C DIFFICILE ARU AS A CARRIER PROTEIN IN VACCINES

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Even with the numerous advances made in vaccination programs, infectious diseases continue to pose serious problems to the health profession. In industrialized countries, opportunistic pathogens such as Clostridium difficile and Staphylococcus aereus continue to cause disease in hospitalized patients. Infections of infants and young children due to Hemophilus, Streptococcus, and Neisseria continue to be a serious health threat. In poorer countries, enteric infections are estimated to kill 10 to 12 million persons a year, most of these being under one year of age. Therefore, it is important to continue developing new approaches for vaccines. The results of studies by Drs. John Robbins and Rachel Schneerson at the National Institute of Child Health and Human Development show that vaccines comprised of capsular polysaccharides conjugated to carrier toxins such as tetanus, diphtheria toxin, and Pseudomonas exotoxin are highly effective. Based on these findings, we propose to evaluate the use of nontoxic recombinant C. difficile toxin A repeating units (rARU) as a carrier molecule. The large size of rARU (a single polypeptide with an Mr of 104,000), its immunodominant and adjuvant properties, and its role in human disease make it a highly attractive candidate as a carrier. Capsular polysaccharides from Shigella sp. will be conjugated to rARU. Groups of mice will be immunized with conjugate and evaluated for antibody response to polysaccharide and rARU. These results will be compared to previous results obtained using other bacterial toxins as carriers. The use of rARU may have widespread application in conjugate vaccines and may be suitable for conjugation with capsular polysaccharides from a variety of pathogens. Proposed commercial applications: Conjugate vaccines prepared using recombinant Clostridium difficile toxin A repeating units (rARU) as a carrier molecule for capsular polysaccharides may be highly effective, due to the immunodominant and adjuvant properties of ARU. The results of this project may lead to the development of vaccines that will be of significant value to the health industry around the world.