The 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, which confer T-cell dependence and booster responses to polysaccharide antigens, have been successful, as exemplified by the Haemophilus influenzae type b (Hib) conjugate vaccine;Hib meningitis (the most common cause of acquired mental retardation) has been virtually eliminated wherever the vaccine has been used. PDMIs methods have yielded conjugate vaccines against pneumococci, Salmonella typhi, nontyphoidal Salmonella, Shigella, Vibrio cholerae. The priniciples that evolved from these studies have been applied to preparing improved vaccines for anthrax and Plasmodium falciparum and vivax malaria. The Vi CP conjugate was >90% protective against typhoid fever in two- to five year-olds. An estimate of the protective levels was based upon experimental and clinical data. Protective levels of IgG anti-Vi were elicited in 90% of infants when Vi-rEPA conjugate was injected along with EPI vaccines. Following successful Phase 1 and Phase 2 studies, a double blinded randomized and vaccine-controlled Phase 3 evaluation of Shigella sonnei and Shigella flexneri 2a O-SP conjugates in Israel, showed them to be safe and immunogenic in 1 to 4 year-olds. Both the antibody levels and the efficacy were age related. The efficacy of the S. sonnei conjugate in the 3-4 year-olds was about 70% (P=0.05). S. flexneri 2a was also reduced but the numbers were too small for statistical evaluation. The immunogenicity of the conjugates was increased by binding low molecular weight O-SP via its KDO residue at the reducing end to the carrier protein using oxime chemistry. This is being applied to other LPS vaccines. Shigella and Escherichia coli are one genus. E. coli O157-rEPA provides an investigational vaccine for the hemolytic uremic syndrome that was safe and immunogenic in infants, and clinical efficacy trials are planned. A recombinant Protective Antigen (rPA) of Bacillus anthracis was prepared in collaboration with NIDDK and NIAID. It elicited in mice neutralizing antibody levels comparable to those of AVA. In a phase 1 trials, rPA was safe and immunogenic. rPA elicited slightly higher antibody levels elicited by 4 injections, spaced apart as recommended by the FDA compared to 6 injections according to the U.S. Armed Forces schedule for AVA. Because anthrax is a capsulated organism, a conjugate with the capsule was produced. It was immunogenic in mice and mAbs produced with its use were highly protective in a mouse model. The spore coat contains a saccharide whose non-reducing terminus is anthrose that is immunodominant. A cross reactive saccharide has been detected in the CP of Shiwanella, marine bacteria, and in the pili of Pseudomonas syringae. The Shiwanella CP was purified and conjugated to proteins that elicited specific antibodies that reacted with B. anthracis spores. Such conjugates could provide other antibodies towards this pathogen. A conjugate against Borrelia burgdorferi (Lyme disease) has been produced. Production of clinical lots of our group B meningococcus polysaccharide and the cross-reacting Escherichia coli K92 conjugates is underway. Despite the high rates of immunization with acellular pertussis vaccine, pertussis occurs in infants too young to be fully immunized and in young adults. A Bordetella bronchiseptica strain was genetically engineered to produce the mutant pertussis toxin and its yield was increased. This mutant pertussis toxin should replace the chemically-inactivated toxin and the other pertussis components in current vaccines. A method for synthesizing B. pertussis LPS-conjugates for inducing complement-mediated bactericidal activity has been published. Micro-methods for testing lipid-based components of group B streptococcus are being developed in order to evaluate the effect of a high degree of asymptomatic colonization of mothers with this pathogen during delivery and of treatment with penicillin causing release of cardiolipin and how these relate to respiratory distress in the newborn. Publications generated by this research are listed in individual project reports.
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