Tooth Decay in the Developing World: Could a Vaccine Help Prevent Cavities?

TOOTH DECAY IN THE DEVELOPING WORLD: COULD A VACCINE HELP PREVENT CAVITIESi GEOFFREY E. SMITH* Introduction During the past 20 years in the industrialised countries of the world, the dental profession has championed a series of preventive measures that have led to a marked decline in dental caries [I]. During the same period, however, tooth decay has increased dramatically amongst children in less developed countries [2]. Overall costs of the sophisticated dental health care systems in North America, Europe, andJapan are considerable. For example, around $24 billion a year is spent on dental care in the United States; in the United Kingdom, only the treatment of mental illness consumes a higher proportion of the National Health Service budget than the treatment of dental disease [3]. These figures indicate that dental care now costs an industrialised country between $50 and $100 per head of population per year; and such a level of expenditure is obviously beyond the financial capacity of developing and Third World countries. In 1984, while the gross national product per capita in the United States was $15,390, it was $260 in India, $310 in China, $380 in Pakistan, and $540 in Indonesia. The total population of these four countries exceeds 2,000,000,000 people with over 700,000,000 in the age group 0-14 years [4]. This is particularly significant since, in developing countries , children aged 14 years now have, on average, four decayed teeth, while in developed countries 14-year-olds have only two decayed teeth. (See fig. 1.) The chief reason for the increase in caries in the developing world is the change away from traditional eating habits toward Western-style soft food/high sugar diets. Data from the World Health Organisation Global Oral Epidemiology Bank reveal a statistically significant correlation (r = *56 Surrey Road, South Yarra, Melbourne 3141, Victoria, Australia.© 1988 by The University of Chicago. All rights reserved. 003 1-5982/88/3 10 1-0592$0 1 .00 440 I Geoffrey E. Smith · Vaccine to Prevent Cavities? E Z 28 ?S ? 20 16 12 102030AO50 Age (in years) Developing countries 60 7080 28 2A 20 16 12 W 102030AO5060 Age (in years) Developed countries 7080 mm Sound teeth Filled teeth Decayed teeth Missing teetn Fig. 1.—Oral health status, developing and developed countries, 1980-1985, modified by permission of WHO from World Health Statistics Annual, 1986, fig. 8, p. 10. .72, P < .005) between sugar supplies and dental caries for 12-year-old children in 47 populations [5]. Between 1975 and 1984, annual sugar consumption per capita in India, China, Pakistan, and Indonesia doubled ; on the other hand, and over the same period, per capita sugar consumption in the United States fell from 42 kg/year to 32.7 kg/year [6]. In many Third World and emerging countries, water fluoridation is impractical in regions where regular supplies ofclean drinking water are nonexistent; school dental services are rudimentary or not available; qualified dental personnel are few and far between; and government funds for the provision of dental care systems are minuscule. Yet, at the same time, consumption of cariogenic foodstuffs is on the increase, and, as an inevitable result, the incidence of tooth decay escalates. Writing in Science, Leverett [7] suggested that, because ofthe declining prevalence of caries in the United States, ... we may be rapidly approaching a situation in which basic research into new caries-preventive measures is of declining importance. A practical anticaries vaccine may not be available before the 1990's. If, however, the prevalence of dental caries continues to decline, such a vaccine may have little practical importance in the United States and other developed countries. It is, of course, conceivable that tooth decay will be "under control" in the industrialised nations by the 1990s; but, by then, there is a real possibility that the disease will be out of control in the less prosperous parts of the world. This raises the question of whether the methods evolved in the west to control caries are applicable on a worldwide scale. Should dental science rest on its laurels and wait until the developing world can afford the costly procedures practised in the West, or is there another way? Since the identification of the bacterium Streptococcus mutans as a principal agent in the etiology of dental caries, there has been considerable interest in the possibility of developing vaccines to prevent tooth decay. The research for such vaccines is based on practical and public health considerations. Vaccines can permanently program the body's immune system to recognise and fight off infectious microorganisms; and the use of an induced immune response to prevent infectious diseases has worked dramatically to eradicate many of these diseases without disturbing the ecology of nature. On a public health basis, vaccination against caries would be an acceptable concept and understood by the public and health professions alike. There is persuasive evidence that dental caries is an infectious disease. Therefore, its prevention by immunological methods should be possible, particularly since components of both the humoral and cell-mediated immune system appear in the mouth. The lack of a blood supply to tooth enamel does not preclude the production of antibodies against bacteria 442 I Geoffrey E. Smith ¦ Vaccine to Prevent Cavities'? that colonise surfaces of teeth. Antibodies can reach the oral environment either in salivary secretions or through the medium of crevicular fluid, which constantly seeps out of the gum margins around necks of teeth [8]. In addition, recent studies suggest that the oral mucus membranes contain both the effector and regulatory cells required for the local production of antibody [9]. By 1980, protection against caries, induced by immunisation with Streptococcus mutans, had been demonstrated in rats, irus monkeys, and rhesus monkeys [10]. Unfortunately, streptococcal vaccines may cause damage to heart tissue in humans, a phenomenon known as crossreactivity in which the antibody raised by the vaccine attacks the wrong target. To overcome this potential problem, investigators are exploring a variety of techniques. For example, recent breakthroughs in genetic engineering promise a new generation of vaccines in which DNA from S. mutans is isolated then synthesised in a harmless bacterium [H]. Other workers have used local passive immunisation with monoclonal antibodies against S. mutans to prevent cavities in monkeys [12, 13]. Yet another approach is being used at the University of Alabama [14, 15], where ribosomal preparations from S. mutans have been used to induce immunity and protection from caries formation. A review of research progress on anti—tooth decay vaccines may, therefore, be timely. Dental Caries Dental caries is a pathological process involving localised destruction of tooth tissues by microorganisms. It is a disease ofcomplex, multifactorial etiology in which three interrelated factors must coexist in order for caries to develop. These factors can be summarised as follows: Microorganisms with cariogenic potential must be present in the mouth. A suitable bacterial substrate, conducive to cariogenesis and capable of supporting growth of cariogenic organisms, must be available in the mouth. Teeth must be present in the mouth that are suboptimally resistant to caries owing directly to compositional, morphological, or positional reasons, or, indirectly , because of salivary characteristics that may include composition, pH, buffer capacity, volume flow, viscosity, and the content of various antibacterial factors . Genetics may play an important role in the control of some of these factors. Most investigators into the subject, but by no means all, now believe that Streptococcus mutans are intimately involved in the initiation of tooth decay in humans [16]. The species contains at least seven and possibly eight serotypes [17, 18]. Before caries can proceed, S. mutans must first gain attachment to the tooth surface, then it must colonise the enamel by producing sticky, tenacious polysaccharide polymers often termed Perspectives in Biology and Medicine, 31, 3 ¦ Spring 1988 \ 443 "plaque." Finally, the bacteria metabolise suitable carbohydrates and excrete weak organic acids that threaten tooth enamel. The formation of cavities could be prevented, therefore, if any of these stages could be interrupted. From the point of view of a vaccine it is useful to distinguish between two phases of infectious disease: 1.The establishment of the organism in the host; and 2.Metabolites or toxins elaborated from the organism during its growth and multiplication that are responsible for the symptoms of the disease. It is possible to develop vaccines which either prevent establishment or neutralize the effect of the toxins secreted. For a number of reasons the ideal antidecay vaccine would prevent decay-causing bacteria attaching to, and colonising, the teeth. The mechanism of attachment of S. mutans to teeth has been extensively studied [19] and seems to involve two stages. a)An initial, and probably reversible, interaction between surface receptors on the organism and macromolecules in the "acquired pellicle"—a structure that covers the tooth surface in the mouth and comprises, essentially, glycoproteins from saliva and antibodies. b)An irreversible stage involving the synthesis of insoluble glue ? polymers from a suitable substrate. Stage (b) plays a key role in the ecology and pathogenicity of S. mutans and involves the enzymatic breakdown of sucrose. The enzymes responsible are glucosyltransferases (GTFs) and fructosyltransferases (FTFs). At present, five main methods of caries prevention are practised. These are: i. Increasing the resistance of teeth to acid attack by systemic and topical fluoride therapy. ii. The most caries-prone areas of the human tooth, that is, the pits and fissures, can be sealed by strongly adherent self-polymerizing and UV light—polymerizing plastic materials. These fissure sealants act as a barrier against microbial attack. iii. Attempts can be made to restrict the intake of certain dietary carbohydrates , especially sucrose. iv. Emphasizing and teaching effective oral hygiene techniques. v. Control of certain oral bacteria by using antibacterial mouthwashes or rinses, such as Chlorhexidine gluconate. It is not suggested that the availability of an antidecay vaccine would make all the above measures redundant; it would, however, provide an additional and potent weapon in the fight against decay, particularly in emerging and Third World countries. Specific immunity induced by a vaccine involves foreign material, the 444 I Geoffrey E. Smith ¦ Vaccine to Prevent Cavities? antigen, triggering the formation by lymphocytes of specific defence factors , the antibodies. Immunoglobulins are the antibody protein produced by the host in response to antigenic material. In man, there are five major structural types or classes of immunoglobulins: IgG, IgM, IgA, IgD, and IgE. IgG is the main Ig class in normal serum and crevicular fluid, while IgA appears in seromucus secretions such as saliva, where it has the function of defending exposed surfaces of the body against attack by microorganisms. ANTIDECAY VACCINES In 1969, William Bowen [20], of the Royal College of Surgeons in England, reported that he had vaccinated three monkeys with live S. mutans cells, fed them a diet containing biscuits and sweets, and found a year later they they had developed significantly fewer cavities than those not vaccinated. Bowen's pioneering study attracted worldwide interest, and the search for a safe, effective antidecay vaccine began in earnest. Bowen had vaccinated his monkeys with whole cells of S. mutans, but, while such a procedure was acceptable in the monkey, in the case of human vaccination a number of serious problems might arise. For example , it has been demonstrated that with Group A streptococci there is an association between infection with these organisms and heart disease [21]. And in 1976, van der Rijn, Zabriskie, and Bleiweisse [22] reported that rabbit antisera raised against various S. mutans serotypes could cross-react with human heart tissue. These findings were soon confirmed by other investigators, and it was clear that the development of a safe antidecay vaccine would require considerable knowledge of antigens derived from 5. mutans. Streptococcus mutans possesses many surface antigens. These include serotype specific carbohydrates, lipotechoic acid, glucan, peptidoglycan, and proteins [23]. In addition, salivary (IgA) and serum (IgG) antibodies have been elicited by immunisation with distinct glucosyltransferase enzymes , and studies of GTF enzymes are complicated for a variety of reasons. For example, not only are many distinct polymers produced from sucrose, but the enzymes elaborating each exist in multiple forms differing in charge, molecular size, or antigenic structure. Furthermore, GTFs have a tendency to form high-molecular-weight aggregates or complexes that may contain more than one enzyme activity. Given the number of serotypes of S. mutans (at least seven) and the bewildering array of potential antigens that could be isolated from the organism, the problem of determining the most suitable antigen(s) for inclusion in an antidecay vaccine is perplexing. But, characterisation and purification of possible antigens is necessary so as to understand the Perspectives in Biology and Medicine, 31, 3 · Spring 1988 \ 445 mechanism of protection and, more important, to ensure that no potentiaUy harmful components are incorporated in the vaccine. In recent years, workers at the Royal College of Surgeons in England and the Wellcome Foundation have concentrated on four proteins, A to D, present in cell walls of S. mutans strain Ingbritt (serotype c). Antigen B, a 190 kDa glycoprotein, gives excellent protection against caries in experimental animals but possesses immunological cross-reactivity with a heart muscle protein [24]. Lehner and his colleagues at Guy's Hospital, London, have studied a series of antigens they designated I to IV, with the major component being a double antigen named I/II [25]. This antigen was reported to be a 185 kDa moiety that could be detected in the cell of most S. mutans strains. Double antigen I/II has been particularly effective in inducing immunological protection against caries in rhesus monkeys [26]. In 1983, however, Forester, Hunter, and Knox [27] studied the apparent similarity of antigens I/II and B, and showed that double-diffusion serologic analyses with specific antiserum for each antigen indicated absolute immunological identity. Consequently, the authors concluded that antigen I/II must also be considered a heart cross-reactive antigen (HRA). On the other hand, Bergmeier and Lehner [28] found no significant titres of antihuman heart antibodies in rabbits and rhesus monkeys immunised with purified I/II antigen. Obviously, the possible hazards that might be presented if crossreactive antigens were included in antidecay vaccines for humans cannot be underestimated. Tooth decay is not a life-threatening affliction, and, while an element of risk may be deemed admissible in the interests of preventing fatal or severe disabling diseases, no such leeway could be tolerated in regard to what most consider a minor ailment. An ideal antidecay vaccine would have the following characteristics: a)The vaccine must be totally safe, that is, it should not produce any undesirable side effects. b)It should be simple to administer and capable of use from an early age; ideally, from 9 months of age onward. c)It must provide an effective induction of antibodies. d)The antibodies produced should be specific to decay-causing bacteria. e)Preferably, the antigen would induce secretory IgA type antibodies in salivary secretions rather than circulating antibodies (IgG) in serum. /) The antibodies should be able to prevent attachment of 5. mutans to teeth and thus preempt plaque formation. PRESENT STATUS OF ANTIDECAY VACCINES Research efforts are now focused on two aspects of the antidecay vaccine. First, the production of safe antigens; and second, how best to administer the vaccine. In the search for safe antigens investigators at the University of AIa446 I Geoffrey E. Smith · Vaccine to Prevent Cavities? bama [15, 20] have tested vaccines containing ribosomal preparations from 5. mutans. These preparations have induced both humoral and cellmediated immune responses and protection from caries formation in experimental animals [29]. Furthermore, the preparations lack the human heart cross-reactive determinant, which means that ribosomal vaccines should not be pathogenic to human heart tissue [30]. Other investigators are concentrating on the use of distinct glucosyltransferase enzymes as the antigen of choice. Recently, Gilpin et al. [14] reported that chromosomal DNA from S. mutans strain MFe 28 (serotype h) was cloned in the bacteriophage vector ? L 47. 1 . Two classes of recombinants were found that expressed glucosyltransferase activity in phage plaques. At a recent conference, a spokesman for the Wellcome Foundation said that a vaccine now developed by that company was both safe and effective and that the only reason for delaying a clinical trial was the concern over whether it wasjustified to immunise against a nonlethal disease [31]. Lehner et al. [12] have been exploring the possibility ofpassive immunisation with monoclonal antibodies (Mc Ab) to S. mutans. To do this they prepared an IgG class monoclonal antibody to the protein determinant of 5. mutans antigen I/II and applied it repeatedly to the teeth of rhesus monkeys. This procedure resulted in decreased colonisation of the teeth by S. mutans and prevented the development of caries. In addition, local passive immunisation should be devoid of any possible systemic side effects. More recently, Lehner's team have used monoclonal antibodies in local passive immunisation to prevent colonisation of human teeth by 5. mutans [32]. Fifteen subjects took part in the experiment , and no side effects were observed. The authors concluded by suggesting that "local passive immunization by means of MAb might be an alternative approach in the prevention of colonization of teeth by S. mutans and the development of dental caries." IMMUNE MECHANISMS IN THE MOUTH Assuming a safe antigen can be found, there remains the question of how best to administer the vaccine. Because secretory immunoglobulin (SIgA) is the predominant immunoglobulin isotype in saliva, most laboratories have concentrated their efforts on the best ways of inducing the production of salivary IgA antibodies directed against S. mutans antigens [33]. Triggering an immune response involves, first, the collection of the antigen by a specialised scavenger cell. Then, the antigen is retained at a strategic site where lymphocytes can brush past. Genetic processes within the body ensure that a vast army of lymphocytes are produced. Each lymphocyte cell is preprogrammed to form one antibody and disPerspectives in Biology andMedicine, 31, 3 ¦ Spring 1988 \ 447 plays this on its surface as an antenna or receptor. There is a large repertoire of recognition units, sufficient to function in the recognition of any conceivable antigen. When the right lymphocyte, with specific receptors to the antigen being presented by the scavenger cell, meets the antigen, it is stimulated to divide either into cells that secrete antibody in large amounts or into more lymphocytes with the right antennae, thus creating an enlarged group of lymphocytes ready to defend against a second attack by the same antigens. The mucosal surfaces of the mouth are subjected to regular antigenic challenge. As a result, they contain many lymphoid T- and B-cells; also present are Langerhans cells, which play an important role in presenting antigens to specific helper T-cells. In addition, Langerhans cells may be responsible for the immunising capacity of topically applied antigens [34]. Also in the mouth are collections of organised lymphoid tissue, for example, in the lingual tonsillar crypts that are found on the distal aspect of the dorsum of the tongue, and around the minor salivary glands that are particularly abundant in the soft palate. Most of these glands have short ducts; therefore, they are exposed to oral antigens by natural retrograde flow [35]. Similarly, the lingual tonsillar crypts are ideally situated to entrap antigens as they pass out of the mouth during swallowing movements. It is conceivable, though yet to be proved, that a local immune system in the mouth operates in the following manner: Stage i.—Particularly during swallowing, antigens are trapped in either the lingual tonsillar crypts or the minor salivary glands (the primary challenge). In either of these sites they can be collected by scavenger cells (dendritic macrophages) and presented to passing lymphocytes. Stage ii.—Antigen-stimulated immature B-cells travel via regional collections of lymphoid tissue to the subsurface layers of the oral mucus membranes. Stage Ui.—Thereafter, similar antigens penetrating the surfaces of the oral epithelium (the secondary challenge) are collected by Langerhans cells and passed to specific helper T-cells. The T-cells then cooperate with B-cells displaying the same la-antigen complex. Stage iv.—Finally, (a) B-cells may synthesise secretory IgA antibodies that are transported into the oral fluids where they may interfere with the ability of bacteria to attach to surfaces in the mouth, or (b) the secretory antibodies may adhere to the acquired pellicle of the tooth surface, perhaps as IgA-mucin-bound complexes. There, the antibodies could bind to S. mutans and inactivate the organism while it is phagocytosed , killed, and removed by local neutrophil cells, and complement [36]. IfSIgA antibodies pass into oral fluids as described in Stage iv(a), then they would be swallowed every few minutes, and this seems a very waste448 I Geoffrey E. Smith ¦ Vaccine to Prevent Cavities? ful mechanism. If, on the other hand, SIgA-mucin-bound complexes adhere to the acquired pellicle (Stage iv[è]), then we can speculate that in the healthy mouth the surfaces of both hard and soft tissues are covered by a natural protective barrier layer. Finally, if this hypothetical mechanism is correct, then the best way to trigger secretory antibodies against S. mutans would be to incorporate suitable antigens in a mildly abrasive paste formulation and then gently rub the paste into the gums. At present, antidecay vaccines have been developed, and they seem to work, at least in a range of laboratory animals. It is probably reasonable to suggest that they are at the stage where, 80 years ago, some dentists would already be testing them on selected patients. But today, the production of vaccines is a sophisticated process with high standards that need to be maintained. Major public health problems have arisen when people were treated with antigens that retained some pathogenicity. Untoward effects of immunisation, while rare, are widely publicised, and quite rightly; more than extra care has to be taken with an antidecay vaccine so as to be sure that the good effects far outweigh any possible adverse reactions on other organs and tissues of the body. However, at a recent conference a spokesman for the Wellcome Foundation said that a vaccine now developed by the company was both safe and effective and that the only reason for delaying a clinical trial was the concern over whether it was justified to immunise against a nonlethal disease [37]. Discussion In industrialised countries, a significant proportion of adults and the elderly have lost all their teeth; those remaining have fillings and/or prostheses that require regular repair or replacement. On the other hand, caries prevalence among children and adolescents is declining. In developing countries, adults and the elderly have a low level of caries with only a few decayed or missing teeth. However, over the past 10-20 years, caries has been increasing in children, who constitute a very substantial proportion of the population. The problem, therefore, is to control the increasing prevalence of caries in the developing world before it gets out of hand. Water fluoridation has been credited with great success in reducing the incidence of caries, and it is cost effective. For example, the annual per capita cost (in 1981 U.S. dollars) ofwater fluoridation in five United States communities ranged from $0.06 in Denver, Colorado, to $0.80 in rural West Virginia [38]. However, while fluoridation is quite widely practised in the United States, Canada, Australia, and New Zealand, for example, all these countries have "safe" water serving 97-100 percent of their populations [39]. By contrast, in 29 out of 38 countries in the African region, less than 50 percent of people have access to safe water. In addition, even in the United States the Perspectives in Biology and Medicine, 31, 3 ¦ Spring 1988 | 449 population served by public water supplies varies considerably, ranging from 29 percent in Oregon to 99 percent in Illinois and Maryland. In fact, out of60,000 public water supplies in the United States, only about 8,000 are fluoridated. Approximately 46,000 of these systems serve populations ofunder 1,000, and 150 systems serve populations of more than 100,000 [40]. The benefits of water fluoridation have been vigorously promoted by health authorities in the United States for more than 40 years, yet today only 52.2 percent of Americans have access to artificially fluoridated drinking water [40]. In continental Western Europe, less than 1 percent of the population drink fluoridated water, and worldwide it appears that only about 4 percent of people have access to optimally fluoridated drinking water [41]. The World Health Organisation has proposed that well-planned oral health promotion and disease prevention programs can be expected to reverse the upward trend of dental caries in developing nations [2]. But what are these "disease prevention" programs? Most authorities in the West claim that the availability offluoride from a variety ofsources, such as water fluoridation, fluoride tablets, fluoride mouthrinses and dentifrices , and clinically applied fluorides, is primarily responsible for the decline in caries in the industrialised nations. But so far it has proved impossible to attribute the decline to one specific modality, and while most would argue that water fluoridation is the most cost-effective method, the practical problems associated with introducing fluoridation into many areas of the developing world are formidable. Furthermore, the success of preventive dentistry in the West seems to be dependent on continuing ready access to labor-intensive and costly dental care systems. For example, in North America and Western Europe there are now over five dentists per 10,000 head of population. This contrasts starkly with the World Health Organisation African and Southeast Asia regions where there are 0.1 dentists per 10,000 people [42]. The reality seems to be that Western-style dentistry can now contain dental disease, but only at a cost of between $50 and $100 per head of population per year. If this is true, then the problem ofcombating caries in the developing world may require a radical new approach. Dissanayake [43] has pointed out that, in developing nations, most dental practices are in relatively prosperous areas, and consequently the requirement that services be available to poor rural and urban communities is not being fulfilled. He suggests that in the developing world the dental profession is still very preoccupied with "building its own image, distinct from that of medicine, and this tends to hinder innovation ." The answer, according to Dissanayake, is that the long-term goal must be to reduce the need for costly treatment and to do this training schemes for medical auxiliaries, nurses, doctors, and pharmacists should 450 I Geoffrey E. Smith · Vaccine to Prevent Cavities? have a dental health component. No doubt, in the West, some dentists would see this approach as a dilution of professional responsibilities. I would argue that the dental profession must treat the feasibility of developing a safe, effective anti—tooth decay vaccine as a top priority. While the need for such a product in industrialised countries is debatable , it is, paradoxically, only these countries that have the expertise and facilities to develop and market the vaccine on a worldwide scale. Unfortunately, some dentists have little enthusiasm for an anti-tooth decay vaccine; when told of the product a senior colleague of mine commented: "I think it will be one of the self-destructing fads like ladderless stockings. If not, I think we shall have to start a campaign for 'Real Dentistry.' The visit to the dentist is very much part of our way of life and I think people would miss it." Perhaps most of us would miss going to the dentist as much as we would miss having toothache. And of course, there are now tens of millions ofchildren in emerging and Third World countries who cannot even find a dentist when they need one. If a safe and effective antidecay vaccine can be developed, then surely the sooner it becomes available the better. REFERENCES 1.Diesendorf, M. The mystery of declining tooth decay. Nature 322:125-129, 1986. 2.WHO. Statútics Annual. Geneva: WHO, 1986. 3.Smith, G. E. Immunity and dental caries. Sci. 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