The HVS in collaboration with GlaxoSmithKline, Rixensart, Belgium, has developed several candidate live attenuated HAV vaccines. In addition, the HVS has developed a candidate recombinant hepatitis E vaccine that is highly promising and that is currently in clinical trials. In studies to further characterize this candidate hepatitis E vaccine, we have performed extensive pre-clinical trials to determine the potency of the vaccine, the duration of protection, the optimum regimen for administration, its protective efficacy against homologous versus heterologous virus strains, its ability to prevent infection as well as hepatitis and the minimum antibody titer that was effective in preventing infection and hepatitis, respectively. The HVS is studying the technology of DNA vaccines with a model system based upon hepatitis B virus (HBV) vaccine, a vaccine with which the HVS has had extensive experience. We have tested the efficacy of an immunostimulant (CpG) as an adjuvant for DNA vaccines, as well as for protein vaccines. In addition, the utility of DNA vaccines for the control of hepatitis C virus (HCV) has been explored. A DNA vaccine based on the E2 envelope protein of HCV proved to be highly immunogenic in mice and rhesus monkeys and moderately immunogenic in chimpanzees, but the chimpanzees were not fully protected when they were challenged with live HCV. A similar approach has been utilized in the study of a DNA vaccine based on the E1 envelope protein of HCV: various constructs of the E1 gene were prepared as DNA vaccines (expression vector plasmids) and as vectored vaccines (recombinant vaccinia) and tested in mice. The mice had excellent immune responses to the DNA vaccine as well as to the vaccinia boost. In other studies, recombinant HCV E1 envelope glycoprotein is being tested in chimpanzees as an immunoprophylactic and immunotherapeutic vaccine. Passive immunoprophylaxis has also been an important public health tool. For example, normal immunoglobulin has been important in the prevention of hepatitis A. However, monoclonal preparations could be more potent, tailored to specific neutralization epitopes and highly consistent in potency. We have prepared combinatorial libraries from the bone marrow of chimpanzees that had been experimentally infected in sequence with each of the five human hepatitis viruses. Chimpanzee globulins are virtually identical to human immunoglobulins, making them attractive choices for immunoprophylactic and immunotherapeutic agents. To date, we have isolated monoclonal immunoglobulins that react with HAV, HBV, HDV and HEV. In other studies, we have recovered human monoclonal antibodies that react with HCV. Many of the monoclonal antibodies described above are neutralizing and their production is being scaled up for tests of passive immunoprophylaxis in chimpanzees. Similar construction of combinatorial libraries from bone marrow is being carried out for chimpanzees that have been experimentally infected with dengue viruses 1 through 4 and the Norwalk virus. We have now extended these studies to other viruses and bacteria of interest that can be experimentally administered to chimpanzees. For example, in response to new concerns about bioterrorism, we are preparing neutralizing monoclonal antibodies to vaccinia virus for use as an immunoprophylactic/immunotherapeutic agent in those who require immunization with vaccinia but who are susceptible to the side-effects of such immunization. Similarly, we are immunizing chimpanzees with the three components of anthrax toxin, as well as with inactivated encapsulated anthrax bacteria in an attempt to make monoclonal antibodies that could immediately neutralize anthrax in vivo as well as instantly kill existing bacteria. We are also preparing chimpanzee monoclonal antibodies to the three serotypes of poliovirus, to rabies virus, to West Nile virus and to the tick-borne encephalitis virus complex. Some of these will have potential utility in efforts to counteract bioterrorism and all will have immunoprophylactic and immunotherapeutic potential in the battle against emerging and re-emerging pathogens.
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