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Program in Developmental and Molecular Immunity
The Program in Developmental and Molecular Immunity (PDMI) pioneered the development of a new generation of vaccines in which capsular polysaccharides (CP) are chemically bound to immunogenic carrier proteins to form conjugates. Such conjugates, conferring T-cell dependence and booster responses to polysaccharide antigens, have proven successful as exemplified by the H. influenzae type b conjugate vaccine such that H. influenzae type b meningitis has been virtually eliminated wherever the vaccine has been used. The PDMI’s methods have now yielded conjugate vaccines against pneumococci, Salmonella typhi, non-typhoidal Salmonella, Shigella, Vibrio cholerae, anthrax, and malaria.
The Vi CP conjugate was over 90 percent protective against typhoid fever in 2- to 5-year-olds. Found to be protective and of long duration in 2- to 5-year-olds based on IgG anti–Vi levels, Vi-rEPA, administered concurrently with DTP, was evaluated by antibody level measurement in infants, with no serious adverse events observed in any of the infants.
By producing a non-toxic mutant Shigella toxin and conjugating it to the O-specific polysaccharide (O-SP) of E. coli O157, PDMI researchers produced an investigational vaccine against this pathogen, which causes the often fatal hemolytic uremic syndrome, especially in small children. The vaccine was safe and immunogenic in infants; clinical efficacy trials are planned. Following Phase 1 and Phase 2 studies that showed safety and immunogenicity, a double-blinded randomized, vaccine controlled Phase 3 evaluation of Shigella sonnei and Shigella flexneri 2a O-SP–protein conjugates, injected twice into healthy 1- to 4-year-olds in Israel, was completed. No serious adverse reactions related to vaccination occurred. Both the antibody levels and efficacy were age-related. The efficacy of the S. sonnei conjugate in the 3- to 4-year-olds was about 70 percent after two years of follow-up, with a similar trend for S. flexneri 2a. Accordingly, the PDMI has developed methods to increase the conjugates’ immunogenicity by using the KDO residue at the reducing end of the O-SP and oxime chemistry—a method that could have general applicability to lipopolysaccharides (LPS) considered for vaccines.
In an effort to produce an anthrax vaccine with fewer side effects than those associated with the licensed vaccine (AVA), the PDMI, in collaboration with researchers at the NIDDK and NIAID, produced a recombinant Protective Antigen (rPA) of the Bacillus anthracis toxin on an industrial scale. In mice, rPA elicited neutralizing antibody levels comparable to those of AVA; in a Phase 1 trial in adults, rPA caused no serious adverse reactions. The spore coat of B. anthracis contains a saccharide with anthrose (immunodominant) at its non-reducing terminus. A cross-reactive saccharide has been detected in the CP of the marine bacterium Shewanella and in the pili of Pseudomonas syringae. The PDMI conjugated Shewanella CP to proteins; the conjugate-induced antibodies reacted with B. anthracis spores. Such conjugates could provide yet another antibody against B. anthracis to be added to the arsenal of immunologic defense against bioterrorism.
Despite high rates of immunization with a safe acellular pertussis vaccine, pertussis continues to occur in infants too young to be fully immunized and in young adults. The PDMI genetically engineered a Bordetella bronchiseptica strain to produce a mutant pertussis toxin and devised culture conditions to increase its yield; such a mutant pertussis toxin would replace the licensed, chemically inactivated toxin and other pertussis components that constitute the current vaccine. The PDMI published a method for synthesizing LPS conjugates for prevention of B. pertussis and other Bordetellae; the conjugates are undergoing pre-clinical testing.
In other projects, the PDMI is developing micro-methods for measuring lipid components of group B streptococcus (GBS) in order to permit evaluation of the relationship among maternal colonization with GBS, treatment with penicillin, and newborn respiratory distress. To complement its study of autoimmune disease following systemic Group B Neisseria meningitis (GBM) infection, the PDMI has coordinated long-term clinical studies in Denmark and Iceland on the effect of maternal GBM infection on pregnancy outcome. Production of clinical lots of the program’s GBM polysaccharide and the crossreacting Escherichia coli K92 conjugates is ongoing. Work is also in progress to produce a conjugate vaccine against Borrelia burgdorferi, the causative agent of Lyme disease.