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 that antigen I/II must be a heart antigen On the other hand, and Lehner found no significant of heart antibodies in and rhesus monkeys with I/II the possible that might be if antigens were in antidecay vaccines for humans be decay is not a and, while an of may be in the of or no such could be in to most a ideal antidecay vaccine would have the vaccine must be safe, that is, it should not any should be to and capable of use from an from of age must provide an effective of antibodies. antibodies produced should be specific to decay-causing the antigen would induce IgA antibodies in salivary secretions than antibodies (IgG) in The antibodies should be to prevent attachment of 5. mutans to teeth and formation. ANTIDECAY VACCINES are now on two of the antidecay vaccine. the production of safe and to the vaccine. In the search for safe antigens investigators at the University of I Geoffrey E. Smith · Vaccine to Prevent Cavities? have vaccines containing ribosomal preparations from 5. mutans. These preparations have induced both humoral and immune and protection from caries formation in experimental animals Furthermore, the preparations lack the human heart which means that ribosomal vaccines should not be to human heart tissue Other investigators are on the use of distinct glucosyltransferase enzymes as the antigen of reported that DNA from S. mutans strain 28 (serotype was in the ? 1 . classes of were found that glucosyltransferase in At a recent a for the Wellcome Foundation that a vaccine now developed by that was both safe and effective and that the only reason for a was the over whether it to against a disease Lehner have been exploring the possibility immunisation with monoclonal antibodies to S. mutans. To this they an IgG class monoclonal antibody to the protein of 5. mutans antigen I/II and it to the teeth of rhesus This procedure in of the teeth by S. mutans and the development of In addition, local passive immunisation should be of any possible systemic have used monoclonal antibodies in local passive immunisation to prevent of human teeth by 5. mutans in the , and no were The authors by that passive by means of might be an approach in the prevention of of teeth by S. mutans and the development of dental IN THE a safe antigen can be there the question of to the vaccine. is the in saliva, most have concentrated on the of inducing the production of salivary IgA antibodies against S. mutans antigens an immune response the of the antigen by a the antigen is at a where lymphocytes can the body ensure that a of lymphocytes are cell is to form one antibody and in Biology 31, 3 ¦ Spring 1988 \ plays this on its surface as an or There is a of to function in the of any conceivable the with specific receptors to the antigen being by the the antigen, it is to either into cells that antibody in or into more lymphocytes with the an group of lymphocytes to against a attack by the same antigens. The surfaces of the mouth are to regular antigenic a result, they contain many and present are cells, which play an important role in antigens to specific In addition, cells may be responsible for the capacity of antigens in the mouth are of for example, in the that are found on the of the of the and around the salivary that are particularly in the soft Most of these have therefore, they are exposed to oral antigens by the are to antigens as they out of the mouth during It is to be that a local immune system in the mouth in the Stage during antigens are in either the or the salivary In either of these they can be by cells and to Stage of tissue to the of the oral mucus Stage antigens the surfaces of the oral are by cells and to specific The then with the same Stage may IgA antibodies that are into the oral where they may with the of bacteria to to surfaces in the or (b) the antibodies may to the of the tooth surface, as the antibodies could to S. mutans and the organism while it is , and by local cells, and antibodies into oral as in Stage then they would be few and this seems a I Geoffrey E. Smith ¦ Vaccine to Prevent Cavities? If, on the other hand, complexes to the then we can that in the mouth the surfaces of both and soft tissues are by a barrier Finally, if this mechanism is then the to antibodies against S. mutans would be to suitable antigens in a and then the into the At present, antidecay vaccines have been and they to at least in a of It is probably to suggest that they are at the stage years some would be them on the production of vaccines is a sophisticated process with that to be public health problems have people were with antigens that some of while are and more than care has to be with an antidecay vaccine so as to be that the far any possible on other and tissues of the at a recent a for the Wellcome Foundation that a vaccine now developed by the was both safe and effective and that the only reason for a was the over whether it was to against a disease In industrialised countries, a significant proportion of and the have all those have that require regular or On the other hand, caries prevalence children and is In developing countries, and the have a level of caries with only a few decayed or teeth. over the past years, caries has been in a proportion of the The problem, therefore, is to control the prevalence of caries in the developing world before it out of fluoridation has been with in the incidence of caries, and it is For example, the annual per capita (in fluoridation in five United States from in to in while fluoridation is practised in the United States, and for example, all these countries have water of populations By in out of countries in the less than of people have to safe In addition, in the United States the Perspectives in Biology and Medicine, 31, 3 ¦ Spring 1988 population by public water supplies from in to in and In out public water supplies in the United States, only are of these systems populations and systems populations of more than The of water fluoridation have been by health in the United States for more than years, only of have to drinking water In Europe, less than 1 of the population and worldwide it appears that only of people have to drinking water The World Health Organisation has that oral health and disease prevention can be to the of dental caries in developing nations [2]. are these Most in the that the availability from a variety such as water fluoride fluoride and , and is responsible for the decline in caries in the industrialised so far it has to the decline to one specific and while most would that water fluoridation is the most the practical problems with fluoridation into many areas of the developing world are Furthermore, the of preventive in the seems to be on to and costly dental care For example, in North and there are now over five per head of This with the World Health Organisation and regions where there are per people The seems to be that Western-style can now contain dental but only at a of between $50 and $100 per head of population per this is then the problem caries in the developing world may require a new has out that, in developing most dental are in prosperous and the that services be available to and is not being that in the developing world the dental profession is with its distinct from that of and this to The to is that the must be to the for costly treatment and to this for and should I Geoffrey E. Smith · Vaccine to Prevent Cavities? have a dental health in the West, some would this approach as a of I would that the dental profession must the of developing a safe, effective anti—tooth decay vaccine as a the for such a product in industrialised countries is , it is, only these countries that have the and to develop and the vaccine on a worldwide scale. Unfortunately, some have little for an decay of the product a of it will be one of the I we have to a for The to the is of of and I people would most of would to the as as we would And of course, there are now of in emerging and Third World countries a they a safe and effective antidecay vaccine can be then the it available the The of declining tooth decay. E. and dental World for the World E. and dental review of human United and the prevalence of dental against dental and of the oral in the S. immunity to dental protection of by local with S. and of monkeys with antigens from S. mutans. S. with serum and against caries in rhesus and passive by Perspectives in Biology and Medicine, 31, 3 ¦ Spring 1988 \ 1 monoclonal antibodies against streptococcal antigen I/II in the prevention of and and of two mutans glucosyltransferases in E. . S. immunity to dental protection of by local with a ribosomal from S. mutans. and Streptococcus mutans in and saliva, and the development of , and and of Streptococcus mutans from various human and characteristics of Streptococcus mutans serotype and and the formation of dental In by E. A vaccine against dental E. antibodies in the of and disease. In and by and der Rijn, Zabriskie, and S. in Streptococcus mutans with human heart , and of surface antigens of Streptococcus mutans by and . protein antigens of Streptococcus mutans. E. antigens of Streptococcus mutans, purification and of a double with protein antigens from Streptococcus mutans against dental caries in rhesus Hunter, and of a molecular protein of Streptococcus mutans. . and of antibodies to human heart tissue in of rhesus monkeys with Streptococcus mutans antigens. and study of salivary and serum antibody and cell-mediated to local of Streptococcus mutans and whole I Geoffrey E. Smith ¦ Vaccine to Prevent Cavities? of crossreactivity of antibodies to ribosomal preparations from mutans with human heart and antigens. A of microbial and of monoclonal antibodies in local passive to prevent of human teeth by Streptococcus mutans. S. of of humans with Streptococcus mutans on of salivary and serum antibodies and , and The immunological function ofthe and E. of antigens to the salivary in the Oral and and of Streptococcus mutans by in to dental caries in the rhesus Oral A of and The prevention and control of dental In Dental and the Statistics S. Dental health the World Health Perspectives in Biology and Medicine, 31, 3 ¦ Spring 1988 \ ...