Vaccination is a potent and cost-effective countermeasure to the threat of bioterrorism agents, and there is intense interest in the design and use of adjuvants to enhance immune responses to vaccines. This is particularly important for vaccines that are based on subunits from bioterrorism agents, since these antigens are usually not highly immunogenic by themselves. Recent work has shown that the C3d component of the cellular complement pathway can function as an adjuvant to selectively enhance antibody responses to a foreign antigen, as well as accelerated affinity maturation of antibodies. Our central hypothesis is that viral vectors can be engineered to be more potent by expressing antigen covalently linked to C3d. Enhanced potency would allow viral vectors to be used at lower and safer doses to obtain better responses than that seen at higher doses of conventional viral vectors. In addition, this approach would allow viral vectors to be attenuated to a higher degree and still maintain potency. We will test this hypothesis by determining if C3d functions as a molecular adjuvant when expressed from vectors based on the noncytopathic paramyxovirus Simian Virus 5 (SV5). Our recent published work has shown that rSV5 has inherent properties that could be exploited to create novel vaccine vectors.
In Aim 1, we will test the hypothesis that C3d can function as a selective adjuvant for enhancing respiratory tract antibody responses to Y. pestis F1 antigen when delivered by an rSV5 vector, rSV5 vectors expressing either Y. pestis F1 antigen alone or F1 linked to C3d will be tested in our well-developed mouse model system for viral growth properties, the degree of respiratory tract inflammation, and for cytokine expression and cellular infiltration. Timecourse assays and dose-response experiments will test the potency of rSV5 vectors that express F1 or F1-C3d by determining the antibody response and T helper response following respiratory tract infection.
In Aim 2, mice will be infected with various combinations of soluble F1 or F1-C3d along with rSV5-F1 or rSV5-F1-C3d to establish the stage of respiratory tract prime-boost protocols that is best served by C3d: prime only, boost only or both stages.
In Aim 3, we will compare the relative adjuvant effect of C3d when delivered by virus vector or by DNA vaccination. At the conclusion of these studies, we will have developed a powerful new class of viral vectors to elicit a more rapid and potent antigen-specific antibody response in the respiratory tract.
| Johnson, John B; Capraro, Gerald A; Parks, Griffith D (2008) Differential mechanisms of complement-mediated neutralization of the closely related paramyxoviruses simian virus 5 and mumps virus. Virology 376:112-23 |
| Balin, Samuel J; Ross, Ted M; Platt, Jeffrey L et al. (2008) HIV genes diversify in B cells. Curr HIV Res 6:10-8 |
