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Vaccines: Past, Present, and Future TYPES OF IMI!tUNI ZATION Immunization involves the induction (or administration) of antibodies and other natural defense mechanisms to protect against specific pathogens. There are two types of immunization, active and passive. Active immunization is the major focus of this report. It involves the administration of a modified pathogenic agent, or a component of a pathogen, to stimulate the recipient's immune mechanisms to produce long-lasting protection without causing the clinical manifestations or other consequences of disease. Three major types of preparations are employed to produce active immunity. The first consists of vaccines made from whole, inactivated (killed) pathogens or components of a pathogen.] Examples of whole, inactivated vaccines include currently licensed pertussis vaccines, influenza vaccines, and the Salk poliovirus vaccine. The pneumo , ~ 4, coccal, meningococcal, and hepatitis B vaccines are among those that contain the immunity-producing fraction of the pathogen. Toxoids are the second type of active immunogen. The diphtheria and tetanus vaccines are good examples. Toxoids are toxins that have been treated by physical or chemical means until they no longer produce clinical disease, but retain the capacity to induce immunity. Attenuated infectious vaccines are the third type. Virus vaccines in this group are derived from the offending organism after it has undergone repeated passages in the laboratory in culture; it remains infectious for man but loses the ability to induce clinical disease. Examples include the oral {Sabin) poliovirus vaccine. and the measles. mumps, rubella, and yellow fever vaccines. Other examples of this type of vaccine contain live organisms or agents that are related to but different from the species that causes the disease. These vaccines produce "cross-reacting" immunity. Examples include the vaccinia virus vaccine used to prevent smallpox and BOG (Bacillus Calmette-Guerin), which is used in some countries for immunization against tuberculosis, but only rarely administered for this purpose the United States. Passive immunization is accomplished by transferring antibodies against a given disease from an immune person or animal to a nonimmune , ~ 14

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15 individual, usually by injection of serum (antisera) or some partially purified serum extract. Examples are diphtheria and tetanus anti- toxins, and immune serum globulin for the prevention of hepatitis. In some diseases, such as diphtheria, passive immunization is effective not only as a preventive measure, but also as a treatment. Immunity acquired in this way is transient, however; it usually requires recognition or anticipation of exposure, and is not infrequently associated with untoward side effects such as serum sickness, manifested by transient fever and arthritis resulting from hyper- sensitivity to animal sera. HISTORY OF I+UNI ZATION Active immunization began with smallpox and was based on the observation that immunity could be conferred by rubbing smallpox scabs against the skin, which usually resulted in a mild case of the disease.2 Inoculation of susceptibles with infectious material from individuals with mild smallpox was practiced in China and Africa many centuries ago. It was introduced in Britain and the American colonies early in the eighteenth century. It is interesting to note that these inoculations caused an occasional death, resulting even then in controversy about the benefits and risks of the procedure. These concerns led to the search for a "better vaccine." This search eventually focused on the fact that a vesicular eruption of cow udders, known as cowpox, often led to the development of small blisters or ~milkers' nodes on the hands of milkmaids. By the middle of the eighteenth century, physicians recognized that persons infected with cowpox appeared to be protected from later exposure to smallpox, resulting in Edward Jenner's classic experiment in 1796. Use of the smallpox vaccine spread quickly in the United States. In fact, the vaccine was the subject of the nation's first law regulating the distribution of drugs, the Vaccine Act of 1813.3 This act authorized the President to appoint a federal agent to "preserve the genuine vaccine matter, and to furnish the same to any citizens who requested it. It was repealed in 1822, after Congress decided that vaccine regulation should be left to local authorities. The apparent success of early smallpox vaccination efforts and the developing science of microbiology led to other attempts to control feared infectious diseases in the late nineteenth century. Among these was the Pasteur method of active immunization against rabies, first tested in a child in 1885.4 Serum therapy, later called antitoxin therapy, began in the early 1890s with the discovery that animals inoculated with heat-killed broth cultures of diphtheria or tetanus bacilli were able to survive subsequent (otherwise fatal) inoculations with those organisms. Early researchers did not realize at first that the (cell-free) supernatant of the broth culture, not the killed bacteria, was responsible for the development of immunity.5 It also was shown that protection derived

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16 from immunization could be transferred to other animals by inoculating them with body fluids, such as serum, obtained from those that had been immunized. The first child with diphtheria treated with antitoxin was in Berlin in 1891.5 By the mid-1890s, diphtheria antitoxin was produced for widespread use in both Britain and Germany.6 The antitoxin was first produced and tested in the United States in 1895 by the Mulford Company of Philadelphia, later absorbed by Merck Sharp & Dohme. The effectiveness of diphtheria antitoxin in the prevention and treatment of diphtheria (although not 100 percent) led a number of competing companies, both in the United States and abroad, to begin to manufacture it for commercial purposes. In the absence of regulations for testing and certification, substandard, ineffective, or dangerous preparations were sometimes produced and sold! occasionally by charlatans. At first, warnings by responsible authorities went essentially unheeded.6 Concerns about uncontrolled production of smallpox vaccine and diphtheria antitoxin were expressed in editorials in the Journal of the American Medical Association late in 1894.7'8 The potential role of state governments in supervising the propagation of vaccine virus was discussed at the National Conference of State Boards of Health held that December.7 The recognized variability in the efficacy of different smallpox vaccines was attributed, at least in part, to defective preparations. On December 5, 1894, the New York City Board of Health instructed the Health Department to develop a plan that would assure the potency and purity of diphtheria anti-e Oxin preparations sold in New York City.8 Although antitoxin shipped in small amounts from two German manufacturers appeared to exhibit acceptable purity and efficacy, some antitoxins from the United States were never subjected to testing and at least one that was tested was inert. Profiteering by manufacturers of presumably effective antitoxins also was lamented by the authorities. When the concern reached the Congress, an Illinois member recommended that Congress create a national commission for the investigation of the antitoxin treatment of diphtheria.8 unfor- tunately, no definitive action was taken until 1902. This action followed the deaths from tetanus of 13 children in St. Louis who received diphtheria antitoxin prepared from a horse that shortly thereafter died of tetanus.6 (The antitoxin, incidentally, was prepared by the St. Louis City Health Department, not by a commercial firm.) This tragedy and the furor it caused in the public press resulted in the passage of the virus-toxin act by Congress in 1902.6 This act established a board under the Department of the Treasury to develop licensing regulations for the producers of vaccines and antitoxins for interstate or foreign commerce. under the direction of this board, the Hygienic Laboratory of the Public Health Service was authorized to inspect manufacturing establishments, issue and revoke licenses, and in other ways ensure, insofar as possible, the safety

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17 and efficacy of these biologics. By 1904, licenses had been issued to 13 manufacturers of biologics, primarily smallpox vaccine and diphtheria antitoxin. The number of producers licensed reached 41 by 1921. Standards for potency were developed at the Hygienic Labora- tory. Manufacturers failing to meet acceptable standards had their licenses revoked or refused. These responsibilities were later transferred to the National Microbiological Institute of the National Institutes of Health (NIH). The 1902 act subsequently was incorporated into the Public Health Service Act of 1944. In the 1950s, the Public Health Service Hygienic Laboratory was reconstituted as the Division of Biologics Standards at the NIH, and in 1972 these responsibilities were transferred to the Food and Drug Administration (FDA) with the establishment of the Bureau of Biologics. By 1971, regulations had been established for more than 80 generic biological products employed for passive and active immunization. More recently, the Bureau of Biologics (as the Office of Biologics Research and Review [OBRR]) was combined with the Bureau of Drugs in the FDA to form the Center for Drugs and Biologics. Following the transfer of the Division of Biologic s Standards to the FDA in 1972, procedures were developed for the review of safety, effectiveness, and labeling of biologics. The Bureau of Biologics established outside consultant panels, three of which were concerned with vaccines and antitoxins. These panels reviewed vaccines, toxoids, and products used for passive immunization against bacterial diseases; viral and rickettsial vaccines and products used for passive immunization against viral diseases; and bacterial preparations "without U.S. standards of potency" (e.g., older products such as "mixed respiratory vaccines. The panels were charged with evaluating the generic safety and efficacy of all vaccines, immuno- globulins, and antitoxins, and with assessing the individual products. After evaluating the safety and efficacy of a manu- facturer's preparation, the panels' options were to recommend maintenance of licensure, maintenance of licensure for a limited number of years until further evidence of efficacy could be obtained (only for products deemed to be safe), or revocation of licensure. The final reports of these panels were submitted to the Commissioner of the FDA by 1979. Increasing evidence in the early 1900s of the effectiveness of diphtheria antitoxin and smallpox vaccination led to the idea that many or all infectious diseases might be amenable to immunologic prevention and therapy. Tetanus antitoxin, prepared in horses, came into general use in the military during World War I. For the first few months of the war, antitoxin was not employed by the British, and monthly rates of tetanus per 1,000 wounded reached the extraordinary figure of 32.9 With the advent of antitoxin, the British rate was reduced to 1.2. For U.S. wounded during World War I, to whom tetanus antitoxin was given universally, the rate was 0.16 per 1,000.9 Between the two world wars, tetanus toxoid was developed; by 1940, it was obligatory in the French army,9 and its mandated use for U.S. military during World War II kept the number of cases of tetanus in the U.S. Armed Forces to 12.10 By the late 1940s, tetanus toxoid

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18 was recommended as a routine public health measure for all children in the United States and usually was administered in combination with diphtheria toxoid and pertussis vaccine. The ability to induce immunity to diphtheria in animals with diphtheria toxin suggested that the same could be applied to man. The first preparation for active immunization against diphtheria was a mixture of toxin and antitoxin, and was introduced in 1913.11 Although effective, this product was not entirely satisfactory because of instability of the mixture and allergic reaction of some recipients to horse serum. Diphtheria toxoid (toxin inactivated by formalin) was developed in the early 1920s, and it has been used, with minor modifications, since the mid 1930s. The first definitive experiments with pertussis vaccine were conducted in the 1920s.l2 Because the portions of the pertussis organism responsible for clinical immunity to whooping cough had not been identified, the vaccine was composed of whole, killed organisms. Progress in improving the vaccine was slow, and it was still considered experimental in the early 1940s;13 by the late 1940s, however, several studies had demonstrated its efficacy.14'15 The pertussis bacterium has been unusually slow in yielding its biological secrets, and as a consequence current U.S. vaccines, though better standardized, still contain the whole, killed organism. Some progress has been made recently, however, in improving our understanding of this organism and its relationship to human disease and immunity.16 After World War II, remarkable advances were made in the develop- ment of vaccines for other diseases. Such developments were made possible by better understanding of the microorganisms involved, advances in immunology, and the use of cell culture techniques for the propagation of viruses. In rapid succession, viral vaccines were developed for the control of poliomyelitis, measles, rubella, and mumps. Safe, effective vaccines were developed for use under special circumstances in individuals in jeopardy from rabies (replacing older vaccines made from central nervous system tissues of animals), adenovirus infections, meningococcal disease, and others. It is clear that vaccines widely employed as public health measures in the United States and other industrialized countries have had an enormous impact on morbidity and mortality. Major achievements include the following:17~18 The last confirmed cases of smallpox were reported in 1977; in May 1980, the World Health Organization announced global eradication of smallpox.17 Reported U.S. rubella cases dropped from 57,686 cases with 29 deaths in 1969 to 2,325 cases and 4 deaths in 1982. The incidence of measles in the United States decreased from 894,134 reported cases with more than 2,250 deaths in 1941 to 1,497 reported cases and 2 deaths in 1983. The incidence of mumps in the United States dropped from 150,000 reported cases in 1968 to fewer than 3,500 reported cases in 1983. The average incidence of diphtheria in the United States between 1980 and 1984 was 3 cases per year with 1 or no deaths. In contrast,

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19 in the late 1950s the number of reported cases averaged more than 1,000 per year with about 7S deaths per year. Reported U.S. tetanus cases and deaths dropped steadily from a high of 601 cases in 1948 to fewer than 95 cases in 1983. Paralytic poliomyelitis, which afflicted more than 57,000 persons in the U.S. in 1952, is now a rarity; fewer than 4 cases were reported in 1984. The incidence of pertussis in the United States dropped from a high of 265,269 reported cases with more than 7,500 deaths in 1934, to fewer than 2,000 cases with only 4 deaths in 1982.18 Much of the success in the United States can be attributed to the high levels of vaccination among young children that result from the school immunization laws. In the developing world, only about 30 percent of children are vaccinated. THE PRESENT Twelve commercial manufacturers (five of which only produce vaccines abroad), two state laboratories, and one university are licensed to produce one or more vaccines for use in the united States. Vaccines against 20 different infectious diseases are marketed, several in various combinations. Three are licensed for use in the military only. Seven vaccines (pertussis; poliomyelitis viruses 1, 2, and 3; measles virus; mumps virus; and rubella virus; and the diphtheria and tetanus toxoids) are recommended for routine administration to all children. The other vaccines are intended primarily for use in groups of individuals who are at special risk because of circumstances such as age, exposure, life-style, or underlying health problems.- Often, these vaccines have very limited use; an example-is anthrax vaccine, which is recommended only for persons who work with animal hides and a few laboratory personnel who come into;contact with the organism. Many other infections should be amenable to control by immunization, and a variety of potential vaccines are in different stages of development.l9 Vaccines for varicella (chicken pox) and rotavirus diarrhea are being evaluated and probably will be licensed soon.* Studies of vaccines for hepatitis A, both types of herpes simplex infections, cytomegalovirus, gonorrhea, and group B streptococci are in progress. Prospects for vaccines against various viral respiratory and intestinal illnesses are good. The whole field of immunization against parasitic scourges, such as malaria and schistosomiasis, is only beginning to develop. In contrast to the trial-and-error fashion in which the earliest vaccines, such as those for smallpox and diphtheria, were developed, most current vaccine innovation is based on increasing knowledge of - *A vaccine against Hemophilus influenzae type b, the most frequent cause of meningitis in young children, was licensed April 12, 1985.

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20 microbiology, mechanisms of infection and immunity, and the cellular biology of the infecting organisms, including basic biochemical structures and molecular genetics. These developments offer promise of immunologic prevention of many widespread infectious diseases that hitherto have not been amenable to control, an-d will help meet new needs for vaccines. Changes in life-style, hygiene, and the environment cause shifts in the patterns of infectious diseases. Advances in medicine also produce new target populations, e.g., transplant patients and others whose immune systems have been suppressed for therapeutic reasons. Development of Vaccines and Recommendations for Vaccine Use The development of a new vaccine to the point of application for licensure is a complex, arduous, and expensive process involving both public- and private-sector participants. The initial steps in the process include assessments of the impact of the infectious disease (measured by rates of mortality, acute morbidity, and permanent sequelae in the population); of the estimated cost of the disease and the projected costs of development, production, and administration of the vaccine; and of the vaccine's ranking among other health care priorities. Of major importance to commercial manufacturers is the likely utilization, i.e., the market, which is dependent both on acceptance of the vaccine by the public and the enthusiasm of physicians and other health care providers. Assuming that the health and economic impacts of the disease appear to warrant pursuit of a vaccine, many problems of a technical and practical nature must be identified and solved. Identification of the causative organism is only the first step. The pathogenesis of the infection (how the organism produces the disease), what components of the organism are responsible for the manifestations of the disease (infectivity, virulence, pathogenicity) and which determine subsequent immunity, and whether current tech- niques can be anticipated to produce a safe and effective immunizing agent all represent crucial questions. The basic research necessary to answer these questions, which is often extremely time-consuming and expensive, usually is performed by investigators exploring the natural history of the disease. Commercial manufacturers rarely consider the possibility of a specific vaccine until the groundwork has been laid, typically by academic or government researchers. The most basic technical requirement is the ability to consistently produce the organism (maintaining its immunogenicity) in the laboratory in sufficient quantities for study and, ultimately, for vaccine production. A reliable means must be found to measure immunity without exposure to disease. Researchers also must determine if the organism exists as more than one immunologically distinct type. For example, there are more than 80 immunologically distinct types of pneumococci, and infection or immunization with one type generally produces strong immunity only to that specific type. Many questions depend on the nature of the organism. For example,

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21 in the case of an anticipated bacterial vaccine, can the immunity- producing components be separated from irrelevant, potentially toxic moieties? Can the immunogenic antigen of a virus be extracted or, employing techniques of genetic engineering, be incorporated into another organism? In the case of a potential live vaccine, can the virulence of the pathogen be attenuated in the laboratory, and can reversion to the more virulent form be avoided with certainty? The development of an animal model to evaluate toxicity, potency, and, if possible, clinical protection usually is desired. In addition, laboratory tests must be established, insofar as possible, to assess the toxicity and potency of the vaccine in a manner that correlates with test results in man. These steps to understanding an infectious disease and developing preventive measures such as vaccines are conducted with continuing formal and informal consultations among agencies of the federal government, concerned scientists, and manufacturers. conferences, often sponsored by federal agencies and professional societies and sometimes by manufacturers, provide useful opportunities to exchange advice, counsel, and ideas, and to coordinate efforts in the development of a vaccine. After the extensive and complex background work outlined above has been completed and it appears that the proposed vaccine offers promise of safety and efficacy, permission may be sought from the OBRR for studies in humans.20 By regulation, this involves filing a permit referred to as an IND (Notice of Claimed Exemption for Investigational New Drug). To obtain an IND, the responsible investigators must meet appropriate specifications that cover everything from evidence of sterility of the product to the qualifications of the investigators and the approaches to testing in humans. Full background data in support of the proposed vaccine and its use must be provided. Three sequential phases of evaluation must be described in an IND. Phase 1 constitutes initial testing of the vaccine in a small number of persons to determine first its safety and then its immunogenicity at various dose levels and for different routes of administration. Phase 2 studies include administration of the vaccine to a larger number of persons to obtain further data on adverse effects and the immune response, and, perhaps, limited evidence of disease prevention. Phase 1 and 2 studies often overlap, and the results provide the basis for Phase 3 studies, which are controlled field trials with sufficient study subjects to develop reasonable estimates of safety and efficacy. Efficacy usually is measured in terms of protection against clinical disease. Situations in which controlled field trials are not possible or ethical include the testing of an improved, presumably more efficacious vaccine for an otherwise fatal disease, such as rabies, for which there is already a vaccine that protects many or most persons. In these and other cases, it may be necessary to employ serologic or other methods to ascertain the development of immunity. The use of such surrogate methods requires firm evidence of a direct correlation between the results of the method and clinical protection In humans.

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22 By federal regulation, any Phase 1, 2, or 3 study conducted on a population by an institution, such as a university, must be approved by that institution's review committee for protection of human subjects. Strict regulations exist for the institutional review mechanism, and include monitoring of all studies at least once a year. Progress reports by the investigator also must be submitted at least annually to the FDA. It is generally desirable for Phase 3 studies to be conducted at more than one institution and by different investigators. The number of study subjects required varies with the disease and the vaccine, but usually is in the hundreds or thousands. It is important to ensure that there is adequate representation of all population groups for whom the vaccine may be recommended. The license application process includes review of all records of production, testing, and clinical evaluation by the OBRR. The product itself is submitted to laboratory testing by appropriate scientists at the OBRR, who also conduct on-site inspection of the production facilities. Customarily, although not by regulation, the OBRR convenes one or more meetings of the Vaccines and Related Biological Products Advisory Committee for full discussion and review of the product, its projected uses, and its labeling. When the OBRR is satisfied that the product is safe and effective, a license may be granted. Each marketed vaccine requires such a license, as does each vaccine manufacturer. Although hundreds or thousands of individuals may have received a vaccine prior to licensure, these numbers are insufficient to identify rare untoward events resulting from the vaccine. (A classic example of an unexpected, rare reaction was the Guillain-Barre syndrome that occurred at a very low rate in persons who received the swine flu vaccine in 1976 [Chapter 51.) Therefore, the OBRR encourages continuing surveillance of recipients as a vaccine becomes widely used. Any reports of untoward events must be made available by the manufacturer for review by the OBRR. After licensure, the manufacturer must submit data on each new production lot and samples of vaccine to the OBRR for testing. The OBRR also periodically reinspects manufacturing facilities. Recommendations for vaccine use in the United States are made by a number of advisory groups, most notably the Immunization Practices Advisory Committee (ACIP) of the U.S. Public Health Service, the American Academy of Pediatrics, through its Committee on Infectious Diseases, and the Committee on Immunization of the Council of Medical Societies, American College of Physicians (ACP). These committees maintain close liaison with each other and with the OBRR, thus assuring reasonable consistency between manufacturers' labeling and recommendations by the advisory bodies. The Department of the Army oversees efforts to develop vaccines needed to protect military personnel (and others at risk) from a range of pathogens not generally encountered by the U.S. civilian popula- tion.21 These include tropical disease pathogens and potential biological warfare agents. Research conducted for these purposes is often valuable in a broader context, e.g., contributions to the development of a vaccine for malaria. Recommendations for the use of

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23 these vaccines for military personnel are developed by the Armed Forces Epidemiological Board. As with vaccines for general public use, the ultimate availability of these vaccines depends on the willingness of a commercial manufacturer to undertake final development and production. These mechanisms for developing new vaccines, for pursuing licensure, and for establishing recommendations for use are complex and time-consuming, but are clearly necessary to ensure to the extent possible that marketed vaccines are acceptably safe and effective. Further, it is to be expected that the nascent technology for the production of vaccines by genetic engineering will increase the responsibilities and activities of the OBRR and public advisory groups concerned with recommendations for vaccine use. THE FUTURE New technologies and better understanding of the immune process have launched a new era in the field of immunization. On the horizon are effective vaccines for a wide spectrum of human ailments, the viral diarrhea! diseases, malaria, and other parasitic diseases responsible for enormous morbidity and mortality. Many current vaccines (especially the killed viral and bacterial vaccines) contain superfluous materials (some derived from the production substrates) that could contribute to reactivity and that are irrelevant to the production of immunity. Through further research, we may soon have the capability to replace existing vaccines with specific antigens that are more efficacious, safer, and possibly less expensive. It is hoped that these vaccines with improved immunogenicity and stability will lead to greater utilization of immunization throughout the world. Millions of children in less-developed countries are disabled or die from diseases that are preventable. Also, no country can be considered safe from a disease as long as it persists in other populations--geographic isolation from disease threats is an unrealistic concept in the current age of extensive travel. Prospects for new vaccines stem primarily from advances in genetic engineering and the ability to define the antigens responsible for inducing clinical immunity. Current laboratory goals are to determine the precise biochemical structures of these antigens and to synthesize them. The greatest advances have occurred in the area of viral vaccines, but it is expected that these techniques also will be applicable to the production of bacterial vaccines and, ultimately, parasitic vaccines. Among the approaches available are:22 Recombinant DNA Techniques In this approach, the genetic material responsible for production of the immunity-inducing antigen is incorporated into the genetic apparatus of another replicating virus, bacterium, yeast, or animal cell. The result is a hybrid organism that replicates and produces the antigen desired, often in large amounts. A vaccine is made from the purified antigen. The production

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24 of a potential new hepatitis B vaccine illustrates this process: the DNA sequence coding for hepatitis B surface antigen is incorporated into yeast and activated to synthesize the antigen, which is then purified. Preliminary tests indicate that the product is effective in humans.23 A variant of the same approach that shows promise involves incorporation of the gene for a desired immunizing antigen into a virus that produces a generally benign infection in man, such as the vaccinia virus (smallpox vaccine). Preliminary experiments in nonhuman primates indicate that this approach may be efficacious. These recombinant DNA vaccines offer promise of effective products that are less reactive and less expensive. Polypeptide Synthesis The ability to define the amino acid sequence of protein subunits (peptides) has allowed researchers to characterize the structures of some immunogenic peptides. Based on this knowledge, several viral antigens have been synthesized. These early man-made antigens are less immunogenic than natural viral antigens, but researchers believe that this situation will improve with further study. In some cases, adjuvants may be required to boost immunogenicity. The synthetic antigens, because of their purity, are expected to be less reactogenic and safer than their natural counterparts. Also, the cost of large-scale production of these antigens probably will be relatively low. Specific Attenuation of Pathogens The third type consists of modified or attenuated live pathogens, usually viruses. The live, attenuated oral poliovirus vaccine is one example of how this approach can be used. The principal disadvantage of these vaccines is that they contain viruses that have the potential to revert to a virulent, disease-producing form. Fortunately, increasing knowledge of molecular biology is providing a better understanding of many of the changes or mutations that occur in the process of attenuation. Comparing the nucleotide sequences of fully attenuated viruses with those of partially attenuated or fully virulent forms ultimately may provide a mechanism for early recognition of potential mutation of a live vaccine to the more virulent, disease-producing form. Methods of manipulation that result in an attenuated virus incapable of reversion would be even more desirable. Two possible approaches are being studied. One involves gene reassortment, segregation of genes responsible for protection from those responsible for disease manifestations, to produce a nonvirulent but still infectious variant of the same virus. The second approach is "deletion mutation, n which would result in the production of a mutant that is incapable of reversion to virulence because it lacks a specific gene. Anti-Idiotype Antibodies Most remarkable are prospects for the development of anti-idiotype antibodies. The idiotype of an antibody molecule is a recognition site located at or near its antigen-binding site;22 the idiotype acts as an antigenic site when the body makes anti-antibody molecules (a natural immune system mechanism used to control the level of antibodies in the blood). In some cases, the anti-idiotype antibody appears to resemble the antigenic site of the original antigen and can induce a similar immune response. For example, anti-idiotype antibodies directed against antibody to the

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~5 hepatitis antigen HBsAg may induce protection against hepatitis. Theoretically, this approach could produce a vaccine that contained no viral components whatsoever,~but a variety of technical and safety questions must be resolved before its full potential is known. Based on these and possibly other techniques, prospects for new and better vaccines are considerable. Their development, however, may be impeded by the same problems (discussed in subsequent chapters) that deter development of vaccines by traditional methods. These problems must be resolved before the full public health benefits of new approaches to vaccine development can be achieved. REFERENCES AND NOTES 13. Mortimer, EeAe r Jr. 1978. Immunization against infectious disease: active immunization programs are endangered by complacency and litigation. Science 200:902-907. Dixon, C.~. 1962. Smallpox. Boston: Little, Brown. Hutt, P.B. 1983. Investigations and reports respecting FDA regulations of new drugs (Part 1~. Clin. Pharmacol. Ther. 33:537-548; 674-687. Pasteur, L. 1884. Methode pour prevenir la rage aprbs morsure. C.R. Acad. Sci. 98:457-464. Andrewes, F.W., Bulloch, W., Douglas, S.R., Dreyer, G., Gardner, A.D., Fildes, P., and Ledingham, J.C.G. 1923. Diphtheria: Bacteriology, Pathology, and Immunology. London: His Majesty's Stationary Office. Kondratas, R.A. 1982. Death helped write the biologics law. FDA Consum.- 16:23-25. Editorial. 1894. A timely topic. J. AMA 23:919-920. JAMA. 1894. Public health. JAMA 23:923-924. Holmes, W.H. 1940. Pp. 351-382 in Bacillary and Rickettsial Infections. New York: MacMillan. Edsall, G. 1959. Report to the council on drugs. Specific prophylaxis of tetanus. JAMA 71:417-427. 11. Dick, G.F., and Dick, G.H. 1929. Immunization against diphtheria. Comparative value of toxoid and toxin-antitoxin mixtures. J. AMA 92:1901-1903. Miller, D.L., Alverslade, R., and Ross, E.M. 1982. Whooping cough and whooping cough vaccine: the risks and benef its debate . Epidemiol. Rev . 4 :1-24. Holmes, W.~. 1940. Whooping-cough or pertussis. Pp. 394-414 in Bacillary and Rickettsial Infections, W.H. Holmes, ed. New York: MacMillan. 14. Kendrick, P., and Eldering, G. 1939. A study in active immunization against pertussis. Am. J. Hyg. 29:133-153. Sako, W. 1947. Studies on pertussis immunization. J. Pediatr. 30:29-40. Manclark, C .R. 1981. Pertussis vaccine research. Bull. WHO 59: 9-15.

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26 WHO Chronicle. 1980. Decisions of the health assembly. Decla- ration of global smallpox eradication. WHO Chron. 34:258. 18. Eddins, D. 1985. Personal communication, Centers for Disease Control, Atlanta, Ga. 19. Institute of Medicine. 1985. New Vaccine Development: Establishing Priorities, Volume 1. Diseases of Importance in the United States. Washington, D.C.: National Academy Press. This report presents the findings of the Institute of Medicine's Committee on Issues and Priorities for New Vaccine Development, which was asked by the National Institute of Allergy and Infectious Diseases, NIH, to design a comprehensive approach to setting priorities for accelerated vaccine development. The method developed by the committee is based on a quantitative model in which vaccine candidates are ranked according to two principal characteristics: expected health benefits (reduction of morbidity and mortality) and expected net costs of achieving the benefits (which are sometimes negative, i.e., savings). Volume 1 of this study describes application of the model to diseases of importance in the United States. volume 2 will evaluate the usefulness of the model in setting priorities for vaccines needed by technologically less developed nations. 20. Food and Drug Administration. 1966. New drug regulations. Amendment to part 130. Fed. Regist., March 24, 1966, 31 F.R. 4891. 21. Walter Reed Army Institute of Research. 1981. Proceedings of the Workshop on Infectious Disease Threats to the Rapid Deployment Force: Preventive Strategies, July 14-15, 1981. Washington, D.C.: Walter Reed Army Institute of Research. ^2. Chanock, R.~. 1984. Summary. Pp. 439-446 in Modern Approaches to Vaccines. Molecular and Chemical Basis of Virus Virulence and Immunogenicity, R.M. Chanock and R.A. Lerner, eds. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. 23. Jilg, W., Schmidt, M., Zoulek, G., Lorbeer, B., wilkse, B., and Deinhardt, F. 1984. Clinical evaluation of a recombinant hepatitis B vaccine. Lancet II:1174-1175.