Forsyth scientists advance caries vaccine research

June 27, 2001
Researchers at The Forsyth Institute have discovered a potentially important antigen for a vaccine against dental caries.

Researchers at The Forsyth Institute have discovered a potentially important antigen for a vaccine against dental caries. The antigen, reported in the July issue of "Infection and Immunity," gives rise to greater immune response than do many previously tested antigens � and strengthens an already powerful case for embarking on clinical trials for a caries vaccine.

The research team, led by Martin Taubman, DDS, PhD; and Daniel Smith, PhD, aims to prevent tooth decay throughout life by administering an anti-caries vaccine to children aged 12 to 24 months.

"Despite the great advances in caries research over the past few decades, dental decay remains the major infectious disease that affects children worldwide," according to Dominick P. DePaola, DDS, PhD, president and CEO of The Forsyth Institute. "A vaccine for caries would be extraordinarily exciting because it could free tens of millions of children from the ravages of dental disease."

The newly reported antigen is the key component in a new formulation of a mucosal vaccine that can be squirted up the nose, rather than injected or swallowed like some other vaccines. This vaccine and others developed at Forsyth have proved effective in pre-clinical trials.

The researchers have previously received approval to enter clinical trials and are currently seeking support or partners to provide the vaccine.

Dental caries is a widespread infectious disease that occurs when microorganisms accumulate on the teeth, especially in the presence of sucrose, says Taubman, head of the Department of Immunology at Forsyth. The microorganisms � mutans streptococci bacteria � produce lactic acid, a product of sugar metabolism that causes tooth enamel to erode. The vaccine works by stimulating immunity to the mutans streptococcal enzyme, which is responsible for the accumulation of the mutans microorganisms on teeth.

The researchers found that an antigen composed of a combination of peptide constructs taken from the mutans enzyme is more effective at stimulating such immunity than previously-tested individual peptide antigens.

Why a vaccine is needed

In recent years, fluoridation of drinking water and fluoride in toothpaste have contributed to a reduced incidence of caries in the developed world (possibly by making teeth more resistant to the acid produced by the mutans organism). Nevertheless, nearly half of children aged five to 17 in the United States � especially the underprivileged and Native Americans � have caries in their permanent teeth. Elsewhere in the world, where fluoridation or preventive techniques are absent or limited, dental disease has reached near "epidemic" proportions. In China, for example, three-quarters of five-year-olds have dental decay, according to a recent Chinese government report.

"A caries vaccine would be a major public health measure in alleviating such devastating disease," Taubman says.

Forsyth�s strategy is aimed at stimulating the production of antibodies that inhibit the enzyme that allows bacteria to accumulate on teeth. The researchers believe that the best way to protect against caries over the long term is to introduce antigens to children at about the age of one, after teeth have begun to emerge, but before mutans streptococci bacteria have begun to colonize. At this stage, Taubman explains, children�s immune systems are developed enough to produce antibodies to prevent accumulation of mutans bacteria and the tooth-decaying acid the bacteria manufacture. Once the bacteria have begun to accumulate, antibodies form, but are not effective in halting decay.

For several reasons, The Forsyth researchers are focusing on "mucosal" vaccines that can be "painted" or squirted into the nose:

(1) Mucosal vaccines have been less toxic than vaccines that are injected or swallowed

(2) they are better targeted to stimulate nasal-associated lymphoid tissues, which can result in antibodies in saliva or other mucosal areas and

(3) they are easier to administer to young children.

Advantages of the new formulation

To date, a variety of other vaccine formulations have proved to reduce tooth decay in animals. Among them are those based on:

(1) The purified GTF enzyme itself

(2) A mutans streptococcal adhesin called "Pac," which can bind the bacterium to the coating on the tooth

(3) A mutans streptococcal glucan binding protein (GBP), which participate in the accumulation of mutans streptococci on teeth.

The newly reported formulation improves upon previous formulations because it contains peptides from both the catalytic (CAT) and glucan-binding (GLU) regions of glucosyltransferase (GTF) enzyme. Using two different peptides with complementary functions and synergistic (complementary) immunological properties inhibits more enzyme function and gives rise to a greater response, according to Taubman. The new formulation has resulted in enhanced levels of antibody to CAT construct and to GTF, the researchers report.

Recent related discoveries

In February 2001, the researchers and their Forsyth colleagues reported in the journal Vaccine that they had discovered a method for enhancing the delivery of certain mucosal vaccines, That method involves administering material that resembles bacterial DNA. (More specifically, the researchers administered an olignucleotide containing unmethylated CpG motifs along with an immunogen bound to aluminum hydroxide by mucosal as well as injected routes). This finding has positive implications not only for increased effectiveness of caries vaccines, but also for vaccines aimed at protecting against illnesses like E. coli-associated enteritis, ulcers and AIDS, according to Taubman.

In August 2001, the researchers will report on the efficacy of another method of enhancing caries immunity by inhibiting mutans streptococcal enzymatic activity and diminishing glucan synthesis.

Copies of the current article, entitled "Diepitopic Construct of Functionally and Epitopically Complementary Peptides Enhances Immunogenicity, Reactivity with Glucosyltransferase, and Protection from Dental Caries," are available from the Forsyth Institute (617-262-5200 x398) or from Infection and Immunity [email protected].