PROGRAM IN DEVELOPMENTAL AND MOLECULAR IMMUNITY
The Program in Developmental and Molecular Immunity (PDMI) studies the pathogenesis of and immunity to bacterial diseases, especially those of infants and children, with the overall objective of developing vaccines for the prevention of such diseases. Given that almost all pathogens of healthy individuals are inhabitants of humans only, the PDMI brings its investigational vaccines to clinical evaluation for safety, immunogenicity, and, ultimately, efficacy as soon as possible. The PDMI’s research is guided by the principle that “the proper study of mankind is man.”
Members of the PDMI pioneered the development of a new generation of vaccines in which capsular polysaccharides are chemically conjugated to highly immunogenic but nonspecific proteins. These conjugate vaccines, which confer T cell dependence and booster responses to polysaccharide antigens, have been singularly successful, as exemplified by the H. influenzae type b conjugate vaccine. H. influenzae type b meningitis (the most common cause of acquired mental retardation) has been virtually eliminated wherever the vaccine has been used. The methods developed for the vaccine have now yielded conjugate vaccines against pneumococci, Salmonella typhi, nontyphoidal Salmonella, Shigella, and Vibrio cholerae. The Vi capsular polysaccharide conjugate was over 90 percent effective against typhoid fever in 2- to 5-year-olds. Based on a level of anti–Vi that the study found to be protective, clinical trials are under way to evaluate the immunogenicity of Vi-rEPA, which is being administered concurrently with DTP during the primary injection of infants. By producing a nontoxic mutant Shigella toxin and conjugating it to the capsular polysaccharide of E. coli O157, PDMI researchers produced an experimental vaccine against this structure; E. coli O157 causes the often fatal hemolytic uremic syndrome, especially in small children. The investigational vaccine has proven safe and immunogenic in infants, and clinical trials for efficacy are now in the planning stage. In an effort to produce an anthrax vaccine with fewer side effects than those associated with the currently available vaccine, a recombinant protein antigen vaccine against Bacillus anthracis, produced on an industrial scale in collaboration with researchers at the NIDDK, has been shown to elicit levels of neutralizing antibody in mice comparable to the licensed Anthrax Vaccine A; it is now in a Phase 1 trial. Malaria is a leading cause of morbidity and mortality, especially in children, but no licensed vaccine is available. The PDMI is studying an experimental vaccine based on the circumsporozoite protein and another based on the surface protein Pfs25. Work is in progress to produce a conjugate vaccine against Borrelia burgdorferi, the causative agent of Lyme disease.
The PDMI has coordinated long-term clinical studies in Denmark and Iceland confirming that systemic infection with Group B Neisseria meningitides (GBM) does not cause autoimmune diseases. A clinical lot of a GBM polysaccharide conjugate is in production.
