CARIES VACCINE--Dr Thejokrishna.ppt caries vaccine

caries vaccine

1. GOOD MORNING !

2. Cariology symposium
“Caries Vaccine”
Thejokrishna.P
Post-Graduate student
Dept of Pedodontics & Preventive dentistry
Bapuji Dental College & Hospital
Davangere: 577 004

3. Concept of vaccination
Lactobacillus
S mutans & S.sobrinus =mutans
streptococci
large no: of animal expts & small scale
human studies

4. Vaccine: suspensions or products of infectious
agents, used chiefly for producing active
immunity.
Vaccination :- inoculation of any antigenic
material for the purpose of producing active
artificial immunity.

5. Mutans Streptococci group
The Mutans Streptococci
Species Serotype Host
S. mutans c, e, f Human
S. sobrinus d, g Human
S. cricetus a Human, animal
S. ferus . Rat
S. ratti (rattus) b Human, Rodents
S. macacae . Monkey
S. downei h Monkey

6. Steps in developing caries
vaccines
•Identify virulence agents
• Need to induce a protective response
•Animal model
•Human tests (FDA trials)

7. What is the ideal dental caries
vaccines?
Prevent adhesion or function of all common
cariogenic S.mutans strains
•Excellent Safety Profile-low incidence of
adverse reactions
•Could be given by various routes and still be
effective
• Inexpensive
• Delivered by individuals with little training

8. An effective caries vaccine response
requires:
•An antibody response which interferes with early
colonization
•-does not have to be bactericidal
•-must not cause an inflammatory response
•-must persist
•Should be directed to the oral cavity

9. Timing of the Vaccination
Immunization - initiated early -childhood -
interfere with colonization..
requires the mucosal immune system (MALT)
be sufficiently mature to respond
effectively.

10. SPECIFIC IMMUNE COMPONENTS IN SALIVA
Secretory IgA
•dimer connected by a connected by a “J”chain
• contains a secretory component (“Sc protein”)
• Secreted by Plasma cells in Salivary Glands
• Acts as a specific agglutinin of bacteria or
fungus
•Increased caries experience-- salv Ig A

11. Theoretically controls population of
cariogenic bacteria by
Secretory IgA :
Prevents bacterial adhesion to host
cells or salivary pellicle i.e.., initial
colonization
Reacts with bactr surface receptors
Inhibits glycosyl-transferase
Opsonize bactr –PML/macrophage
phagocytosis

12. secretory IgA -absent - saliva and
other secretions at birth,
mature IgA - principal salivary Ig- 1
month of age.
By 6 to 9 months, most children-
more adult- like distribution of
salivary IgA1 and IgA2 subclasses.

13. significant maturation of the mucosal
immune response -- end of the first
year of life.
The best moment to immunize is
around 1yr of age..

14. Timing of Colonization of the Oral
Cavity by Streptococcus
Colonization of oral cavity:
-sterile at birth
-S. mitis, salivarius- - (within24 h)
- S. sanguis - 9 months of age
-. S.mutans, S. sobrinus- in 18- 24
months (window of infectivity )

15. Mechanisms by which a Dental
Caries Vaccine may Function
• Early Oral Clearance of Micro- organisms
•Antibody Blockade of initial colonization
• block the receptors -(adhesin & GBPs)- necessary for
colonization
• salivary phase – Ab mediated aggregation & clearing of
adhesin, bearing Str cocci prior to colonization..

16. Potential Streptococcal components -- targeted
Adhesion Antigen of cell wall-type I & II
Glycosyl-transferase (GTF)
Glucan- binding proteins (GBP )

18. Antigen A & B
Russell 1980—protein antigens on cell
wall
Surface fibrillar protein—impr for
initial sucrose independent adherence
of S mutans
Disadv: occurs S mutans & S rattus,
not in S sobrinus( Jenkins & Demuth 1997)

19. GTFs:
•S mutans synthesizes several GTFs --considerable sequence
homology..
•GTF-1, GTF- S1 & GTF- S
•Natural/ induced mutations in GTF genes—loss of Glucan
production—significant reduction of disease in animal models
•Presence of antibodies to GTF– amount of biofilm
•Passive administration of GTF Ab in diet --- protective
•GTFs—of S mutans, S sobrinus—very similar sequence—
protection over many species.

20. Glucan binding proteins
Surface of SM – receptors for Glucan
mediated aggregation
– induce protective immune response
young children saliva-- GBPs B –IgA –
indicates initial inft of S mutan.
disadv : Specific species protection—
unlikely GTFs

21. Routes of administration
Oral route
Submucous route
Active gingivo-salivary route
Nasal route
Tonsillar route
Active immunization
Passive immunization

22. Oral route
Stimulation of MALT /GALT
McGhee- whole cells of S mutans-SIgA-rats-reduced caries
incidence.
GTFs— [Smith DJ & Taubman ]
S sobrinus-GTF—repopulation interference seen.
Human volunteers- capsules-formalin killed S mutans—salv &
lacr IgA—with in week.
Disadv:- rapid breakdown of proteins/peptides, short
duration effects.

23. Subcutaneous route
Whole cell or cell wall or surface antigens-
s.c/ i.d –IgG/IgM & late IgA rise.
Serum Abs-GSF oral cavity.

24. Active gingivo-salivary route
Gingival sulcus route
Low molecular wt surface Ag of S mutans—as
topical appl—Sr IgG + salv IgA level rise–
adherence interference.
Modalities tried:-
•Direct injt of lysosomes in to rabbit gingiva—local
Ab production.
•Brushing live S mutans onto gingiva—Rhesus
monkeys— antibodies production failed

25. Intranasal Immunization
•Sites -closer anatomical relationship -oral cavity
• Intranasal installation of Ag, targeting NALT
•Protective immunity –seen rat model
•Advantages:
•-lower doses of Ag needed (low denaturation)
•-easy administration
•-induces both systemic and local

26. Tonsillar Immunization
Tonsillar tissue -- immune induction of secretory IgA
response
IgA response-characteristics are dominant in this
tissue :Palatine tonsils (nasopharyngeal tonsils)
Topical application of killed S. sobrinus cells - rabbits -- a
salivary immune response that can significantly decrease
infection
Repeated Tonsillar application can induce the-- IgA antibody-
producing cells in major and minor salivary glands [ rabbit].

27. Active immunization
Antigens tried:-
* whole cells of killed S mutans
•Cell free cultures
•GTFs
•Other purified antigens
Smith et al 2003: protein Ags-recombinant
DNA tech
n.
Basis: Mucosal route of immunization

28. Strategies for enhancing mucosal
immune responses:-
Co-Administration:-mucosa adjuvant + heat labile
enterotoxins, cholera toxins etc
Coupling to cell binding proteins:- B subunits of heat
labile enterotoxins.
Coupling to caries micro particles & membrane bound
vesicles –promote uptake of Ags

29. Expression of Ags in attenuated /
commensal bacteria
*live bacterial vectors:- attenuated
Salmonella
*live viral vector:- Vaccinia, Adenovirus, Polio
virus.
Expression of antigens in engineered virus
—undergo limited replication in mucosa
( MW Russell)

30. Human trials
Smith & Taubman:- sevr small scale human trails—oral – in
Salv IgA.

•GTF + AgI/II – enteric capsules]
*Liposome – phospholipid membr vesicles—homes to MALT
*Poly lactide co gylcolide [PLGA]—
•microcapsules & macro particles
•controlled release rate & evades Abs clearance mechns and
•degrade slowly without eliciting an inflammatory response to
polymer
•Mucosal application with use of PLGA –enhances mucosal response

33. Starch micro particles --- incr
mucosal responses.
Biggest problem:
•Cross reactivity to heart tissue
•Hypersensitivity reaction.

34. Passive immunity[ Ma etal1999]
•Monoclonal antibodies –mouse origin—in Rhesus monkeys[
Lehner etal 1985] & human expts– resurgence of S
mutans upto 2 years [Ma etal ]
•Bovine milk & Whey
•Egg yolk antibodies
Hamada [1990]— Abs against GTFs---IgY Abs – caries
incidence in rat model.

35. Transgenic plants: to give antibodies.
Adv—
Genetic matr can be easily exchanged
Manipulate the Ab structure –avoid
cross reactivity.
Large scale production possible

36. Other methods
Genetically modified bacteria- “lactobacillus zeae”
•Produces Abs to attach surface receptors of S
mutans-- “Kiss of death”

37. Mutans effectors strains
Hillman of Florida—BCS3-L1 –effector strain of
S mutans—lacks LDH enzyme.
Designed to produce “Mutacin-1140”- kills
cariogenic S mutans without harming other
commensals

38. •Strain of S mutans – UREASE enzyme
•Converts urea---NH
3
—conductive to enamel
remineralisation.

39. Conclusions
• Both passive and active immunization --
demonstrated success in animal models and human
clinical trials..
• The efficacy of active immunization with subunit
vaccines from S.mutans -- proved - prevent dental
caries in animal models..
However, , there are few studies on efficacy in
humans.
The primary target -- young children, who are at
high risk at this disease..

40. Risk - free and more effective approach to prevent
human dental caries should be
Recent advances in research on mucosal vaccines will
lead to a safe and effective
Local passive immunization with monoclonal Ab specific
for S.mutans antigens has . received recently much
attention.

41. Key Question?
Is there a demand for a dental
caries vaccine?