Transcript Mucosal Vaccines: Prevention of Caries and Periodontal Diseases

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
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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
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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