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Transcript
Mucosal Vaccines: Prevention of Caries and Periodontal Diseases Most infections occur or emanate from mucosal surfaces • Gastrointestinal tract – Helicobacter pylori, Vibrio cholerae, enterotoxigenic E. coli, Salmonella, Shigella spp., Campylobacter jejuni, Clostridium difficile, rotaviruses, and calici viruses • Respiratory tract – Mycoplasma pneumoniae, influenza virus, respiratory syncytial virus (RSV) • Urogenital tract – HIV, Chlamydia, Neisseria gonorrhoeae, herpes simplex virus (HSV) and E. coli (urinary tract infections) • Oral cavity – Streptococcus mutans, Porphyromonas gingivalis, Candida albicans Goals for the development of a vaccine • Prevent agent from attaching or colonizing the mucosal epithelium (non-invasive agents) • Prevent penetration and replication within the mucosal epithelium (invasive agents) • Block binding or action of toxin • Induce a protective sIgA response • Modulate systemic response? Requirements of Protective Vaccines • • • • • • • • Block adherence of microorganism to host Facilitate clearance from host Neutralize toxin Must induce recognition of “virulence” epitopes Must be immunogenic Must not induce autoimmune disease Should induce long-lasting immunity Must induce the type of response that is effective to eliminate pathogen (eg. TH1 or TH2) Strategies for Mucosal Immunization • Requirements – Safe taken orally – Long-term maintenance of memory – Survive in gastric and intestinal environments – Must escape normal clearance mechanisms – Must compete for inclusion within M-Cell transport – Must arrive intact to antigen-processing cells – Must induce dimeric sIgA reactive with cell surface Strategies for Immunization (cont’d) • Strategies for Delivery of Vaccine Into O-MALT – Inert particulate carriers • Biodegradable copolymers • Immune-stimulating complexes (ISCOMs) • Hydroxyapatite crystals – Live vaccine vectors (recombinant) • Vaccinia virus • Salmonella • Mycobacterium bovis Strategies for Immunization (cont’d) • Strategies for Enhancing Mucosal Immune Response – Co-delivery with cytokines – Co-immunogens (Cholera toxin) – Peptides presented with potent T-cell epitopes Time course of sIgA appearance Gestation 8w Birth 11w 19w 26w SC Bronchial Epithelium SC Salivary Gland Peyer’s Patches 2-4w Saliva: Adult SC No IgA IgA Cells Adapted from Taubman & Smith, 1993 1m 3m Salivary Antibody to Initial Oral and Gut Flora Saliva sIgA 6m Tooth Eruption Early IgA Peak 2y ? Adult Concentrations Many Salivary IgA Concentrations in Adult Range Issues in Oral Health • Most oral infections are polymicrobial infections • Most are chronic infections • What is the etiologic agent? – Caries – Periodontal disease • • • • • What are the virulence factors? What is the “at risk” population? Are there easier alternatives? Who do you immunize? Most are not life-threatening What are the risks? • Cross-reaction with host antigens • Infection with live vaccines • Syndromes An example of a phase I anti-caries clinical trial • Goal of study – Induction of sIgA by mucosal immunization with S. mutans antigen in lipid monolayer – Comparison of nasal vs. tonsillar immunization (topical spray) – Safety • Antigen – E-GTF (enriched glucosyltransferase preparation) neet or in a liposomal vaccine preparation (lipid monolayer) • Subjects – Twenty-one adults (20-50 years of age) Goals (cont’d) • Examine sIgA response in: – Parotid saliva – Nasal washes – Serum (IgG and IgA) Protocol • Samples collected at various intervals following immunization (0, one to two week intervals for three months) Anti-GTF in Nasal washes • Panels – Upper (IN immunized) • No difference between soluble and liposomal – Lower (IT vs IN) • Nasal better than tonsil Anti-GTF in Parotid Saliva • Panels – Upper (IN immunized) • No difference between soluble and liposomal – Lower (IT vs IN) • Nasal better than tonsil on day 35 Anti-GTF Serum Responses • Panels – Upper (IgG response) • Nasal better than tonsil • Not statisticallysignificant – Lower (IgA response) • Nasal better than tonsil • Not statisticallysignificant Conclusion • Soluble and liposomal GTF appear to be safe • Immunogenic when given in nasal route – In conflict with other studies • These were adults, may be different in children