Dental caries, the disease that causes tooth decay, is infectious, and the mutans streptococci bacteria have long been identified as the primary disease-causing agents. Caries vaccines showed promising results in experimental studies; however, it remains far the effective use in humans due to political-economic and ethical issues. Progress towards practical vaccine development requires evaluation of candidate vaccines in clinical trials. Promising strategies of passive immunization also require further clinical evaluation. The purpose of this chapter is to review the literature on the main research projects aimed at developing caries vaccines.
Dental caries is a multifactorial infectious disease, dependant on diet, oral microbiota and host response, and resulting on the demineralization located in the hard dental tissues [
Advances in molecular biology have facilitated the cloning and the functional characterization of virulence factors of mutans streptococci. The glucan polymer matrix produced by this microorganism, as well as the antigens (Ags) of virulence found on its surface, is considered mainly responsible for their biofilm-forming ability
and are thus important for their adhesion and accumulation in the biofilm [
In search of new preventive measures against caries, in addition to the consolidated ones, as the disorganization of the biofilm by brushing and using toothpaste with or without fluoride [
Thus, the purpose of this article was to conduct a brief review of the literature on the prospects for caries control by means of a vaccine, which would be able to inhibit or attenuate the virulence factors of S. mutans in biofilm.
The biofilm is a cluster of bacteria dispersed in a matrix of extracellular polymers (polysaccharides, proteins), DNA and other metabolites. One of the main virulence characteristics of S. mutans is its ability to produce glycosyltransferases (Gtfs), enzymes that synthesize intracellular polysaccharides (ICP) and extracellular polysaccharides (ECP) from the diet’s sucrose. The glucans, polysaccharides synthesized by the Gtfs of the streptococci, provide attachment of sites microorganisms within dental surfaces, starting a biofilm formation and aggregation of S. mutans to other oral streptococci [
Several measures are being used in the prevention and control of caries, as the disorganization of the biofilm through oral hygiene and use of fluorides [
Three main groups of Ags associated with the surface of S. mutans participate in the adherence and accumulation of this biofilm: the GTFS, the adhesin antigen I/II (Ag I/II) and the glucan binding proteins (GBP), considered the main targets for the development of a caries vaccine [
Dental caries involves the interaction between the bacterial attack and host defense and may be modulated by the interference of these factors [
Passive immunization consists of the topical application of antibodies (Abs) performed antigen-specific on the surface of teeth against the virulence factors of S. mutans. As for the active immunization, it involves the application of microbial antigens (Ags), inducing the mucosal immune system, by stimulating the production of specific SIgA; besides induction of the systemic immune system, stimulating the production of serum Abs [
Since it does not provoke a stimulation of the host immune system and therefore does not generate a response of immune memory, passive immunization is considered less effective than the active [
Active induction of the immune system is aimed at incorporating Ags purified from S. mutans in the mucosal immune systems [
Active immunization by direct topical application of Ag in the oral cavity stimulates the production of specific SIgA in saliva while the application of Ag via intramuscular or subcutaneous route only induces the production of serum Abs (IgM and IgG), which would only reach the tooth surface through the gingival crevicular fluid. The SIgA prevents adhesion of microorganisms to the surface of the tooth, preventing the beginning of bacterial colonization [
Some experiments were performed with Ag purified peptide, obtained from the regions amino and carboxyl- terminal domain with Gtfs of S. mutans, for active immunization of rats. An increase of specific IgG serum for Gtfs and a consequent significant reduction in caries infected with S. mutans and S. sobrinus [
The most used animal models for anticaries vaccine tests are rodents, mostly mice and rats [
Despite the relative success of research with rodents and primates [
The genetic sequences of certain oral microorganisms, such as the S. mutans UA159 [
Generally, for the development of a genetic anticaries vaccine, the catalytic region (CAT) and the glucans binding domain (GBD) of the glucosyltransferase B (GtfB) of Streptococcus mutans have been used as Ags. These regions have been selected because, in theory, they include epitopes associated with its enzymatic function. [
The DNA vaccine is safer and more stable due to its method of application and storage; easy preparation and administration, and ability to induce effective immune response while stimulating T and B lymphocytes. It also presents great potential for further modification and improvement [
DNA vaccines associated with mucosal adjuvants, like heat-labile enterotoxins of Vibrio cholerae and Escherichia coli aggregated to chitosan and bupivacaine have been successful in animal models. However, these vaccines are still not effective due to their poor capacity to induce and maintain the oral fluid antibodies [
Some important studies are summarized in
Other approaches such as the use of certain small peptides corresponding to binding regions of streptococcal adhesin, including receptors of carbohydrates, have been used as a means of preventing the adhesion of specific microorganisms [
Despite the promising laboratory advances, anticaries vaccines are still far from being a current reality, since most studies are done in small animals, making it difficult to extrapolate to humans. Despite the large number of
Author and Year | Type of study (in vitro or in vivo) | Type of vaccine (DNA or protein-antibody) | Type of animal (in vivo studies) and type of cell | Route of administration (in vivo studies) | Results | Conclusion |
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[ | In vivo | Vaccine DNA pGJA-P/VAX | Gnotobiotic mice and rats | Intranasal | Increased production of IgG and SIgA. Decreased growth of caries lesions in enamel, dentin light lesions and dentin moderate lesions of 21.1%, 33.0% and 40.9%, respectively. | The production process of pGJA-P/ VAX preparation was efficient. The vaccine showed a high degree of purity and desired efficiency, thereby facilitating future clinical trials of this anticaries DNA vaccine. |
[ | In vivo/in vitro | Vaccine DNA pGJA-P/VAX1 pGJA-P pGLUA-P | Gnotobiotic hamster/human dendritic cells | Intramuscular/ intranasal | Vaccines pGJA-P/vax1 and pGJA-P induced higher response of salivary and serum antibodies than pGLUA-P. Fewer caries lesions were observed in hamsters immunized with pGJA-P/vax1 and pGJA-P. | The antigen encoded by CTLA-4 associated to DNA vaccine pGJA-P/vax1 can bind specifically to human dendritic cells. Furthermore, this combination increased the immunogenicity and protective efficacy of the vaccine. |
[ | In vivo | Vaccine DNA pGJA-P/VAX | Mice | Intranasal | Antibody responses induced by pGJA-P/ VAX lasting more than 6 months. Furthermore, the pGJA-P/VAX could still be detected either at the site of inoculation, and in the cervical lymph nodes draining, 6 months after immunization. | The persistent immune responses are probably due to the deposit of DNA into the host, which acts as a booster immunization. Thus, there is a greater immunological memory. |
[ | In vivo | Vaccine DNA pGJA-P/VAX | Rats | Intranasal | SIgA response were induced, resulting in reduction of enamel and dentin lesions caused by S. mutans and reduced enamel lesions in individuals infected with S. sobrinus | pGJA-P/VAX induces immune response only to infection by S. mutans, but also provided cross-protection against S. sobrinus strain infection in rats. |
[ | In vivo | CAT or GLU (specific region of Gtf de S. mutans) | Rats | Infection with the regions of GTF. | Increased of specific serum IgG for Gtf; Significant reduction of caries. | Immunization with peptides derived from functional domains of S. mutans Gtf are protective for infection with S. sobrinus or S. mutans. |
[ | In vivo | Antibodies (milk immune) | Rats | Topic | The group of rats receiving milk with antibodies had significantly less caries development than the control group. | Immunization showed decrease in caries development in rats and may present similar results in humans. However, the duration is uncertain and because it is a passive immunization does not generate a lasting response. |
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[ | In vivo | Protein (purified Gtf) | Monkeys | Subcutaneous | Immunized monkeys showed elevated levels of serum antibodies against Gtf, but there was no difference in the development of dental caries among immunized animals and the control group. | The Gtf showed no ability to induce specific immune response against cariogenic pathogens. |
[ | In vivo | Protein (Antigens I, II e III) | Monkeys | Orally | There was no reduction of caries in monkeys immunized with antigen III. The reduction of caries in the immunized animals with antigens I or I/II was discrete. | The protection against caries was associated predominantly to IgG antibodies of gingival fluid, driven, possibly to antigen I. |
[ | In vivo | Vaccine of DNA pGJA-P/VAX | Rabbits and monkeys | Intranasal/ Intramuscular | The antigens vaccine fused to cytotoxic T lymphocytes induced increase in specific antibody responses in serum and in saliva compared to DNA vaccine without fusion, in rabbits. Significant levels of IgG in specific serum and salivary IgA were also detected in monkeys immunized with fusion vaccine. | The fusion of the CTLA4 antigen results in improved immunological efficacy and strongly suggests that it may represent a promising approach to prevent dental caries and other infectious diseases. |
[ | In vivo | Vaccine of DNA pCIA-P | Gnotobiotic rats | Intramuscular/ submucosa/ sub-cutaneous (salivary gland) | Lower levels of caries and high levels of serum sIgA and IgG after direct application in salivary gland were observed. | The DNA vaccine pCIA-P recombinant can induce anticaries protection and immune responses through the injection salivary gland are a promising strategy for inhibiting dental caries. |
[ | In vivo | Vaccine of DNA pGJA-P/VAX | Gnotobiotic rats | Intramuscular/ intranasal | Vaccine was successful in the reduction of levels of caries caused by S. mutans in gnotobiotic animals. However, its protecting effect against the infection by S. sobrinus proved to be weak. | After cloning the catalytic region (cat) of the Gtf-I fragment of S. sobrinus, a synthesis inhibition of the insoluble glucan in water by S. sobrinus, which can result in a new variation of pGJA-P/VAX to produce an anticaries DNA vaccine. |
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[ | In vitro | Vaccine DNA pGJA-P/VAX | ______________ | ____________ | In comparison with the system of Chitosan/ traditional DNA, the new design has yielded higher transfection efficiency and increased residence time of anionic lipsome/Chitosan/DNA, which will induce a higher level of sIgA on “in vivo” study. | While this new complex appears to have minimal toxicity, the results suggest that the developed nanoparticles have a “delivery” potential of DNA vaccines, which will make mucosal immunity more efficient. |
[ | In vitro/in vivo | Vaccine DNA pCI-IL-6 | Rats | Intranasal | Mice immunized with the variation pCI-IL-6 showed less decay than the control group | Intranasal co-administration of IL-6 significantly improves the immunogenicity of the anticaries DNA vaccine. |
laboratory studies with experimental animals and the evidence of vaccines’ efficacy, there is no marketability for human use [