Degree Type

Dissertation

Date of Award

2019

Degree Name

Doctor of Philosophy

Department

Veterinary Microbiology and Preventive Medicine

Major

Immunobiology

First Advisor

Michael J. Wannemuehler

Second Advisor

Balaji Narasimhan

Abstract

Design of a high-quality vaccine requires more than just initiation of a robust immune response, as there are several other factors that should be considered during development. An ideal vaccine should be efficacious and cost-effective, with minimal side effects and reactogenicity. Additionally, it is important to consider required number of doses and storage requirements.

Streptococcus pneumoniae is the major causative agent of bacterial pneumonia, a debilitating disease and the leading cause of death in children under the age of five worldwide. There are several existing vaccines against S. pneumoniae, though none are protective across all serotypes. Pneumococcal surface protein A (PspA), a key virulence factor of S. pneumoniae, shows promise as a target antigen for future vaccines, to address challenges presented by diversity of the capsular antigens.

Yersinia pestis, the causative agent of bubonic, septicemic, and pneumonic plague, induces a highly lethal infection if left untreated. There are no currently existing licensed vaccines against Y. pestis. New research using the recombinant fusion protein F1-V, in vaccine formulations against pneumonic plague, have shown protection across several species.

Biodegradable polyanhydrides have been studied as a nanoparticle-based vaccine (i.e., nanovaccine) platform for stabilization of labile proteins and enhanced shelf storage. Nanovaccines have also been shown to have inherent adjuvanticity and induce humoral and cell-mediated immune responses. The STimulator of INterferon Genes (STING) agonists cyclic dinucleotides (CDNs) have been shown to be promising next-generation adjuvants capable of initiating rapid, protective humoral responses.

Vaccine formulations, described herein, were comprised of either polyanhydride nanoparticles alone or in conjunction with the CDN R,R-CDG, against Y. pestis or S. pneumoniae. Immunization with a single-dose of these nanovaccine formulations, induced protective immunity against lethal challenge at both early (14 days post-immunization) and late (180 days post-immunization) time points, and maintained efficacy following shelf-storage at 25˚C for 60 days. The ability of these vaccine formulations to be efficacious following a single immunization, induce rapid and durable protective humoral responses, and maintain potency after shelf storage, highlight the potential of polyanhydride nanoparticles as a promising next-generation adjuvant and vaccine delivery platform.

Copyright Owner

Danielle Ann Wagner

Language

en

File Format

application/pdf

File Size

157 pages

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