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cosal and systemic lymphoid cell systems are distinct and exhibit separate modes for the induction of immunity. The use of particulate VLPs that bind epithelial cells and M cells of mucosal sites such as the Peyer’s patches or GALTs may represent ideal modes for the induction of mucosal immunity to viruses.

Although polysaccharide vaccines are usually not very immunogenic in infants, the titers of antibodies are increased by covalent coupling to protein carriers such as tetanus or diphtheria toxoid. Studies indicate that conjugates elicit T-cell-dependent antibody responses characterized by higher titers and switching to non-IgM isotypes. The current major conjugate vaccines have been developed to Hib or to several different capsular polysaccharide types of Streptococcus pneumoniae, and these represent important advances that have used molecular immunology, chemistry, and infectious disease expertise.

Novel Vaccine Delivery Systems

A number of major breakthroughs have occurred in the development of particulate vaccines. These range from lipid- or detergent-based enclosures; for example, liposomes (Gregoriadis, 1990) and immune-stimulating complexes (ISCOMS) (Morein et al., 1984; Claassen and Osterhaus, 1992), to chemical polymers, for example, microspheres (Eldridge et al., 1990; O’Hagan et al., 1993). Microphages are briefly described here to illustrate the promise of inert particles for vaccine delivery. Several types of microspheres have been used. The coating material is usually a biodegradable polymer, and methods for microencapsulation usually involve the separation of two-phase polymers. Emulsions from solvent evaporation-extraction are common. The microspheres produced in this way are spherical. Those ranging from 1 to 10 g are most effectively taken up by antigen-presenting cells as well as M cells in mucosal inductive sites (Eldridge et al., 1990). In general, the copolymer poly (dl-lactidecoglycolide) has been more extensively studied, and variations in polymer ratios can affect the rate of hydrolysis and antigen release. Other promising microspheres involve the polyphosphacenes-polyalignates. Because of their hydration properties, they are amenable to encapsulation of proteins in physiologic buffers, which avoid denaturation.

Salmonella strains were the first to be used to investigate the potential for expression and delivery of recombinant vaccine proteins to the host immune system. This approach has been elegantly extended to other enteric gramnegative organisms, that is, recombinant V. cholerae and Shigella—as well as to recombinant bovine growth hormones, and to commensal bacteria—for example, oral streptococci and Lactobacillus, which is present in yogurt. However, recombinant Salmonella has remained the prototype for this approach and can be used to illustrate the principle (Hone et al., 1991; Chatfield et al., 1992; Tackett et al., 1992; Roberts et al., 1994). An important benefit of using recombinant Salmonella is that it remains an enteric bacterium that, following oral admini-



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