1. Mucosal Vaccines: Prevention of Caries and Periodontal Diseases

2. 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

3. 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?

4. 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. T H1 or T H2 )

5. 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

6. 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

7. 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

8. Time course of sIgA appearance 3m6m2y?1m2-4w8w11w19w26w Gestation Birth SCBronchialEpithel-ium Peyer’sPatches SCSalivaryGland IgACells Saliva: Adult SC No IgA SalivasIgA Salivary Antibody to Initial Oral and Gut Flora Early IgA Peak ToothEruption Many Salivary IgA Concentrations in Adult Range AdultConcen-trations Adapted from Taubman & Smith, 1993

9. 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

10. What are the risks? Cross-reaction with host antigens Infection with live vaccines Syndromes

11. 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)

12. Goals (cont’d) Examine sIgA response in: –Parotid saliva –Nasal washes –Serum (IgG and IgA)

13. Protocol Samples collected at various intervals following immunization (0, one to two week intervals for three months)

14. Anti-GTF in Nasal washes Panels –Upper (IN immunized) No difference between soluble and liposomal –Lower (IT vs IN) Nasal better than tonsil

15. 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

16. Anti-GTF Serum Responses Panels –Upper (IgG response) Nasal better than tonsil Not statistically- significant –Lower (IgA response) Nasal better than tonsil Not statistically- significant

17. 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