Mucosal Vaccines: Mucosal Vaccines: Prevention of Caries and Prevention of Caries and

Periodontal DiseasesPeriodontal Diseases

Most infections occur or emanate Most infections occur or emanate from mucosal surfacesfrom 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 vaccineGoals 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 VaccinesRequirements 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 ImmunizationStrategies 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 Strategies for ImmunizationImmunization (cont’d) (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 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 Time course of sIgA appearanceappearance

3m3m 6m6m 2y2y ??1m1m2-4w2-4w8w8w 11w11w 19w19w 26w26w

GestationGestation BirthBirth

SCSCBronchialBronchialEpithel-Epithel-iumium

Peyer’sPeyer’sPatchesPatches

SCSCSalivarySalivaryGlandGland

IgAIgACellsCells

Saliva:Saliva:Adult SCAdult SCNo IgANo IgA

SalivaSalivasIgAsIgA

Salivary Salivary Antibody toAntibody toInitial OralInitial Oraland Gut Floraand Gut Flora

Early IgAEarly IgAPeakPeak

ToothToothEruptionEruption

Many Salivary IgAMany Salivary IgAConcentrationsConcentrationsin Adult Rangein Adult Range

AdultAdultConcen-Concen-trationstrations

Adapted from Taubman & Smith, 1993

Issues in Oral HealthIssues 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?What are the risks?

• Cross-reaction with host antigens

• Infection with live vaccines

• Syndromes

An example of a phase I anti-caries An example of a phase I anti-caries clinical trialclinical 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)Goals (cont’d)

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

ProtocolProtocol

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

Anti-GTF in Nasal washesAnti-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 SalivaAnti-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 ResponsesAnti-GTF Serum Responses

• Panels– Upper (IgG response)

• Nasal better than tonsil• Not statistically-

significant

– Lower (IgA response)• Nasal better than tonsil• Not statistically-

significant

ConclusionConclusion

• 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