Title

Developing a Novel Vaccine Adjuvant

Date of Award

12-2008

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Dr. Rob Eversole

Second Advisor

Dr. Karim Essani

Third Advisor

Dr. Charles Ide

Abstract

This thesis investigates in vitro and in vivo evaluation methods for characterizing suitable adjuvants for animal vaccines. First, I proposed a suite of rigorous but inexpensive physicochemical characterization methods for testing vaccine quality and consistency, using thermogravimetric analysis (TGA), high-performance liquid chromatography (HPLC) and mass spectrophotometry (MS). Together these methods may be used to evaluate the potential of vaccine candidates to transition into manufacturing.

Second, I used gene expression profiling techniques to identify the molecular mechanisms of Pfizer's proprietary Q-series, a configurable adjuvant comprised of multiple interchangeable molecules, including Quil A, cholesterol and DDA (dimethyl dioctadecyl ammonium bromide). Q-series components produce robust humoral, cellular and molecular immune responses, protection against several antigens, and possess an excellent safety profile. Additional gene expression experiments examined the effects of coadjuvation of the Q-series components, as well as two known adjuvants, Carbopol 974 P NF and/or Bay-R1005, without antigen in bovine alveolar macrophages. These studies demonstrated that coadjuvation with the Q-series provides adjuvant plasticity, as well as cooperative enhancement of immune protection in cultured rat peritoneal lavage cells and bovine alveolar macrophages.

Lastly, to assess the safety, efficacy and cross-protection of the Q-series adjuvants in coordination with the target antigens, I tested the Q-series coadjuvants, Carbopol 974 P NF, and/or Bay-R1005 together with inactivated bovine viral diarrhea virus 2 (BVDV-2) antigens in vivo in naïve beef calves. The treatments were comprised of either live attenuated or killed BVDV antigen plus single adjuvants. Compared to the currently marketed killed virus vaccine against BVDV-2, the BVDV-2 killed virus vaccines containing the novel Q-series reagents were more efficacious than a vaccine containing a modified live BVDV-2 extract and the Q-series adjuvant.

These studies establish a succinct basis for future endeavors, including validating the gene expression assays in other livestock species, and then systematically testing several novel and proprietary adjuvants. Employing the most contemporary methods in the development of animal health vaccine formulations will enable manufacturers to move from empirically characterized vaccines to more rationally designed products.

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