Review article Int J Pharm Biomed Sci 2013, 4(4), 131-136

ISSN No: 0976-5263

Research Drops
PharmaInterScience Publishers

Immunology of dental caries and caries vaccine - Part I

Avninder Kaur1*, Nidhi Gupta2, Dental caries is a multifactorial infectious disease which has reached
Sunila Sharma1 epidemic proportions in recent times. In India, surveys done on school children
revealed caries prevalence of approximately 58%. A wide group of
1
Department of Paediatric & Preventive microorganisms are identified in the initiation & development of dental caries, of
Dentistry, Bhojia Dental College & which Streptococcus mutans, Lactobacillus acidophilus, and Actinomyces
Hospital, Baddi, Himachal Pradesh, India
viscosus are the main pathogenic species involved. Though various preventive
2
Department of Paediatric & Preventive measures like flourides, pit & fissure sealants etc. are being adopted for the
Dentistry, DY Patil Dental College &
control, eventually the ultimate objective of public health is the elimination of the
Hospital, Navi Mumbai, Maharashtra,
India disease. Recently, dental caries vaccine has been the prime area of research due
to its promising nature in prevention & control of caries. The article thus presents
a comprehensive literature review of caries vaccine encompassing all the possible
aspects of this immune-biological substance.
*Correspondence:
Dr. Avninder Kaur Key words: Dental caries vaccine, Immune mechanism, Prevention, Antibodies
Tel: +91 9814319434
E-mail: avninder21@yahoo.com

Received: 24 Oct 2013 / Revised: 15 Dec 2013 / Accepted: 20 Dec 2013 / Online publication: 23 Dec 2013

1. INTRODUCTION infants increases with age or as the number of emerged teeth

increases [4,5]. Perhaps newly emerged teeth represent a
Dental caries is the most common infectious "virgin" habitat which enables S. mutans to colonize the oral
multifactorial disease, resulting from the interaction between cavity, avoiding competition with other indigenous bacteria
the host, diet, and the microflora on the tooth surface over a already established or better suited for adhering to enamel
given period of time, resulting in localized dissolution and surfaces. Another window of infectivity for S.mutans will be
destruction of the calcified tissue. This process can be present when the permanent teeth begin emerging between
interfered with by the presence of an effective immune six to 12 years of age. It may also be possible that children,
response [1]. who have already acquired S. mutans, acquire additional
A wide group of microorganisms have been identified strains of S.mutans during this "second window" [6,7].
from the carious lesions [2]. Various preventive measures The latest approach for combating dental caries is through
have been implicated for the prevention of dental caries. Use the development of an effective vaccine that is well suited for
of fluoride in its many forms, sugarless products and sealants, public health applications especially in environments that do
and increased access to dental care are among the approaches not lend themselves to regular health care [8].
which are effective in reducing dental caries.
However, recently the spectrum of prevention for dental 2. NATURAL IMMUNITY TO DENTAL CARIES
caries has been shifted to immunological approach i.e.
vaccination. Vaccine is an immuno-biological substance Antibodies of many organisms, including S. mutans, are
designed to produce specific protection against a given naturally present in the oral cavity of humans.
disease. It stimulates the production of a protective antibody
and other immune mechanisms. Vaccines are prepared from 2.1. Maternal protection
live modified organisms, inactivated or killed organisms,
extracted cellular fractions, toxoids or a combination [3]. Following birth, the breast-fed infant receives maternal
Vaccines are well suited for public health application, Igs, mostly in the form of salivary IgA (S-IgA), which is
especially in environments that do not lend themselves to abundant in colostrum (12mg/mL) but declines in mature
regular health care. Both longitudinal and cross-sectional milk. Also protection against oral pathogens is provided by
studies show that the prevalence of S.mutans acquisition by non immune factors (epithelial barrier), the innate salivary

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Avninder Kaur et al, Int J Pharm Biomed Sci 2013, 4(4), 131-136 132

defense factors such as lactoferrin, lysozyme, peroxidases,

and antimicrobial peptides. However, S-IgA is not absorbed
into the circulation, and therefore confers passive protection
confined largely to the oro-gastrointestinal and perhaps upper
respiratory tracts [9]. Maternally derived Igs not only provide
passive protection with antibodies transferred to the infant,
but may also influence the development of the infant’s own
immune responses [10].
The two main mechanisms can be postulated for this:
• Colostral (mainly S-IgA) antibodies influence the
microbiota that colonizes the infant, and thereby determine
which antigens are available to stimulate the infant’s
immune system;
• Placentally transferred (IgG) antibodies may regulate the
immune response to absorbed antigens by complexing with
them and processing within antigen-presenting cells [11].
Fig.1. Association of oral colonization with S-IgA immune responses

2.2. Natural caries immunity in children, adolescents,

and adults
3. IMMUNE MECHANISMS IN THE PREVENTION OF
CARIES
In the young infant before eruption of teeth (0-5 months),
the streptococci have no teeth to adhere to, so that oral
The experiments in rats and monkeys suggest two
colonization does not occur (Fig.1). However, S-IgA anti-
principal immune mechanisms of protection against caries.
streptococcal antibodies may be elicited either
One involves saliva and acts on the salivary domain and the
(a) By direct entry of antigen into the minor salivary glands
other involves GCF which affects the gingival domain. Saliva
scattered under the oral mucosa, or
contains approximately 1-3% of immunoglobulin
(b) Indirectly by swallowing an adequate concentration of
concentration, a majority of which is secretory IgA.
streptococci and stimulating the gut associated lymphoid
However, saliva also contains the humoral immunoglobulin
tissue to mount an immune response.
IgG and IgM from the gingival sulcular fluid.
Although secretory IgA antibody in saliva and other
secretions is essentially absent at birth, mature s-IgA, i.e.,
3.1. Salivary domain
dimeric IgA with a bound secretory component, is the
principal salivary immunoglobulin secreted in individuals by • The salivary glands produce secretory IgA antibodies by
one month of age. Immunological interception of the initial direct immunization of the gut associated lymphoid tissue
attempts of S. mutans to colonize the tooth surface would (GALT), from where sensitized B-cells may be home to the
seem to be the preferred vaccine strategy since these salivary glands.
organisms are exceedingly difficult to displace once they • S-IgA is produced in salivary glands by mucosal plasma
become part of the dental biofilm [12]. cells which secrete polymeric IgA, and is then taken up and
transported by a receptor, secretory component, expressed
2.3. Apparent failure of natural immunity in protection
on the basolateral surface of glandular epithelial cells and
against dental caries
released into the saliva as S-IgA [13].
• The salivary immunoglobulin may act as a specific
S. mutans is a poor immunogen, as it preferentially
agglutinin interacting with the bacterial surface receptors
colonizes enamel surfaces. Sensitization to the organism
and inhibiting colonization and subsequent caries
might depend on entry of a sufficient dose of antigenic
formation. They may prevent S. mutans from adhering to
material through the junctional epithelium of gingival to
the enamel surface. S-IgA is synthesized and secreted by
immunologically component cells and the efficiency of this
plasma cells located in the salivary glands, adjacent to the
route of immunization or particulate antigen is limited.
ducts and acini (primarily the parotid and minor salivary
Immunization with S. mutans should induce an immune
glands).
response which might prevent the organism from colonizing
the tooth surface and thereby prevent decay. Indeed, natural
3.2. Gingival domain
immunization induces a low antibody titre which is relatively
higher in IgM, IgG antibodies and these may not be directed • The gingival crevicular mechanism involves all the humoral
against an essential antigen of S. mutans. and cellular components of the systemic immune system,
which may exert its function at the tooth surface.

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Avninder Kaur et al, Int J Pharm Biomed Sci 2013, 4(4), 131-136 133

Table 1
Possible mechanisms of antibody mediated intervention against S. mutans
Isotype Steps in caries pathogenesis Mode of action Antibody specificity
S-IgA Adherence to salivary pellicle Blocking of adhesion receptor interaction AgI/II
Reduction of hydrophobicity Surface antigens
Agglutination and clearance Surface antigens
Binding to early colonizers Blocking of adhesion receptor interaction AgI/II
Sucrose dependent accumulation Inhibition of glucan production: GTF:
Inhibition of substrate binding Catalytic region
Inhibition of polymer synthesis Glucan binding region
Blocking of adhesion GTF (glucan binding region)
GBP
Acid production and other metabolic activities Blocking of glucose uptake Not known
Synergism with:
Peroxidase (inhibition of acid production) Not known
Lactoferrin (inhibition of iron acquisition) Iron uptake molecules?
IgG Colonization of cervical tooth sites Opsonisation and phagocytosis AgI/II; other surface antigens?
Invasion dentinal tubules Inhibition of collagen binding AgI/II

• After subcutaneous immunization with S. mutans, the several, sequentially separate, residues in the N-terminal third
organism is phagocytosed and undergoes antigenic of the molecule [16, 17].
processing by macrophages. Polymorphonuclear leucocytes The C-terminal region of the GTF molecule contains a
have specific receptors for the Fc part of IgG to enable the pattern of repeating sequences which have been identified in
antibody bound S. mutans to adhere to the all GTFs from mutans streptococci. This region has glucan-
polymorphonuclear membrane. The complex is then binding function [18].
internalized in vacuoles called phagosomes which may S. mutans that have lost the ability to make glucan
combine with the lysosomes of the leucocyte to form through natural or induced mutations in GTF genes do not
phagolysosomes. The organism will then be killed by the produce significant disease in animal models. Thus it is not
action of lysosomal enzymes. surprising that immunization studies using intact GTF
vaccines successfully protected animals infected with S.
4. EFFECTIVE MOLECULAR TARGETS FOR mutans.
DENTAL CARIES VACCINES
(C) Glucan-binding proteins
Several stages in the molecular pathogenesis of dental
caries are susceptible to immune intervention. Antibody The ability of S. mutans to bind to glucans is mediated, by
could block the receptors necessary for colonization (e.g., cell-wall-associated glucan-binding proteins (Gbp). Many
adhesins) or accumulation (e.g., glucan binding domains of proteins with glucan binding properties have been indentified
GBPs and GTF), or inactivate GTF enzymes responsible for in S. mutans and S. sobrinus. Each glucan-binding protein has
glucan formation. the ability to bind α 1-6 glucan. S. mutans secretes at least
three distinct proteins with glucan-binding activity: GbpA,
(A) Adhesins GbpB and GbpC [19].
Mechanism of antibody mediated protection involving the
Adhesins from the two principal human pathogens are: above targets is explained in Table 1.
• S.mutans (antigen I/II, PAc, or P1) and
• S.sobrinus (SpaA or PAg). 5. DEVELOPMENT OF TYPES OF VACCINES
Antigen I/II (AgI/II) was found both in the culture
supernatant as well as on the S. mutans cell surface [14]. These include internal image antiidiotype vaccines,
Antibody directed to the intact antigen I/II molecule or to its recombinant regulatory molecules, synthetic peptide
salivary-binding domain blocked adherence of S. mutans to vaccines, subunit vaccines, recombinant vaccines, and
saliva-coated hydroxyapatite [15]. recombinant infection vectors.

(B) Glucosyltransferases (GTFs) 5.1. Antiidiotype vaccines

S. mutans and S. sobrinus each synthesize several The antibody combining site i.e. epitope consists of
glucosyltransferases. The activity of GTF is mediated highly diverse amino acid sequences on six hyper variable
through both catalytic and glucan binding functions. The regions. The unique antibody-combining site itself is an
catalytic activity of GTF appears to be associated with
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Avninder Kaur et al, Int J Pharm Biomed Sci 2013, 4(4), 131-136 134

antigen, or idiotype, and an immunogen potentially capable exist on the parent molecule. The in vivo effectiveness of the
of inducing antiidiotypic antibodies [20]. synthetic vaccine approach has been realized for several
The immune system cannot distinguish between an infectious diseases such as influenza, cholera, and group A
idiotype and an antiidiotype vaccine. Antiidiotypes behave streptococcal infections. Most importantly, peptides have
like the original epitope because they can share the identical actually been used as oral vaccines to elicit secretory
amino acid sequence with the immunogenic epitope. This is antibody and to confer immunity to humans. However, B cell
particularly significant for poor immunogens such as antigenicity and Immunogenicity are the two characteristics
carbohydrates. Thus, they can be used as substitute antigens of critical importance in investigations of synthetic peptide
for inducing specific immunity to replace antigens that are vaccines: Synthetic peptide technology and various passive
unsafe or toxic or for inducing anticarbohydrate immunity. immunization strategies are mechanisms to avert any
For example, infants do not respond immunologically to potential heart reactive antibody formation when using intact
certain polysaccharide antigens. Idiotype vaccines that are antigen I/II.
proteins could be used to induce a protective immune
response. Such vaccines could be of significance in affecting (B) Recombinant bacterial vector
the developing flora of the oral cavity, where many important
molecules in adherence and colonization are carbohydrates This vector involved expression of S. mutans antigens on
[21]. a virulent Salmonella typhimurium that attached to, and
invaded, Peyer’s patches. Experiments did not result in
5.2. Subunit vaccines sufficient protective antibody to affect dental caries, probably
because of the relatively sparse production of S. mutans
Subunit vaccines, which contain structural elements of the protein by these strains. Several of these approaches have
Ag I/II adhesin family, GTFs or GbpB, have been designed successfully induced protective immune responses for
for a variety of reasons. Studies have attempted to optimize experimental dental caries in rats or mice by means of
immune responses to functional epitopes associated with chimeric proteins or vectors expressing either adhesin or GTF
salivary binding, catalytic processes, or glucan-binding epitopes [24].
activities by designing subunit vaccines whose constructs
contain single or multiple copies of epitopes from these 5.3. Conjugate vaccines
domains. The multivalent subunit vaccines could be
constructed of multiple epitopes which target different Another vaccine approach which may intercept more than
functions on the same component (e.g., GTF catalytic and one aspect of mutans streptococcal molecular pathogenesis is
glucanbinding activities) or functions on different the chemical conjugation of functionally associated
components (e.g., AgI/II salivary binding and GTF catalytic protein/peptide components with bacterial polysaccharides.
activity). Conjugation of functionally associated peptides to Advantage is that the conjugation of protein with
carbohydrate components, for example glucan, or to other polysaccharide enhances the immunogenicity of the T-cell-
vaccine proteins (e.g., tetanus toxoid) also would increase the independent polysaccharide entity [25].
immunogenicity of the peptide and broaden the reach of the
vaccine [22]. 5.4. DNA vaccine
Designing vaccines in this way also permits one to
eliminate regions which may induce unwanted antibody A DNA vaccine is a bacterial plasmid that is designed to
specificities. The Ag I/II family of proteins shares extensive express a gene for the antigen of interest in the cells of a host.
sequenc [23]. These homologous sequences may induce In DNA immunization, memory cells could be generated
cross-reactive responses that could influence colonization, during the initial period after inoculation, when expression
attachment, or accumulation of commensal microbiota. levels of target protein are presumably the highest. Unlike
undifferentiated myocytes, mucosal tissues have a more rapid
(A) Synthetic peptides cell turnover. Gene expression from plasmid DNA was
transient in the mucosal tissues [26]. DNA vaccines have
The basic concept emanates from the demonstration that advantages, such as:
chemically synthesized peptides can elicit antibodies that (a) long-term and stable expression of endogenously
react with the original protein. Several factors can be produced antigenic protein, which is similar in conformation
managed in synthetic vaccine design, which increase its to natural protein;
desirability as a vaccine over the parent protein. For example, (b) stronger antigenicity, with the capacity to induce both
one can theoretically include epitopes that trigger protective cellular and humoral immune responses; and
aspects of the immune response (e.g., antibody formation: (c) the possibility for creation of a polyvalent vaccine against
helper T-cell activity) and omit epitopes that trigger several kinds of pathogens.
suppressive responses. Synthetic vaccines can also be
designed to avoid host tissue cross-active epitopes that may
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Avninder Kaur et al, Int J Pharm Biomed Sci 2013, 4(4), 131-136 135

6. ADJUVANTS AND DELIVERY SYSTEMS FOR administration to the oral mucosa of bioadhesive degradable
DENTAL CARIES VACCINES starch microparticles containing dinitrophenyl-bovine serum
albumin, in combination with L-a-lysophosphatidylcholine
Mucosal routes of antigen delivery often require (as a penetration enhancer) and interleukins IL-5 and IL- 6,
additional components which can potentiate aspects of the potentiated long-lived salivary IgA responses, compared with
immune response to induce sufficient antibody to achieve a antigen delivered in soluble form [28].
protective effect.
(C) Liposomes
(A) Cholera and E.Coli-heat-labile enterotoxins
Liposomes, which are phospholipid membrane vesicles
Cholera toxin (CT) is a powerful mucosal immune manufactured to contain and deliver drugs and antigens, have
adjuvant which is frequently used to enhance the induction of been used to enhance mucosal responses to Mutans
mucosal immunity to a variety of bacterial and viral streptococcal carbohydrate and GTF. Liposomes facilitate M
pathogens in animal systems. CT is an ADP-ribosylating cell uptake and delivery of antigen to lymphoid elements of
bacterial toxin with A and B subunits. The adjuvant effects of inductive tissue. Gastric intubation of rats with GTF-
CT are broad-based and can include increased mucosal liposome vaccines induced responses which diminished
epithelial cell and macrophage production of pro- dental caries caused by subsequent infection with S. mutans.
inflammatory cytokines, up-regulation of B7-2 co- Clinical studies comparing intranasal immunization with
stimulatory factors on APCs, and increased antigen transfer GTF-liposomes vs. GTF alone showed that both vaccines
from the mucosal to the systemic compartment. Mucosal increased local (nasal) and salivary IgA antibody responses to
application of soluble protein or peptide antigen alone rarely GTF up to fivefold [29].
results in elevated or sustained IgA responses. However,
addition of small amounts of CT or the closely related E. coli (D) Other approaches
heat-labile enterotoxins (LT) can greatly enhance mucosal
immune responses to intragastrically or intranasally applied Other methods to enhance mucosal responses are being
Mutans streptococcal antigens or to peptides derived from adapted for dental caries vaccine use. Monophosphoryl lipid
these antigens [27]. A, when administered intranasally to mice as an aqueous
One approach to reduce or eliminating toxicity while formulation with soluble GTF or incorporated into liposomes
maintaining adjuvanticity was to remove the A subunit from containing GTF, induced primary and secondary salivary IgA
the CT complex. Other approaches have been sought to responses which exceeded those achieved with GTF-
modify CT or LT, since the increase in CTB-assisted immune liposomes. Oligodeoxynucleotides containing unmethylated
response was significantly less than that achieved with the CpG dinucleotides (CpG ODN) induce proliferation of B-
CT holotoxin, and since, in some systems, the presence of a cells and activation of macrophages. Intranasal or oral
small amount of intact CT was required for response administration of CpG ODN with tetanus toxoid (TT)
enhancement. enhanced murine IgA responses in many mucosal secretions,
Alternatively, detoxification of CT and LT has been including saliva. Similarly, intragastric administration of
attempted with the use of site-directed mutagenesis CpG ODN with TT- Al(OH)3 enhanced systemic IgG
techniques to modify amino acid residue areas of the toxic responses to TT, compared with those achieved with TT -
A1 subunit which are critical to its enzymatic activity or to Al(OH)3 [30].
the required proteolytic cleavage required for activation.
7. CHARACTERISTICS OF IDEAL DENTAL CARIES
(B) Microcapsules and microparticles VACCINE

Microspheres and microcapsules made of poly-lactide-co- Mutans streptococcal GTFs, adhesins, and GbpB each
glycolide (PLGA) have been used as local delivery systems induce caries protective immunity in experimental systems,
because of their ability to control the rate of release, evade thus are likely candidates for initial pediatric clinical trials.
pre existent antibody clearance mechanisms and degrade Mucosal application would be expected to be safe since
slowly without eliciting an inflammatory response to the children are already naturally exposed to these components
polymer. Denaturation can be significantly diminished by during the first years of life. Several routes of administration
methods which incorporate antigen into microparticles in an can induce protective immune responses, at least in model
aqueous phase. Intranasal immunization of aqueously systems. Traditional vaccine therapy ideally induces
incorporated GTF-PLGA microparticles, which also protective immunity prior to infection with the target
contained 1% gelatin as bioadhesive, induced long-lasting pathogen. The “window” of Mutans streptococcal infection
salivary immune responses. Starch microparticles can also be opens in the middle of the second year of life under normal
used to increase mucosal responses to soluble antigens. infectious challenge. To meet this challenge, year-old
Montgomery and Rafferty (1998) have shown that topical children would receive a caries vaccine in order to intercept
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Avninder Kaur et al, Int J Pharm Biomed Sci 2013, 4(4), 131-136 136

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