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studies with antigen-specific monoclonal IgA antibodies have provided evidence that antigen-specific IgA alone was able to protect against intranasal influenza virus infection (Renegar and Small, 1991), intestinal infection with Vibrio cholerae or S.typhi (Winner et al., 1991; Michetti et al., 1992), and gastric infection with Helicobacter felis (Czinn et al., 1993). Antigen-specific IgA presumably forms immune complexes with the colonizing pathogen and thereby inhibits the interaction of the pathogen with host epithelial cells, a protective mechanism known as immune exclusion (Mestecky and McGhee, 1987). In fact, passive transfer of monoclonal IgA antibodies by a backpack hybridoma method provided protection against mucosal challenge with virulent organisms but was generally unable to prevent infection when the organisms were introduced parenterally, suggesting that mechanisms for protection at a mucosal surface do not correlate with protection from systemic challenge (Michetti et al., 1992). Therefore, induction of antigen-specific IgA responses may provide a means of totally preventing bacterial infections or at least greatly reducing the size of the infectious inoculum at the sites of initial contact between most infectious agents and the host, the mucosal surfaces.

Molecular Aspects of Virulence and Design of Recombinant Protein Vaccines

The use of recombinant techniques for the production of protein-based vaccines as well as three-dimensional immunogenic structures is well exemplified by the safe and effective recombinant HBV vaccine. Even though an effective plasma-derived vaccine for HBV has been available for many years, the recombinant DNA-derived vaccine has resulted in two licensed vaccines, the baculovirus- and yeast-derived HBV vaccines. This example can be extended to virtually all current killed or partially purified bacterial or viral vaccines. Improvements in DPT involve the use of recombinant partial structures for diphtheria (CRM 197) and tetanus (fragment C) toxoids as well as partially purified proteins from Bordetella pertussis, the so-called acellular pertussis vaccine. The acellular pertussis vaccines were found to be effective following several trials in Italy, Sweden, and Germany during the past 3 years. This new generation rDaPrT vaccine should be followed by a completely recombinant form of pertussis vaccine in the next few years.

Another important feature of new, recombinant vaccines involve the use of the insert baculovirus system to express genes for several proteins that comprise the virus capsid, which encloses the nucleic acid. The nucleic acid-free, viruslike particles (VLPs) represent important structures for vaccine development. For example, most pathogenic viruses express ligands in capsid proteins for receptors on host epithelial cells, which are the major initial site for virus entry into the host.

In many instances, the VLPs also retain the receptor binding ligand that allows their uptake into a mucosal inductive site. As discussed above, the mu-



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