee Member

Prossnitz, Eric

Third Committee Member

Rubin, Robert L

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