Past, present & future perspectives

1. rrrr
Caries Vaccine
Dr Sucheta Prabhu
12/4/18

2. Questions asked previously
• Caries vaccine (7marks)
• Comment on caries vaccine “myth or
reality”(20 marks)
• Current status of caries vaccine (100
marks)

3. Definitions
Antigen
• Any substance
which
stimulates
production of
antibody with
which it reacts
specifically and
in an observable
manner.
Antibody
• Substance
which appears
in serum/tissue
fluids which
react with the
antigen
specifically and
in an observable
manner.
Immunity
• It is defined as
resistance
offered by the
host to the
harmful
pathogenic
microbial
infection.

4. Types of Immunity

5. Primary Immune Response
Antigen Administered
Latent period of
induction 3-10 days
Antibodies appear in
blood
First antibody elicited
IgM type
Antibody titer gradually
raises in next 2-3 days
Reaches its peak &
declines quickly
IgG appears in few
days if antigenic
stimulus is adequate
IgG reaches its peak in
7-8 days & declines
over weeks/months
Outcome:B&T
lymphocytesnproduce
memory cells

6. Secondary/Booster response
Involves production of IgM & IgG
antibodies too
IgM production brief & longer,IgG
antibody shows prolonged
production.
Accelerated response attributed
to immunological memory

8. Vaccine
Immunobiological
substance designed to
produce specific
protection against a
given disease.
They may be prepared
from live modified
organisms, inactivated or
killed organisms, cellular
fractions, toxoids or
combinations of these.

10. History
1960
Vaccine target
Streptococcus
Mutans
1930
Vaccine
attempted
against
lacobacillus
Louis Pasteur
Edward
Jenner

11. Might caries control involve
immunisation and gene
therapy?

12. Evolution in management of
caries
• Drill & Fill
• Extension for
prevention
Conventional
• Minimal tooth
preparation
• ART
Conservative
• Sealants
• Modalities
interfering with
substrate,microbes
etc
Preventive

13. Requirements of a caries vaccine
Identify component
of immune system
that should be
stimulated/induced
Should not
harm host
Identify
target

14. Immunology of caries in
humans
Non
specific
• Lysozyme
Lactoperoxidase
Lactoferrin
Specific
• Particular
microbe within
immunologic
memory
Oral Cavity Defense

15. Antibodies in the mouth
Secretory salivary
antibodies
IgA
Serum antibodies
IgG,IgM,IgA

16. Why a vaccine against caries?
Streptococcus
mutans is a poor
immunogen.
Entry of S.mutans
through junctional
epithelium of gingiva
not sufficient to elicit
an immune response.
T-cell response to
S.mutans is of low
order and needs
boosting for
sensitization.

17. Streptococcus Mutans
WHAT?
Gram +ve
Facultative
Anaerobe
8 serotypes
Type h most
prevalent
S. mutans
S.Sobrinus
S.Ratti
S.Criceti
S.Downei
S.Ferus
S.macacae

18. Acquisition of S.mutans
DNA probe technology have
suggested that low levels of
mutans streptococci may be
found in the oral cavity
during the first year of life.
 Thus, data suggests that
‘window of vaccine
opportunity’ could exist
between 12 and 18 months
for most populations.

19. Molecular pathogenesis of
dental caries
Acquired pellicle forms on
tooth surface
Interaction of bacterial
proteins(adhesins) with
pellicle
Further accumulation of
acidogenic streptococci
GTF provide scaffolding for aggregation of mutans and other oral streptococci
through interaction with bacterial call- associated glucan binding proteins.
Antigen II/III
or Pac
Glucosyltranf
erases GTF-
B/C

20.  Function of Glucans: provide
scaffolding for the aggregation of mutans
and other oral streptoccocci through
interaction with bacterial cell- associated
glucan binding proteins.
 Also, Glucans modify the porosity of
the dental biofilm, thus increasing the
availability of nutrients for continued
bacterial metabolism.

22. Glucosyltransferase
Three forms of GTF:
 Water insoluble
glucan synthesizing
enzyme: GTF-I
 Water insoluble and
water- soluble glucan
synthesizing enzymes:
GTF-SI
 Water- soluble
glucan synthesizing
enzymes: GTF-S

23. Glucan binding proteins
 3 distinct proteins with glucan binding activity: GBP-A, GBP-B and
GBP-C.
 Only GBP-B has been shown to induce a protective immune
response to experimental dental caries.

24. Molecular Targets
Glucosyltransferase
(GTF) : 1967
Guggerheins &
Shroeder
Glucan binding
proteins:1996 Mal
et al
Surface antigens I/II
or cell wall
antigens:1991Brady
et al
Lipoteichoic acid

25. Mechanism of action of caries
vaccine
sIg
Bacterial
surface
receptors
Inactivate
GTF
Reduce
glucans,
plaque

26. Mechanism of action of caries
vaccine
SECRETORY IgA from salivary glands due
to direct immunization of gut associated
lymphoid tissue (GALT)
May prevent MS from adhering to the
enamel surface.
May also prevent formation of dextran by
inhibiting the activity of
glucosyltransferase (GTF)

27. Mechanism of action of caries
vaccine
..
Gingival crevicular mechanism :
All humoral and cellular components of
systemic immune system, that exert its
function at tooth surface.

28. Types of vaccine
Subunit
vaccine
Recombinant
vaccine
(Attenuated
expression
vectors)
Conjugate
vaccine

29. Routes of immunisation
Oral/mucosal
Systemic(subcutaneous)
Active Gingivo salivary
Passive dental immunisation

30. Action of local immunity
Antigen administration in vicinity of
salivary glands
Introduction of salivary IgA to S.mutans
Adverse effects:Localised inflammation,
systemic serum antibody reaction

31. Common mucosal immune
barriers
Preferred for induction of secretory IgA antibodies in salivary compartment.
Several mucosal routes used to induce protective immune responses to
dental caries vaccine antigens:
Oral
Intra Nasal
Tonsillar
Minor salivary gland
Rectal

32. Oral
GALT: Antigen target(Smith & Taubman
1987)
Oral route failed to reduce caries
significantly, as compared with
subcutaneous immunization
The rise in secretory antibodies
produced was small and of short
duration.
Immunological memory in secretory IgA
responses is rather limited.
Effect of stomach acidity on antigen,
Inductive sites were relatively distant.

33. Intranasal route
 NALT is Antigen target
(Brandtzaeg & Haneberg,1997).
Vaccine causes increased production of
immunoglobulin IgA which fights
tooth decay by interrupting the colonization of the
bacterium S.mutans.
Advantage:
lower doses of antigen needed
easy administration
induces both systemic & mucosal immunity

34. Tonsillar route
Has both IgA and IgG response:
IgG is more dominant.(Van
Kempen ,Boyoka et al 2000)
Palatine tonsils and
nasopharyngeal tonsils contribute
precursor cells to mucosal effector
sites: such as salivary gland.
Positive results in rabbits.

35. Minor salivary gland route
Populate the lips, cheeks, and soft palate.
Their short, broad secretory ducts facilitate retrograde
access of bacteria and their products: potential routes for
mucosal induction of salivary immune responses.
(Crawford,Nair,Schroeder,1983)
Smith & Taubman lips 1990
Used in children with respiratory ailments where
intranasal application is
not possible.

36. Rectal
Colorectal region as an inductive
location for mucosal immune
responses in humans: it has the
highest concentration of lymphoid
follicles in the lower intestinal tract.
Preliminary studies have
indicated that this route could also
be used to induce salivary IgA
responses to mutans streptococcal
antigens such as GTF.(Lam et al)

37. Systemic Route of immunization
 Antibodies reach oral cavity via
gingival crevicular fluid.
 Whole cells, cell walls and the
185 KD streptococcal antigen have
been administered.
 IgG develop within months of
immunization , reaching a titre of
upto
1:1280.
IgG,IgM ,
IgA

38. Active Gingivo salivary route
 To limit potential side effects of other routes and to
localize the immune response.
 Associated with increased IgG and IgA.
 Positive response via direct injection of lysozyme
into rabbits gingiva ,
 Using smaller molecular weight streptococci antigen
for better penetration.

39. Passive Immunisation
Suface antigen I/II
(Ma et al 1990) Polyclonal IgG
antibodies
(Loimaranta et al
1997)
Hamada hen yolk
against GTF
Ma et al 1995
Tobacco plant
Ag I/II

40. Adjuvants & Delivery Systems
Heat labile
enterotoxins
(Cholera & E.coli)
Katz 1993
Microcapsules &
microparticles
Liposomes
Fusing with
salmonella
Synthetic peptides

41. Risk of using caries vaccine
 All vaccines have risks.
.
 Due to potential of S.mutans whole cells to induce
heart – reactive Antibody, the development of subunit
vaccine (AgI/II) for caries has been focused of intense
research interest.

42. Caries vaccine response
requirements
interfere
with early
colonization
not
necessarily
bactericidal
non-
inflamatory
response
persistent
response
site
directed
response
(oral cavity)

43. Final report of panel 2003
Safe in children at early age?
(Underdeveloped immune
system)
Lack of longitudinal studies
Passive immunity may be
considered
Reactions to other vaccines
given at this age

44. Current status of vaccine
Dr Martin
Taubman &
Dr.Daniel Smith
Forsyth institute
GTF & Glucan
binding protein
Intranasal
administration
And Polyactide
biopolymer
microparticle
delivery
Dr.Noel
Childers
University of
Alabama
Biosafe
liposomes
100nm(oral,to
nsillar,nasal
safe) Nasal
best and dose
specific
response
produced.

45. Current status
Dr.Michael
Russel
SUNY,Buffalo
Antibodies
against saliva
binding region of
Antigen I/II
(Anti adherence)

46. New fusion anti caries DNA
 Wuhan Institute of Virology, China:
developed a new DNA vaccine : pGJAP/
VAX
 pGJA-P/VAX: Encoding two antigenic
domains , Pac and GLU of S mutans
 Induced accelerated and increased
specific antibody response in serum and
saliva compared with non fusion DNA
vaccine in rabbits.
 Limitation:
 Weak protective effect against S sobrinus.

47. Why is it not in practice?
§ Etiologic agent part of indigenous flora
§ Vaccination should be done on periodic
basis
§ Development of tolerance or immune
exclusion
§ Caries occurs on non living surface

48. References
• Moro I, Lehner T. Symposium report: Sixth International congress of
mucosal immunology; Dental caries vaccine. J Dent Res July 23rd
1990. p. 1863-4.
• Russell RR. The application of molecular genetics to the
microbiology of dental caries.Caries Res 1994;28:69-82.
• Smith DJ. Dental caries vaccines: Prospects and concerns. Crit Rev
Oral Biol Med 2002;13:335-49.
• Lehner T. Immunology of dental caries. Immunology of oral
diseases. 3rd ed. Blackwell scientific publications; 1992.
• Wilton JM. Future control of dental disease by immunization:
Vaccines and oral health. Int Dent J 1984;34:177-83.
• Lehner T, Challacombe SJ, Caldwell J. Immuologic basis for
vaccination against dental caries in Rhesus monkeys. J Dent Res
1976;55:C166-80.

49. • Russell MW, Hajishengallis G, Childers NK, Michalek SM.Secretory
Immunity in defense against cariogenic Mutans streptococci. Caries Res
1999;33:4-15.
• Curtis R 3rd. 1984 Kreshover lecture: Genetic analysis of S. mutans
virulence and prospects for an anticaries vaccine. J Dent Res
1986;65:1034-45.
• Marwah N 3rd. 2015.Textbook of Pediatric Dentistry.Jaypee Publications