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Dental caries an infectious disease:

Dental caries an infectious disease Developing countries:- caries is epidemic 25% of 3-yr old children in Brazil Developing lesions in 1 st 18 months of life Mattos- Graner et al,1996 Gibbons & Van Houte, 1975; Loesche , 1986

S.mutans & Caries:

S.mutans & Caries Clark, 1924 facultative, anaerobe,non-haemolytic fulfills Koch’s postulates - found in plaque - grown in pure culture - infection of germ free rats - antibodies to S.mutans

Acquisition of Mutans S:

Acquisition of Mutans S W.Bowen, 1960 :- i.v. monkeys with mutans S.mutans in plaque; animal studies Acquisition by infants:- 2 nd & end of 3 rd yr Page Caufield – “ Window of Infectivity” Window of vaccine opportunity : 12- 18 mths

Ontogeny of immunity in saliva:

Ontogeny of immunity in saliva Smith & Taubman : - immunity undergoes rapid early development SIgA: - is principal immune component - primary mediator of adaptive immunity - absent at birth, principal Ig at 1 month - IgA Ab to E.Coli, S.mitis & S.Salivarus 6-9 mths -SIgA Ab to MS 2-3 yrs

Need for caries vaccine:

Need for caries vaccine Extremely caries active children Immuno-compromised children Individuals in developing countries

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- Various routes of immunization in oral cavity. - Adjuvant & delivery systems caries vaccine. - Recent approaches in active & passive immunization. - Current strategies in pipeline. - Current Studies on caries vaccine.

Good Morning:

Good Morning

Caries Vaccine:

Caries Vaccine


Contents Introduction Definitions - Vaccine - Caries Vaccine Historical evolution of Immunization Immunological Mechanisms - Local - Systemic Role of Secretory IgA in Immunization

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Molecular pathogenesis Specific vaccine targets - Adhesins - GTFs ( glucosyltransferases ) - GBPs ( glucan binding proteins ) Historical evolution of Caries Vaccine Various routes of immunization in oral cavity. Adjuvant and delivery systems

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Recent approaches in active & passive immunization Current strategies in pipeline. - CaroRx - SMaRT therapy Future prospects & Concerns References CURRENT




In 1796 Edward Jenner's use of cowpox ("vacca" means cow in Latin), biological preparation used to establish or improve immunity to a particular disease. Vaccines VACCINE prophylactic therapeutic


CARIES VACCINE a vaccine currently under development to treat dental caries by inoculating against bacteria commonly known to contribute to their formation, particularly S. mutans. ( Mosby's Dental Dictionary, 2 nd ed)

Historical Evolution :

Historical Evolution 1930s :- primary micro-org for caries Lactobacilli Williams, 1944 :- immunized humans with LB decline in no. of LB x protection from caries

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Bowen et al, 1976 & Hamada & Slade , 1980 level of Ab against S.Mutans & freedom from caries Challacombe,1980 :- titers of specific serum Ab against S.mutans higher in subjects with low DMF than with high DMF

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Hypogammaglobulinemia:- - low levels of specific serum Ig - salivary S.mutans Ab - levels of S.mutans - caries. Bolton & Hlava,1982 :- S-IgA Ab to MS (but not LB) were higher in children with no detectable caries than in a comparable group with lesions. levels of Antibody (S-IgA) in ging fluid low level of caries

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Immune responses liberated via saliva or cells to migrate over tooth surface 2 main immunological mechanisms Production of SIgA in saliva LOCAL RESPONSE Production of Ab that travel through ging epithelium into crevicular fluid SYSTEMIC RESPONSE IMMUNOLOGICAL MECHANISMS

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Major Ig in saliva :- S-IgA & IgG (McGhee & Michaelek,1981 ) IgA resistant to digestion by enzymes; effective in oral environment System functional in infants (Smith & Taubman 1992) Imp role in defense of host against colonization SIgA = dimer of IgA+J chain+ protein

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GALT, Peyer’s patches Mesenteric LN Thoracic duct

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Sucrose independent Attaches to glycoprotein in pellicle PAc or Ag I/II Sucrose dependent Adherence & aggregation GTF & GBP Mechanism of action of IgA Ab (Russell et al., 1999)

Molecular pathogenesis:

M o l e c u l a r p a t h o g e n e s i s

Specific Vaccine Targets:

Specific Vaccine Targets

A. Adhesins :

A. Adhesins S Mutans ( Ag I /II, PAc ) S Sobrinus ( PAg ) have been purified. In vitro & in vivo evidence : Ab against Ag I/II Active immunization Passive immunization (Lehner et al;1981 ) (Katz et al;1993) (Ma et al;1990)


B. GLUCOSYL TRANSFERASES Sucrose glucose + fructose activated glucose glucan polymer Ab to GTF interferes with activity of this enzyme & in vitro plaque formation ( Taubman & Smith, 1972) GTF


C. GLUCAN BINDING PROTIENS 3 S.Mutans GBPs identified GbpB :- protective immune response Smith & Taubman ,1996 protection by s.c inj of GbpB in salivary gland region or mucosal application by intranasal route.

Historical evolution of Caries Vaccine:

Historical evolution of Caries Vaccine

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Bowen 1969 :- whole cells of MS as Ag in monkeys decrease in carious lesions - problem with whole cells ;- cross reactivity ( Vande Rijn 1976 ) so the search for suitable Ag ------- purified Ag preparations

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- Russell & Lehner 1978 :- Ag I /II - Holt et al 1982 :- Spa A Lehner et al 1981 :- demonstrated protective immunity to caries in monkeys with Ag I/II Gregory et al 1983 :- ribosomal prep from MS & immunized rats by local injection in SG region test animals developed higher SIgA Ab

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Carlsson & Krasse 1968 ;- Ab to GTF inhibit GTF activity protective immunity against caries


ROUTES OF ADMINISTRATION OF VACCINE Orally administered Ag IgA class Ag administered parenterally IgG class

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Oral administration of S.mutans vaccines clearance of S.mutans from humans Ag administered into parotid gland ducts SIgA Ab from vaccinated gland only but not in serum (Bowen et al 1976)

Routes to response :

Routes to response Mucosal application :induction of SIgA Ab Exposure of Ag :- - gut - nasal - bronchial - rectal “ CMIS , common mucosal immune system ” ( Mestecky, 1993)

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- oral induction of immunity by [ GALT ] :- to elicit SIgA Ab - Ag applied:- oral feeding, gastric intubation or vaccine containing capsules or liposomes - Enzyme GTF is of paramount importance A. Oral

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Disadvantage: - Rapid breakdown of antigenic proteins - Inductive sites distant Mucosal immunity alone is sufficient to change course of MS inf & disease in animal models ( Michalek et al., 1976 ) & humans ( Smith & Taubman.,1987)

B. Intranasal:

B. Intranasal Mucosal inductive sites : in closer anatomic relationship to the oral cavity Intranasal installation of Ag : targets NALT (Brandtzaeg & Haneberg,1997 ) Protection with S.mutans AgI/II (Katz et al, 1993) SBR of Ag I/II ( Hajishengallis et al 1998 )

C. Tonsillar:

C. Tonsillar Fukuizumi & co-workers in 1999 - topical application of formalin killed S. Sobrinus cells in rabbit induced salivary immune response Repeated tonsillar application of Ag appearance of IgA Ab producing cells in both major & minor SG ( Inoue et al, 1999)

D. Minor Salivary Glands:

D. Minor Salivary Glands Potential routes for mucosal induction of salivary immune response (Schroeder,1983 ) Smith & Taubman in 1990 - S.Sobrinus GTF admn onto lower lips of young adults lower proportion of MS in saliva during 6 week period foll prophylaxis

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subcutaneous administration of antigen. serum IgG , IgM & IgA antibodies. Enter oral cavity via GCF SYSTEMIC

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- explored to exclude potential side effects of oral & systemic routes. - localize immune response, GCF:- route of administration Modalities: 1. direct injection of lysozyme in gingiva. 2. brushing live S.mutans in to gingiva. 3. use of smaller mol. Wt Ag for better penetration. ACTIVE GINGIVO-SALIVARY ROUTE

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Recent advances & current status of immunization against dental caries


ACTIVE IMMUNIZATION Synthetic peptides:- - Ag from plant, animal----- hypersensitivity rxn - chemically synthesized peptides ----- no rxn - enhance immune response - give Ab in saliva & GCF - derived from GTF

Past, Present & Future Human Applications In Active Immunization :

Past, Present & Future Human Applications In Active Immunization

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1. Enterotoxins : Cholera toxin, Labile toxin . - suppresses colonization of MS - effectively binds to lymphoid cells - intra-oral route of administration ( Katz et al., 1993) Adjuvants & Delivery systems

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2 . Microcapsules & Microparticles : PGLA (poly lactide –co- glycolide). - Control rate of release of Ag - evade pre existent Ab clearance mechanisms. - degrade slowly without eliciting any inflammatory response ( Eldridge et al., 1990)

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3. Liposomes : - phospholipid membrane vesicles, - to contain & deliver drugs & Ag - enhance mucosal response to MS carbohydrate & GTF ( Childers et al., 1996) - facilitate delivery of Ag to lymphoid ts

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Few clinical trials ------ protective effect of active immunization mucosal exposure of humans to immunization with GTFs from MS ----- SIgA Ab production

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Childers & co-workers,1994:- orally immunized adults enteric coated capsules (GTF Ag) parotid SIgA Ab in 5 out of 7 subjects Nasal immunization with liposomes (GTF) induced IgA Ab response in nasal washes but less parotid SIgA (Childers 1997)

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Smith & Taubman 1987-1990:- after prophylaxis delay in MS re emergence after topical application of GTF on lower Lip - Mucosal immunization with GTF in enteric coated capsules with aluminium phosphate after prophylaxis increased parotid SIgA Ab .

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Monoclonal antibodies:- bovine milk antibodies hen egg yolk antibodies plantibodies PASSIVE IMMUNIZATION

Passive immunization approaches :

Passive immunization approaches mouth rinses containing bovine milk (Filler et al 1991) or hen egg yolk IgY Ab (Hatta et al 1997) topical application of mouse monoclonal IgG or transgenic plant SIgA Ab (Ma et al 1998)

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teeth treated for 9 days with CHX Ab topically applied for 3 weeks re colonization with MS did not occur – 2 years after t/t with mouse monoclonal Ab for 4 months after t/t with transgenic Ab explanation for long term effects on MS after short exposure to Ab ---- UNRESOLVED parallel in children

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thus topical or dietary administration of immune reagents with specificity for these proteins may have potential human application

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Mouthrinses containing bovine milk( IgG) , hen egg yolk IgY antibody to S. mutans led to modest short term decrease in number of indigenous mutan streptococci in saliva and plaque. (Filler etal. 1991, Hatta 97.) Young children who do not become naturally infected with mutan streptococci during ’ window of infectivity ‘ remain undetectively infected for several years. (Caufield etal ,1993)

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Genetic chimeric protein SBR- saliva binding region of Ag I.II. GLU- of gtf. (SBR-GLU)= Chimeric construct. Immunization of mice with chimeric protein SBR-GLU resulted in significantly enhanced levels of serum IgG anti SBR- antibody activity , compared to SBR, GLU SBR+GLU groups. (Hajishengalis, Michalek 2002)

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Synthetic antibody prepared from transgenic tobacco plants. Planet Biotech, - 1 st clinically tested plantibody & - currently undergoing Phase II US clinical trials under US-FDA approved (IND application. (Oct. 2007). T M CaroRx USE : clean teeth with oral antiseptic. Immediately followed by CaroRx application 2 applications per week for 3 weeks. No further t/t :- 6mths -1 yr

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Dr. Jeffrey D. Hillman produced genetically modified strain of Streptococcus mutans , BCS3-L1. (Nov. 2004) Mutant strain is - incapable of producing lactic acid - aggressively replaces native flora. - BCS3-L1 produces antibiotic, mutacin 1140 that allow it to out-compete S.mutans SMaRT Therapy swab modified strain on patient teeth using cotton tipped applicator for 5 minute period, one treatment may last for life time.



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Caries develops slowly & occurs throughout life immune protection be lifelong Page Caufield – “ Window of Infectivity” Window of vaccine opportunity : 12- 18 mths

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Immunize infants/young children Booster immunization Young mothers be immunized Ab of MS in breastmilk to provide passive immunity against caries

Goals of vaccination:

Goals of vaccination Provide near complete protection against inf Achieve high prevalence of immunity in population However, biology of caries is different immunization:- not attain complete effectiveness Adjunct & efficacy as much as 50%

References :

References 1. Damle SG. Textbook of pediatric dentistry; 2 nd edition: 2002 Arya 2. Tandon S. Textbook of Pedodontics; 1 st edition: 2002 Paras 3. D.J Smith, Caries Vaccine for the 21 st century.J Dent Edu 2003; 69: 1130-38 4. Michael W.Russell et al, A Caries Vaccine. Caries Res 2004;38:230-35

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J.H.Guo et al, Construction & immunogenic Characterisation of Fusion Anti-caries DNA Vaccine. J Dent Res 2004;83:266-70 Ping Zhang et al, Enhanced immunogenicity of a genetic chimeric protein. Inf & Immun 2002:6779-6787 H Hatta et al, Passive immunization against plaque in humans. Caries Res 1997;31:268-74

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T Koga et al, Immunization against dental caries. Vaccine 2002;20:2027-2044 D.J.Smith, Dental Caries Vaccine: Prospects & concerns. Crit rev oral bio med 2002;13:335-49 S.M.Michaelek, development & outlook for a caries vaccine. Oral biology & medicine 1990 K.L Wycoff, Secretory IgA Antibody from plants. Current pharm design 2004;10:1-7

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