SBIR-STTR Award

To counter the threat of diarrhea diseases, Antex Biologics is developing an orally administered, non-living combined pathogen vaccine that will protect against disease due to Shigella flexneri, S. sonnel, C. jejuni, and enterotoxigenic Escherichia coil (ETEC). This vaccine also will be formulated with and without a mucosal adjuvant which may also provide an additional antigen against ETEC. The retention of immunogenicity of each of the vaccine components in the combined vaccine will be determined by analysis of local and systemic humoral immune responses. The utility of rabbit oral challenge model previously developed for study of shigellosis to demonstrate infection or disease due to challenge with the enteric pathogens of interest will be established. Also, the ability of the prototype combined agent traveler's diarrhea vaccine to protect rabbits against oral challenge with S. sonnel will be determined. Homologous and heterologous protection against infection with other enteric pathogens will be carried out in phase II of this STTR. Additional studies will be carried out to adapt Antex's NST technology to enhancement of the CFA/l antigen of ETEC and evaluate the immune response to this organism following oral vaccination with killed whole cells. These preclinical studies will guide formulation of a prototype GMP vaccine against traveler's diarrhea to be tested in phase II of this STTR.

Benefits:
This vaccine will be a major benefit to military personnel and other travelers. Further, it will provide an important pediatric vaccine for use in developed and developing countries. The technology developed during this project will also have broad commercial applications for other vaccines which may be similarly formulated for mucosal delivery.

The objective of this Phase II proposal is to continue the successful Phase I, proof of concept project, through production of a commercially practical multivalent, broad spectrum, oral vaccine against major bacterial pathogens responsible for traveler's diarrhea. The vaccine produced for clinical use as a result of this STTR effort will consist of inactivated whole cells from Shigella felxneri 2a, Shigella flexneri 3a, and Shigella. The vaccine will be formulated with and without a mutated form of labile toxin of enterotoxigenic E. coli (termed mLT) which serves not only as an important antigen of ETEC, but also is a potent mucosal adjuvant. The whole cell components of the vaccine will be prepared using Antex's proprietary Nutriment Signal Transudation (NST) technology. Animal models developed during Phase I of the STTR will be used during Phase II to establish that protection may be provided by specific Shigella vaccine components of the vaccine against homologous challenge. The preclinical vaccine will be similar to that to be produced for clinical evaluation, but it will also contain C. jejuni, S. flexneri 6 and will be formulated with CFA 1, CS 3, and CS 6 as components of ETEC. As a parallel effort to the preclinical studies, a multicomponent vaccine containing S. flexneri 2a, S. flexneri 3a, and S. sonnei with or without mLT will be produced under GMP and tested for safety and immunogenicity in a Phase I trial. These efforts will not only result in a means to achieve immunoprotection against enteric infections, but they will also establish a new medical approach that should quickly result in more effective oral vaccines against a broad range of infections. This vaccine will be a major benefit to military personnel and other travelers. Further, it will provide an important pediatric vaccine for use in developed and developing countries. The technology developed during this project will also have broad commercial applications for other vaccines which may be similarly formulated for mucosal delivery.

Keywords:
TRAVELER'S DIARRHEA, VACCINE, ORAL IMMUNIZATION, ETEC, SHIGELLA, CAMPYLOBACTER