Learning Objectives
- Analyze caries as an infectious condition
- Discuss the ethical and scientific importance of creating a vaccine for caries
- Distinguish between passive and active immune responses in caries prevention
- Understand the major antigens used to stimulate an immune defense against caries
- Investigate different methods for delivering a caries vaccine
- Evaluate the effectiveness and duration of the anti-caries vaccines studied to date
- Consider future possibilities for vaccine production and distribution
Background and Overview
Dental caries, being the most widespread infectious disease in the world, should be well understood by dental professionals. While scientific advancements, improved dental care accessibility, and enhanced clinical interventions have significantly reduced the occurrence of caries in developed countries, it still affects approximately 80% of Americans by age eighteen. Vulnerable groups, including young children, the elderly, the chronically ill, and those from lower socio-economic backgrounds or institutional settings, remain particularly at risk.
According to the Forsyth Institute, two-thirds of underprivileged children in the United States have untreated tooth decay, showcasing significant disparities in access to dental care. Economic challenges prevent many children from receiving proper dental attention, contributing to a substantial caries burden. In developing nations, tooth decay often goes untreated until it becomes painful, leading to extraction as the only remedy. The lack of access to early treatment and preventive measures makes dental caries a serious health concern in these areas.
During the 82nd General Session of the International Association for Dental Research in 2004, researchers underscored that it is both a scientific and moral responsibility of the dental community to develop a vaccine to prevent caries in disadvantaged populations. An easily distributed and administered vaccine for caries prevention could be the most practical solution for disease reduction in populations with minimal access to dental care.
In the United States, the National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health, plays a leading role in funding the research on caries vaccine development. NIDCR has been supporting foundational research on dental caries for many years and is now looking at clinical trials as the next logical step. Multiple studies indicate that the creation of such a vaccine is feasible, and several successful animal trials have already been conducted. Moreover, initial phase I clinical trials in limited human groups have produced encouraging preliminary results.
Process of Caries Development
The current understanding of caries formation emphasizes the role of acid-producing bacteria in damaging the hard tissues of the mouth. In 1968, Loesch's research identified Streptococcus mutans and Streptococcus sobrinus as the primary contributors to dental caries. These two strains of mutans streptococci are largely responsible for caries in humans, and reducing their impact could decrease caries rates by 90%.
The caries development process involves three distinct phases:
- Formation of a biofilm: The bacterial enzyme glucosyl transferase produces glucans and glucose, aiding bacterial accumulation on the tooth surface
- Bacterial attachment to the tooth surface: Bacteria utilize adhesins to adhere to the hard tissues
- Acid production leading to demineralization: Lactic acid, produced through bacterial metabolism, demineralizes the tooth's hard tissues
Approaches for Caries Vaccine Development
The primary focus of most current vaccine research is to disrupt the initial binding and accumulation of mutans streptococci on tooth surfaces. Preventing these bacteria from adhering to hard tissues would prevent the formation of a critical bacterial mass, thereby avoiding concentrated acid deposition on vulnerable tooth surfaces. Animal models, such as rodents and primates, have demonstrated that salivary gland secretion of IgA antibodies can effectively protect against caries by inhibiting both bacterial adhesion and their metabolic functions. Multiple studies have sought to increase IgA secretion in salivary glands to prevent tooth decay, with varying degrees of success in both animal and human trials.
Studies conducted by Taubman and Smith in 1998 showed that although babies are born with nearly no IgA antibodies, salivary IgA production begins within the first week of life, as their mouths are colonized by "pioneer" bacteria, primarily transferred from their mothers. The first wave of oral flora typically consists of species like Streptococcus midus and Streptococcus salivarius. As the primary teeth begin to emerge at around six months of age, another round of bacterial colonization occurs, with Streptococcus sanguis being the dominant bacterium. Mutans streptococci become prevalent in children only between 18 and 36 months of age. Additional potential "windows of opportunity" for bacterial colonization are thought to exist during early school years, when social interaction with a broader group of peers occurs, and during the eruption of the permanent teeth.
One of the primary goals of vaccine development has been to identify the antigens unique to mutans streptococci and then isolate these antigens to stimulate an immune response that would prompt IgA production. Similar to other vaccines, the aim is for the body to generate an "active" immune response against the presented antigen, creating immune memory that can be activated when encountering the antigen later in life.
Researchers are currently studying and isolating several key antigens for potential incorporation into a vaccine:
- Antigen I-II: This large surface protein, unique to Streptococcus mutans, has been successfully cloned following the complete sequencing of the bacterium's genetic code. It has both a saliva-binding region that helps it attach to the tooth pellicle and a gram-positive wall anchor. IgA antibodies could inhibit this region, preventing the bacterium from adhering to hard tooth surfaces. This research is being led by Dr. Michael Russell at SUNY Buffalo and Dr. Noel Childers at the University of Alabama.
- Glucan binding proteins: These adhesion molecules are involved in attaching bacteria to tooth surfaces and serve as effective immune system stimulants. Dr. Taubman's team is also conducting research on this antigen.
- Glucosyl transferases (GTF): These enzymes synthesize glucan-binding proteins (adhesins), which help bacteria attach to teeth. Stimulating the production of IgA antibodies can inhibit these enzymes, hindering the accumulation of mutans streptococci. Dr. Martin Taubman and his team at the Forsyth Institute, as well as Dr. Debra Trantalo at Cambridge Scientific in Boston, are at the forefront of this research.
These vaccination methods focus on stimulating an "active" immune response to increase the body's production of IgA antibodies that specifically target mutans streptococci. Booster doses may be required to sustain this active immunity over time.
An alternative approach, known as "passive" immunity vaccination, involves administering pre-formed IgA antibodies to patients. This strategy does not induce an active immune response or generate immune memory, but it also avoids the risks associated with active immunity inoculations. However, the effectiveness of passive antibodies is short-lived, generally lasting for a few hours to two days. Despite this limitation, a 1985 study by Lehner demonstrated that topically applied IgA antibodies could inhibit Streptococcus mutans colonization in monkeys for one year. A small study on adult humans in 1998, conducted by Ma and associates, showed that topical application of human IgA antibodies after thorough oral prophylaxis inhibited Streptococcus mutans for four months. The antibodies likely prevented recolonization by blocking bacterial adherence to teeth, allowing other bacterial species to occupy the ecological niche instead. However, a 2001 study by Weintraub and colleagues in a larger human sample did not find similarly prolonged effects.
Although the findings on passive immunity have been mixed, they indicate a potential for success. The downside of passive immunity lies in its requirement for frequent antibody administration, which can be costly, inconvenient, and unfeasible in developing regions. Advances in antibody production, such as using plants to produce large amounts of specific antibodies ("plantibodies"), offer a potential solution. These antibodies could be incorporated into products like mouthwash or toothpaste, providing prolonged and consistent antibody levels at a reasonable cost.
Another promising approach involves immunizing young mothers, either actively or passively, to prevent bacterial transmission to their infants. Any transferred bacteria would be coated with IgA antibodies, reducing their ability to colonize the infant's oral cavity. Alternatively, actively immunizing mothers to increase IgA levels in breast milk could confer passive immunity to infants during the early colonization periods. This method would be particularly beneficial in regions where breastfeeding is more prevalent and continues for longer durations.
Dr. James Larrick at Planet Biotechnology, California, has developed a passive immunity product called Cario Rx®. In this approach, monoclonal IgA antibodies are produced using plants and then incorporated into a solution applied directly to teeth. Phase 1 and Phase 2 trials involving 100 patients showed that this passive immunity method reduced recolonization by mutans streptococci in 60% of participants for up to one year. These promising results indicate that passive immunity could play a significant role in combating dental caries.
Routes of Administration
Several potential methods have been studied for delivering a caries vaccine that could stimulate an active immune response:
- Intranasal: Dr. Martin Taubman’s research group at the Forsyth Institute proposes administering 2-3 doses of the GTF antigen intranasally between 12 to 24 months of age. They hypothesize that this nasal spray could effectively trigger an active immune response with substantial memory and long-lasting effects. Dr. Noel Childers and his research team at the University of Alabama support this timeframe, believing that immunizing during this period will prevent the initial colonization of the oral cavity by mutans streptococci, stopping these organisms from establishing themselves. A nasal spray is also advantageous for its ease of use, simplicity of distribution, and acceptance by young patients.
- arenteral Injection: The fear of needles and safety concerns have largely ruled out subcutaneous injection as a viable method for caries vaccine administration. Injections also come with greater costs and the need for skilled healthcare providers, which would complicate distribution in developing countries.
- Oral Administration: Studies have shown that oral ingestion, such as enteric capsules, does not result in efficient absorption through the intestines compared to direct mucosal application. As a result, a pill or capsule form of the caries vaccine is not considered ideal.
- Mucosal or Tonsillar Swab: Directly applying the antigen to the oral mucosa or tonsils has shown effectiveness in animal studies. However, administering this method comfortably to human subjects poses challenges, and precise dosage control is more challenging compared to other methods.
Clinical Trials
Several animal trials have shown promising results, and a few human trials with small numbers of adult participants have been completed, yielding mixed outcomes. In 1987, Smith and Taubman immunized 14 young adults with orally ingested capsules containing GTF from Streptococcus sobrinus. The control group consisted of 11 participants who received placebo capsules. The vaccinated subjects showed increased salivary IgA antibody levels against GTF and delayed repopulation of mutans streptococci.
The same research team conducted a similar study in 1990, vaccinating 23 young adults with a topical application of Streptococcus GTF on the lips' mucosa. This method also delayed bacterial recolonization, though it did not significantly elevate intraoral IgA antibody levels.
In 1994, Dr. Noel Childers and his team conducted oral vaccination trials using Streptococcus mutans GTF and Antigen I-II, resulting in increased intraoral IgA antibodies. The Childers group repeated these studies in 1997, 1999, 2002, and 2003 with similar antigens but explored different routes of administration, including intranasal spray and tonsillar application, which also effectively elevated salivary IgA antibody levels.
Conclusions
Decades of basic science research and clinical trials in animal models suggest that developing an effective caries vaccine against mutans streptococci is achievable. Human clinical trials on a limited basis have been promising, indicating the potential for a safe and effective caries vaccine to address one of the most widespread infectious diseases globally. The next step involves conducting trials in younger populations to establish safety and efficacy.
However, several significant public concerns remain, particularly regarding the number of vaccinations children already receive. Safety and convenience issues must be addressed, and decisions must be made about which group of healthcare professionals will administer the vaccine.
The ultimate success of producing, distributing, and administering a caries vaccine on a national or global scale will depend on political and economic factors. Major health organizations currently do not highlight dental caries as a major health concern in their vaccination protocols. The economic benefits and potential product liability will play a significant role in whether pharmaceutical and industrial partners collaborate with academia to make a caries vaccine a reality. Fortunately, the market for such a vaccine is substantial, and studies conducted so far indicate that a scientifically feasible solution could be developed in the foreseeable future.
Quiz For Development of Caries Vaccine
