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Editorial

Dental caries vaccines: prospects and concernsExpert Rev. Vaccines 9(1), 1–3 (2010)

“The WHO has estimated that more than 5 billion people have experienced tooth decay.”

Dental caries remains one of the most pervasive infectious diseases of mankind, despite the availability of preventive meas-ures such as fluoride supplements, regu-lar dental care, sealants and knowledge of the bacterial etiology of the disease. The WHO has estimated that more than 5 billion people have experienced tooth decay [1]. In addition, epidemiologic stud-ies in the USA have noted that after many years of declining caries rates, there has been a recent increase in childhood car-ies [2]. Clearly, the disease is still with us in a major way.

“…the recently immigrated, urban and some rural

populations have poorer access to good dental healthcare for reasons of economics and/or

infrastructure…”One questions why this is so, as popula-

tions within developed societies, most of whom have access to public and private health measures, now enjoy relatively good oral health. However, without recent dis-ease experience, factors leading to the accumulation of a cariogenic flora, such as refined sugar intake, are underappre-ciated. Thus, dietary vigilance declines. Even within these societies, the recently immigrated, urban and some rural popu-lations have poorer access to good den-tal healthcare for reasons of economics and/or infrastructure; thus these com-munities have more experience of caries. These issues are magnified in develop-ing countries, as a larger percentage of the population is economically deprived, contributing to more broad-based dental

caries experience. For this reason, differ-ent approaches are required to address this deficit in oral health [3].

Infectious diseases have long been inter-cepted by enabling host defense mecha-nisms through immunization prior to infection. This approach has often been successful, is generally cost effective and can reach a large percentage of the popu-lation. Thus, active and passive immu-nization strategies have been pursued to deal with infections leading to dental caries. Although several microorganisms have been associated with various forms of dental caries, mutans streptococci, especially Streptococcus mutans [4], have been the foci of these immunological approaches, owing to the high frequency of their recovery in pediatric forms of the disease. These streptococci also offer obvious cell wall and extracellular tar-gets that are central to their attachment and accumulation in the oral biofilm. As the oral microbiome becomes more fully catalogued, other acidogenic microorgan-isms, separately or in combination, may be found to participate in the end result of dental caries. Nonetheless, S. mutans remains prominent in most molecular genetic profiles of incipient dental dis-ease, and thus continues as a reasonable candidate for elimination [5].

“…without recent disease experience, factors leading to

the accumulation of a cariogenic flora … are underappreciated.”Over the last four decades, many experi-

ments, performed by a surprisingly small number of laboratories, used various

Daniel J Smith, PhDDepartment of Immunology, The Forsyth Institute, 140 The Fenway, Boston, MA 02115, USA Tel.: +1 617 892 8309Fax: +1 617 892 8437 dsmith@forsyth.org

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Editorial Smith

adaptive immune regimes to explore the protective effect of salivary IgA antibody to S. mutans or Streptococcus sobrinus [6]. Mutans streptococcal components that participate in adhesion, glucan formation or binding, or cell wall synthesis, alone or in combination, have been shown to inhibit experimental dental caries formation in rats or mice. Protection was observed with intact proteins, derived recombinant or synthetic peptides, and DNA vaccines encoding one or more of these antigens or their fragments. Mucosal routes, which would be expected to increase salivary antibody levels and also be more acceptable to children, could be used effectively in these models with the appropriate adjuvant. Clearly, proof of principle exists for a dental caries vac-cine. However, despite the use of human-derived S. mutans patho-gens, several features of the experimental animal model, includ-ing antibiotic alteration of oral flora, elevated dietary sucrose, large infectious doses and coprophagic rodent behavior, must be taken into account when evaluating the transfer of this approach to humans.

“…Streptococcus mutans remains prominent in most molecular genetic profiles of

incipient dental disease, and thus continues as a reasonable candidate

for elimination…”Passive immune approaches have also been shown to be prom-

ising [7]. Dietary supplements of polyclonal IgG or IgY antibody to glucosyltransferease, glucan-binding proteins, or monoclonal or transgenic reagents that have specificity for other S. mutans cell surface antigens, have each successfully reduced dental car-ies in experimental animals during infection with cariogenic strepto_cocci. Small-scale human clinical trials in which trans-genic IgA/G antibody was administered in dental trays to adults over several weeks have had mixed success in preventing mutans streptococcal recolonization of tooth surfaces after chlorahexi-dine treatment [8,9]. Subject compliance issues may have compro-mised consistent application, leaving the utility of this approach in adults unresolved. Using passively administered antibody dur-ing the period of initial colonization with cariogenic streptococci, either alone or in concert with adaptive immune approaches, may be a more productive use of this strategy. Effective methods of delivery of non-host-generated antibody need to be identified for human applications.

Despite the abundance of experimental evidence for the effec-tiveness of dental caries vaccines, none yet exist for human use. In part, there has been an unwillingness of commercial entities to underwrite the investment required for vaccine development. Although the current economic climate behooves companies to invest wisely, the long-term financial (and social) gain should be appreciable, given the extent of the disease. Furthermore, pediatric vaccine approval boards are reluctant to add a vaccine for a normally non-life-threatening disease to the already long list of pediatric immunizations. This reasoning is somewhat parochial and may be influenced by the more limited amount of dental disease seen in the segment of society which has access

to good dental care. Clearly, both US and international sur-veys indicate otherwise for the great majority of underserved children worldwide.

There is some concern that mucosal-based vaccines may not induce host responses that are strong enough or are of suffi-cient duration to block colonization of cariogenic streptococci. The chief rebuttal to this concern is that we will not know until we have tried, since there is very little experience with human mucosal immunization applications using nonrepli-cating components. Certainly replicating oral (Sabin polio-virus) and nasal (FluMist®, MedImmune, Inc., MD, USA) vaccines have been quite successful. The current search for more effective adjuvants for mucosal vaccines should benefit dental caries vaccine strategies [10]. Recent data also suggest that salivary IgA antibody to pioneer f lora epitopes that are shared with mutans streptococci can impede the subsequent colonization by cariogenic mutans [11]. Not only does this sug-gest that dental caries vaccines may indeed be effective in young children, but it also identifies a potential pathway for vaccine enhancement.

The nature of the bacteria that would fill the biofilm niche normally occupied by mutans streptococci has also been an issue in the dental caries vaccine debate. The short answer to this concern is that mutans streptococci are confirmed pathogens, fulfilling most, if not all, of Koch’s postulates. There is long-standing evidence from cross-sectional and longitudinal studies in Sweden indicating that individuals with low or nondetect-able levels of mutans streptococci early in life enjoy better dental health as they mature. Furthermore, the number and variety of streptococcal species that colonize the oral biofilm prior to mutans streptococcal accumulation would suggest that at least one of these commensal species would outcompete vaccine-targeted cariogenic mutans streptococci as these niches emerge during tooth eruption.

“…individuals with low or nondetectable levels of mutans streptococci early in

life enjoy better dental health as they mature.”

Prospects for dental caries vaccines remain hopeful as new technologies identify strategies to elevate host responses to protective levels and provide improved reagents and applica-tion methods to intercept emerging or ongoing infection with cariogenic streptococci.

Financial & competing interests disclosureGrant support for the author’s research has come from the US Public Health Service (DE-06153, TW-06324, DE-04733 and DE/AI-12434). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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EditorialDental caries vaccines: prospects & concerns

References1 Petersen P. Research for oral health in

developing countries. Presented at: WHO Global Forum for Health Research. Mexico City, Mexico, 16–20 November 2004.

2 Dye BA, Tan S, Smith V et al. Trends in oral health status: United States, 1988–1994 and 1999–2004. National Center for Health Statistics. Vital Health Stat. 11(248), 1–92 (2007).

3 Taubman MA, Nash D. The scientific and public-health imperative for a vaccine against dental caries. Nat. Rev. Immunol. 6, 555–563 (2006).

4 Loesche WJ. Role of Streptococcus mutans in human dental decay. Microbiol. Rev. 50, 353–380 (1986).

5 Kohler B, Andreen I, Jonsson B. The earlier the colonization by mutans streptococci, the higher the caries prevalence at 4 years of age. Oral Microbiol. Immunol. 3, 14–17 (1988).

6 Smith DJ, Mattos-Graner RO. Secretory immunity following mutans streptococcal infection or immunization. In: Antibodies in Infectious Diseases, Current Topics in Microbiology and Immunology. Manser T (Ed.). Springer, Berlin, Germany, 319, 131–156 (2007).

7 Smith DJ, Godiska R. Passive approaches for dental caries prevention. In: The Amazing Egg. Sim JS, Sunwoo HH (Eds). University of Alberta Press, AB, Canada, 341–354 (2006).

8 Ma JK, Hikmat BY, Wycoff K et al. Characterization of a recombinant plant monoclonal secretory antibody and

preventive immunotherapy in humans. Nat. Med. 4, 601–606 (1998).

9 Weintraub JA, Hilton JF, White JM et al. Clinical trial of a plant-derived antibody on recolonization of mutans streptococci. Caries Res. 39, 241–250 (2005).

10 Mestecky J, Nguyen H, Czerkinsky C, Kiyono H. Oral immunization: an update. Curr. Opin. Gastroenterol. 24, 713–719 (2008).

11 Nogueira RD, Alves AC, Napimoga MH, Smith DJ, Mattos-Graner RO. Characterization of salivary IgA responses in children heavily exposed to the oral bacteria Streptococcus mutans: influence of specific antigen recognition in infection. Infect. Immun. 73, 5675–5684 (2005).