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ORAL BIOLOGY Will Vaccine Defense Help Polish Off Tooth Decay? Mucosal Delivery Demonstrates Gains Against Cavities According to the World Health Organization, in every community worldwide 50 to 90 percent of the population is affected by dental caries, a chronic problem that can cause teeth to painfully deteriorate and eventually lose function. Children are particularly vulnerable, especially those of lower socioeconomic status and those in developing nations where good dental hygiene is often absent. Now, in the July and August issues of Infection and Immunity, researchers at the Forsyth Institute show they are close to developing a vaccine that promises lifelong protection against the disease and could help make cavities a thing of the past. Martin Taubman (left) and Daniel Smith have developed a vaccine against S. mutans, the major cause of dental caries, which they plan to take to clinical trials. Photo by Steve Gilbert Caries is caused by lactic acid, a by-product of bacterial metabolism, which erodes dental enamel and starts the process that results in tooth decay. Among the acid-secreting bacteria that inhabit the oral cavity, Streptococcus mutans is by far the most insidious, not only producing most of the lactic acid but also adhering to dental surfaces and forming an almost impenetrable biofilm—better known as plaque—that is difficult to remove. So the key to preventing dental caries lies in controlling S. mutans. Luckily, the niche where this bacterium lives is highly specialized. Hard dental surfaces must be available for it to grow. For this reason, it fails to colonize the mouths of young infants whose teeth have not yet emerged. This habitat requirement is the bug's Achilles heel and the key to a vaccination strategy. "If we can get the babies immunized before the bacteria have had a chance to colonize, then we can offer protection for perhaps the rest of their lives," said Daniel Smith, HSDM associate clinical professor of oral biology and pathophysiology. An Infant Vaccine With their young patients in mind, Smith and Martin Taubman, professor of oral biology at HSDM, have worked to develop a vaccine that is effective and easily administered. Part of their strategy is to deliver the vaccine to the body's mucosal layer in the form of a nasal spray since exposure of nasal-associated lymphoid tissue has been shown to induce production of immunoglobulin A (IgA) in saliva—right where it is needed to fight oral bacteria. This mode of administration is also easier and likely to be better tolerated in small infants than are more traditional procedures such as injection. And it comes with a bonus: a broader range of adjuvants to boost the immune response can be used. Still, this delivery method creates its own problems. Antigens administered in this fashion generally evoke a weaker immune response. The researchers have surmounted this obstacle by utilizing potent adjuvants. In the February 2001 Vaccine, they report that oligodeoxynucleotides, particularly those with CG motifs, can turn a poor antigen into a powerful one. Tetanus toxoid, for example, administered to rats through the gastric mucosa, failed to elicit an immune reaction. When combined with an oligonucleotide adjuvant, however, it rivaled that of subcutaneous injection. In a follow-up study reported in the August Infection and Immunity, Smith and Taubman, together with colleagues from the Forsyth Institute and Cambridge Scientific Inc., successfully immunized rats with an S. mutans antigen administered intranasally in combination with either of two mucosal adjuvants, cholera toxin or a detoxified heat-labile E. coli enterotoxin. The combinations elicited immune responses vastly superior to S. mutans antigen alone and induced significant levels of IgA in the saliva. Though a nasal spray is a relatively safe and painless way to immunize, Smith and Taubman want to push the boundaries back even further by developing a vaccine based on a non-replicating antigen. Decreasing the Danger To date, all mucosal vaccines have relied on live, attenuated antigens. These include weakened viruses that replicate in vivo and thereby provide a strong challenge to the host and elicit a correspondingly powerful immune reaction. The Forsyth researchers have elected to pursue a safer vaccine based not on whole organisms but on proteins found on their surface. The difficulty with this type of vaccine is making it potent enough to provoke immunity. As reported in July's Infection and Immunity, the researchers have engineered peptide-based antigens with multiple antibody binding sites that elicit strong immune responses. These antigens, carrying epitopes from the catalytic and glucan-binding domains of the S. mutans enzyme glucosyltransferase, not only induce antibodies in serum and saliva but also can confer protection against caries in rats. The Forsyth team, bolstered by the success of their vaccine in animals, and encouraged by the recent success of an intranasal flu vaccine, hopes soon to test the vaccine in clinical trials. —Tom Fagan