There is urgent need worldwide for the development of new and improved vaccines to control infectious diseases, including influenza. Vaccination remains the most cost-effective biomedical approach for controlling these diseases, but developing and producing the flu vaccines in sufficient quantities has proved problematic. To date, clinical trials with aluminum-based adjuvants (alum)-the only ones licensed in the U.S.-in combination with pandemic influenza virus vaccines, have failed to provide evidence of a significant immunostimulating effect on influenza-specific responses. A promising solution to the supply problem is to incorporate an antigen-sparing adjuvant(s) into vaccine formulations, prompting the search for alternative adjuvants capable of safely boosting protective anti-influenza antibody titers to minimize immunogen consumption, while still enhancing vaccine efficacy and thus increasing the number of available vaccine doses. We have identified a naturally occurring secreted protein with intrinsic immunostimulatory properties from Onchocerca volvulus (rASP-1) and showed that it is a powerful immunostimulatory adjuvant;it promotes a balanced Th1/Th2 antibody response and cellular responses to several soluble vaccine candidate antigens, and commercial inactivated viral vaccines, including trivalent-inactivated flu vaccines (TIV). Further, the rASP-1 protein induces maturation and activation of naive human DCs and potentiates their activity as APCs. It also stimulates Th1-biased cytokine secretion from normal PBMCs via the activation of dendritic cells (DCs) and the TLR2 and TLR4 receptors, suggesting that rASP-1 is a novel immunostimulatory adjuvant. We propose to maximize its promising beneficial applications by designing a focused preclinical and product development approach that will ultimately produce a highly effective and safe rASP-1 adjuvanted flu vaccine in a simple aqueous formulation that requires a minimal antigen quantity per dose. By enhancing vaccine efficacy in this way, we can effectively increase the number of vaccine doses available. We plan to develop a scalable production process for the rASP-1 adjuvant using the yeast expression system;it will feature a series of critical assays used for in-process, buffer formulation, release, and stability testing. We will evaluate functionality and potency in vitro an then validate the induction of the desired antibody and cellular responses after one immunization with the co-administered TIV flu vaccine in mice and ferrets using minimal immunogen consumption. We are confident the project will produce all the information and processes necessary for compilation/ submission of an IND and entry into clinical development of the rASP-1 adjuvant for human use. The application has three aims: 1) process development, characterization, buffer formulation, and stability testing of the rASP-1 adjuvant;2) efficacy testing of the rASP-1 adjuvanted flu vaccine using antigen dose sparing;and 3) technology transfer, cGMP manufacture, GLP toxicology, and IND preparation.
Adjuvants are integrated into vaccines to insure their effectiveness and to support antigen sparing. Currently, alum is the only adjuvant licensed in the U.S., but it has had limited effectiveness when used with commercial flu vaccines. Our objective is to produce a highly effective and safe rASP-1 adjuvanted flu vaccine in a simple aqueous formulation that requires a minimal antigen quantity per dose. By enhancing vaccine efficacy in this way, we can effectively increase the number of vaccine doses available.