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Caries Vaccine

W. Shi et al. Flagellin Enhances Saliva IgA Response and Protection of Anti-caries DNA Vaccine. Journal of Dental Research, Published online Oct. 25, 2011 DOI: 10.1177/0022034511424283

We and others have shown that anti-caries DNA vaccines, including pGJA-P/VAX, are promising for preventing dental caries. However, challenges remain because of the low immunogenicity of DNA vaccines. In this study, we used recombinant flagellin protein derived from Salmonella (FliC) as a mucosal adjuvant for anti-caries DNA vaccine (pGJA-P/VAX) and analyzed the effects of FliC protein on the serum PAc-specific IgG and saliva PAc-specific IgA antibody responses, the colonization of Streptococcus mutans (S. mutans) on rat teeth, and the formation of caries lesions. Our results showed that FliC promoted the production of PAc-specific IgG in serum and secretory IgA (S-IgA) in saliva of rats by intranasal immunization with pGJA-P/VAX plus FliC. Furthermore, we found that enhanced PAc-specific IgA responses in saliva were associated with the inhibition of S. mutans colonization of tooth surfaces and endowed better protection with significant fewer caries lesions. In conclusion, our study demonstrates that recombinant FliC could enhance specific IgA responses in saliva and protective ability of pGJA-P/VAX, providing an effective mucosal adjuvant candidate for intranasal immunization of an anti-caries DNA vaccine.

Hajishengallis and Michalek-1999-Current status of a mucosal vaccine against dental caries.-Oral Microbiol Immunol-14-1-20-

The evidence of a specific bacterial cause of dental caries and of the function of the salivary glands as an effector site of the mucosal immune system has provided a scientific basis for the development of a vaccine against this highly prevalent and costly oral disease. Research efforts towards developing an effective and safe caries vaccine have been facilitated by progress in molecular biology, with the cloning and functional characterization of virulence factors from mutans streptococci, the principal causative agent of dental caries, and advancements in mucosal immunology, including the development of sophisticated antigen delivery systems and adjuvants that stimulate the induction of salivary immunoglobulin A antibody responses. Cell-surface fibrillar proteins, which mediate adherence to the salivary pellicle, and glucosyltransferase enzymes, which synthesize adhesive glucans and allow microbial accumulation, are virulence components of mutans streptococci, and primary candidates for a human caries vaccine. Infants, representing the primary target population for a caries vaccine, become mucosally immunocompetent and secrete salivary immunoglobulin A antibodies during the first weeks after birth, whereas mutans streptococci colonize the tooth surfaces at a discrete time period that extends around 26 months of life. Therefore, immunization when infants are about one year old may establish effective immunity against an ensuing colonization attempts by mutans streptococci. The present review critically evaluates recent progress in this field of dental research and attempts to stress the protective potential as well as limitations of caries immunization.,

Fontana, et al.-1999-Intranasal immunization against dental caries with a Streptococcus mutans-enriched fimbrial preparation.-Clin Diagn Lab Immunol-6-405-9-

Streptococcus mutans has been identified as the major etiological agent of human dental caries. The first step in the initiation of infection by this pathogenic bacterium is its attachment (i.e., through bacterial surface proteins such as glucosyltransferases, P1, glucan-binding proteins, and fimbriae) to a suitable receptor. It is hypothesized that a mucosal vaccine against a combination of S. mutans surface proteins would protect against dental caries by inducing specific salivary immunoglobulin A (IgA) antibodies which may reduce bacterial pathogenesis and adhesion to the tooth surface by affecting several adhesins simultaneously. Conventional Sprague-Dawley rats, infected with S. mutans at 18 to 20 days of age, were intranasally immunized with a mixture of S. mutans surface proteins, enriched for fimbriae and conjugated with cholera toxin B subunit (CTB) plus free cholera toxin (CT) at 13, 15, 22, 29, and 36 days of age (group A). Control rats were either not immunized (group B) or immunized with adjuvant alone (CTB and CT [group C]). At the termination of the study (when rats were 46 days of age), immunized animals (group A) had significantly (P < 0.05) higher salivary IgA and serum IgG antibody responses to the mixture of surface proteins and to whole bacterial cells than did the other two groups (B and C). No significant differences were found in the average numbers of recovered S. mutans cells among groups. However, statistically fewer smooth-surface enamel lesions (buccal and lingual) were detected in the immunized group than in the two other groups. Therefore, a mixture of S. mutans surface proteins, enriched with fimbria components, appears to be a promising immunogen candidate for a mucosal vaccine against dental caries.,


Fukuizumi, et al.-1999-Tonsillar application of formalin-killed cells of Streptococcus sobrinus reduces experimental dental caries in rabbits.-Infect Immun-67-426-8-

Living Streptococcus sobrinus cells were orally inoculated into nonimmune rabbits and rabbits immunized with formalin-killed cells of S. sobrinus through tonsillar application to examine the anticaries potential of this method of immunization. The living S. sobrinus cell numbers and the caries areas in the rabbits immunized by tonsillar application decreased to a level one-fifth of that in nonimmune rabbits., Wizemann, et al.-1999-Adhesins as targets for vaccine development.-Emerg Infect Dis-5-395-403- Blocking the primary stages of infection, namely bacterial attachment to host cell receptors and colonization of the mucosal surface, may be the most effective strategy to prevent bacterial infections. Bacterial attachment usually involves an interaction between a bacterial surface protein called an adhesin and the host cell receptor. Recent preclinical vaccine studies with the FimH adhesin (derived from uropathogenic Escherichia coli) have confirmed that antibodies elicited against an adhesin can impede colonization, block infection, and prevent disease. The studies indicate that prophylactic vaccination with adhesins can block bacterial infections. With recent advances in the identification, characterization, and isolation of other adhesins, similar approaches are being explored to prevent infections, from otitis media and dental caries to pneumonia and sepsis.,

Kato, et al.-1999-The immunogenicity of various peptide antigens inducing cross-reacting antibodies to a cell surface protein antigen of Streptococcus mutans.-Oral Microbiol Immunol-14-213-9-

A cell surface protein antigen (PAc) of Streptococcus mutans may be involved in the binding of bacteria to the tooth surface, and has long been focused upon as a candidate for a preventive vaccine of dental caries. Previously the peptide PAc (365-377) was shown to raise an antibody in B10.D2 mice which inhibited the binding of salivary components to the PAc molecule. Using this peptide as a unit peptide, two constructs based on multiple antigenic peptides, and several types of tandem repeats of two or three copies were synthesized to estimate the immunogenicity of these peptides. Increase in the immunogenicity was observed for all constructs with the use of an adjuvant compared to the unit peptide alone. However, the tandem repeat constructs generally induced antibody production in the absence of adjuvant, while the multiple antigenic peptide constructs did not induce antibody production under the same condition. Although such a phenomenon may be restricted to this particular peptide sequence, these results may influence the strategy for the design of peptide vaccines.,

Cirino and Scantlebury-1998-Dental caries in developing countries. Preventive and restorative approaches to treatment.-N Y State Dent J-64-32-9-

The rate of dental caries in developing countries is rising. Because more than 80 percent of the world's children live in these countries, this alarming trend is of great concern from a public health standpoint. Currently, most dental care in developing nations consists of dental surgery in urban areas. Decay is usually left untreated until it becomes so extensive and/or painful that extraction is the only option. Traditional approaches to treating carious lesions have met with marginal success. There is a need for widespread implementation of preventive strategies, which have proven extremely effective in industrialized nations. Also, promising new techniques and materials are being developed that are enabling dentists and dental personnel to make less costly treatment of dental caries more readily available to underserved populations.,

Childers, et al.-1996-Properties of practical oral liposome-Streptococcus mutans glucosyltransferase vaccines for effective induction of caries protection.-Oral Microbiol Immunol-11-172-80-

Here we report the effectiveness of various liposome vaccines containing Streptococcus mutans glucosyltransferase (GTF) in protecting against dental caries after oral immunization. Rats were immunized by gastric intubation of the appropriate liposome vaccine at weaning and boosted 3 times. Rats were infected with S. mutans following initial immunization and fed cariogenic diet (Diet 305). Saliva and serum were collected during the study and assessed for antibody activity by enzyme-linked immunosorbent assay. Mandibles were removed on day 47 and assessed for S. mutans levels and then for caries. Animals immunized with sonicated, filtered and microemulsified GTF liposome preparations had decreased levels of dental caries compared with control animals given empty liposomes. Rats given dehydrated/rehydrated or purified liposomal GTF also had significantly less caries than control group (GTF alone). Because of economy, ease of preparation and efficiency in amount of antigen used, filtered, dehydrated/ rehydrated and purified liposomal GTF preparations are most practical for use in further assessing the efficacy of liposomal GTF in oral immunization., Mandel-1996-Caries prevention: current strategies, new directions.-J Am Dent Assoc-127-1477-88- Despite major advances in caries prevention, a large subset of the U.S. population still needs additional control measures. In numerous other countries, needs are escalating as caries rates continue to rise. Building on current strategies and new insights into the specific mechanisms of caries initiation, researchers are creatively using a variety of new technologies, especially in molecular biology, to fashion a new generation of preventive measures.,

Gregory-1994-Dental caries vaccines: science and status.-Compendium-15-1282, 1284, 1286 passim; quiz 1294-

Dental caries, caused by the etiologic agent Streptococcus mutans, is considered the most common human infectious disease. Development of a vaccine has been under investigation for more than 25 years. Possible approaches include immunizing patients using an oral vaccine containing components of the causative bacterium and by intramuscular injection. Although both approaches have proved promising, several considerations have delayed further development of a vaccine. This article reviews the scientific results and status of the various vaccines.,

Marsh-1993-Antimicrobial strategies in the prevention of dental caries.-Caries Res-27 Suppl 1-72-6-

Antimicrobial agents, applied either professionally or delivered from dentifrices or mouthwashes, could reduce caries by controlling plaque formation, suppressing cariogenic species, or by inhibiting bacterial metabolism. Chlorhexidine has proven anticaries activity; other agents might also prevent caries by means of their antiplaque properties. Sugar substitutes stabilize the microflora by reducing the number of acid challenges to plaque and stimulating saliva flow; some also have antimicrobial properties, especially against mutans streptococci. Vaccines have been prepared from purified antigens of mutans streptococci. These vaccines confer protection in non-human primates, but have yet to be tested in a human clinical trial.,

Mandel-1993-Caries prevention--a continuing need.-Int Dent J-43-67-70-

The frequently iterated, optimistic view of the demise of caries is not supported by the epidemiologic data. What is in evidence is a changing pattern of caries in developed countries. Among the young there is a polarisation in prevalence with 20 per cent of the children experiencing 70 per cent of the decay. The ageing population is at increasing risk because of longer tooth retention and exposure of root surfaces. A realistic view would envision control rather than extinction of caries with enhancement of current methods of combating tooth decay and more effective employment of multiple anticaries strategies.,

Russell-1992-Immunization against dental caries.-Curr Opin Dent-2-72-80-

The development of a vaccine against dental caries involves identification of appropriate antigens of mutans streptococci against which protective immune responses can be mounted, and the selection of a method of immunization that will generate sustained levels of salivary antibodies. Antigens receiving most attention include streptococcal surface proteins that are involved in attachment to tooth surfaces and glucosyltransferases that synthesize adhesive glucans from sucrose. Recent advances in mucosal immunology and the introduction of novel strategies for inducing mucosal immune responses now raise the possibility of constructing an effective and safe vaccine. Passive immunization by the oral application of performed antibodies against selected antigens of mutans streptococci has also shown promise and may facilitate understanding of the mechanisms of protective immunity against caries.,

Iwaki, et al.-1990-Oral immunization with recombinant Streptococcus lactis carrying the Streptococcus mutans surface protein antigen gene.-Infect Immun-58-2929-34-

A recombinant Streptococcus lactis strain which carries the structural gene for a surface protein antigen (PAc) of 190,000 daltons from Streptococcus mutans serotype c was constructed for development of an oral vaccine against dental caries. The gene from S. mutans MT8148 joined to shuttle vector pSA3 was successfully transformed into S. lactis IL1403. A small amount of PAc was detected in the cell homogenate and cytoplasmic fraction of the recombinant S. lactis, but not in the culture supernatant of the recombinant, by Western immunoblotting and dot immunoblotting. The level of PAc-specific mRNA in the recombinant strain was lower than that in S. mutans MT8148. However, significant salivary immunoglobulin A and serum immunoglobulin G responses to PAc were induced in mice immunized orally with the recombinant S. lactis.,

Jackson, et al.-1990-Liposomes containing anti-idiotypic antibodies: an oral vaccine to induce protective secretory immune responses specific for pathogens of mucosal surfaces.-Infect Immun-58-1932-6-

By using a gnotobiotic rat model system to study the induction of protective immune responses by anti-idiotype (anti-id) vaccines specific for antibodies directed at the cariogenic microorganism Streptococcus mutans, it was shown that administration of such an anti-id vaccine provided partial protection against dental caries after challenge with virulent microorganisms. Protective effects were first demonstrated by direct parenteral administration of the anti-id vaccine into salivary gland regions, as determined by reductions in microbial colonization and caries scores. Subsequently, the anti-id was incorporated into liposomes and administered by gastric intubation. Immunization by this regimen also resulted in a significant reduction in caries as well as S. mutans colonization of the oral cavity, with concomitant increases in salivary immunoglobulin A anti-S. mutans antibodies. These data provide evidence that anti-id vaccines specifically targeted at the secretory immune system can induce protective immune responses to pathogens of mucosal surfaces.

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