Mucosal Vaccines: Prevention of Caries and Periodontal Diseases

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Mucosal Vaccines Prevention of Caries and
Periodontal Diseases
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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

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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?

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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)

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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

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Strategies for Immunization (contd)

• 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

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Strategies for Immunization (contd)

• Strategies for Enhancing Mucosal Immune Response
• Co-delivery with cytokines
• Co-immunogens (Cholera toxin)
• Peptides presented with potent T-cell epitopes

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Time course of sIgA appearance
Gestation
Birth
3m
6m
2y
?
1m
2-4w
8w
11w
19w
26w
SC Bronchial Epithel- ium
SC Salivary Gland
Saliva Adult SC No IgA
Salivary Antibody to Initial Oral and Gut Flora
Tooth Eruption
Adult Concen- trations
Peyers Patches
IgA Cells
Saliva sIgA
Early IgA Peak
Many Salivary IgA Concentrations in Adult Range
Adapted from Taubman Smith, 1993
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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

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What are the risks?

• Cross-reaction with host antigens
• Infection with live vaccines
• Syndromes

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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)

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Goals (contd)

• Examine sIgA response in
• Parotid saliva
• Nasal washes
• Serum (IgG and IgA)

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Protocol

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

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Anti-GTF in Nasal washes

• Panels
• Upper (IN immunized)
• No difference between soluble and liposomal
• Lower (IT vs IN)
• Nasal better than tonsil

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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

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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

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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