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1 Introduction Ciro A. de Quadros, M.Do, M.P.H. Director, Division of Vaccines and Immunization Pan American Health Organization, Washington, D.C. HISTORY AND PROSPECTS FOR DISEASE ERADICATION The concept of "disease eradication" originated in the late 18th cen- tury, when Edward lenner inoculated lames Phipps with the cowpox virus and subsequently infected him with the lethal smallpox virus. The inocula- tion protected Phipps from the smallpox, demonstrating the first successful vaccination against an infectious disease. lenner concluded, "This practice would wipe out this scourge from the face of the earth" (penner, 1801~. Since then, eradication has been defined in many different ways. In 1997, the Dahiem Workshop on the Eradication of Infectious Diseases defined several levels of deliberate efforts of disease control, including eradi- cation, as follows (Dowdle and Hopkins, 19981: . Control: reduction of disease incidence, prevalence, morbidity, and mortality to acceptable levels; . Elimination of disease: reduction to zero incidence of disease in a defined geographic area; · Elimination of infection: reduction to zero incidence of infection caused by a specific agent in a defined geographic area; · Eradication: permanent reduction to zero worldwide incidence of infection caused by a specific agent; · Extinction: the specific agent no longer exists in nature or the laboratory. 22
INTRODUCTION 23 The first three levels of disease control require that intervention mea- sures be continued in order to reduce and prevent reestablishment of trans- mission. Once eradication anchor extinction are/is achieved, intervention measures can be discontinued. These definitions were debated at the Conference on Global Disease Elimination and Eradication as Public Health Strategies in Atlanta, Geor- gia, in February, 1998. There was no consensus on the proposed defini- tions, so a small group convened after the conference to continue the de- bate. The group concluded that because the terms elimination and eradication were synonymous in many languages, thus they proposed that elimination be discontinued with subsequent use of the following three levels of deliberate efforts at disease control:) . i' Control: the reduction of disease in a defined geographic area; ntervention measures cannot be discontinued; . Eradication: the absence of a disease agent in nature in a defined geographic area; control measures can be discontinued once the risk of importation of the agent is no longer present; · Extinction: the specific disease agent no longer exists in nature or the laboratory. With these definitions, the term eradication can be used in different geographic levels, such as "eradication of a disease in a given area or country," "eradication from a region or regions of the world," and, ulti- mately, the "eradication of a disease globally." PRECONDITIONS FOR DISEASE ERADICATION Several preconditions must be met before eradication can be consid- ered. These include biological characteristics of the infectious agent, as well as various social and political factors outlined by the 1997 Dahiem Work- shop (Dowdle and Hopkins, 1998~: The microbial agent can infect only humans. · There cannot be a non-human reservoir for the microbial agent. · The infection must induce life-Ion" immunity. · There must be a too! or intervention that effectively interrupts the chain of transmission of the infectious agent from one individual to an- other. 1These definitions reflect the author's experience and are not necessarily consistent with those of other authors contributing to this book.
24 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION . There must be political committment in the form of sufficient hu- man and financial resources to carry the initiative from beginning to end. · The burden of disease must be considered of great public health importance with broad international impact. HISTORY: SUCCESSES AND FAILURES Past major attempts at disease eradication are noted in Table 1-1. Not included in Table 1-1 is the 1909 initiative of Dr. C. W. Stiles, U.S. Public Health Service, with support by the Rockefeller Foundation, to interrupt hookworm transmission in the southern United States. This effort was later expanded to 56 countries in 6 continents and 29 island groups. Other initiatives not included are those aimed at the eradication of other helmin- thic diseases and those aimed at disease vectors, such as the successful Soper initiative to eradicate Anopheles gambiae from Brazil and the failed attempt to eradicate Aedes aegypti from the Americas. Yellow fever eradication efforts failed majorly because the disease did not fulfill the biological preconditions for eradications yellow fever has a non-human reservoir (i.e., it is transmitted by mosquitoes). Smallpox was the first globally eradicated disease. Smallpox eradica- tion was an extraordinary initiative which set the example for future dis- ease eradication programs. The smallpox eradication program was initially based on the premise that mass vaccination campaigns would stop trans- mission, but the program managers soon recognized that this strategy was not sufficient to achieve the objective. Cases of smallpox continued to occur in areas of the world reporting very high immunization coverage. There- fore, in 1967 the focus of the program switched from vaccination alone to TABLE 1-1 Major Attempts at Disease Eradication Year Program Leader Program (Location) 1801 Edward Jenner 1911 William Gorgas 1915 Rockefeller Commission 1950 Fred Soper 1 954 WHO 1 955 WHO 1958 Viktor Zhdanov 1985 PAHO 1986 WHO 1988 WHO 1 994 PAHO Smallpox (Global) Yellow Fever (Americas) Yellow Fever (Global) Smallpox (Americas) Yaws (Regional) Malaria (Global) Smallpox (Global) Polio (Americas) Guinea Worm (Global) Polio (Global) Measles (Americas)
INTRODUCTION 25 a two-prongect effort combining vaccination with surveillance and contain- ment. The main lesson to be learned from the success of smallpox eradication is that all of the preconditions for disease eradication were met: All biological conditions for disease eradication were fulfilled. There was an effective too! available for interrupting the chains of transmission (i.e., an effective heat-stable vaccine easily administered with a bifurcated needle). tions. Endemic countries were politically committed to the effort. The strategy was clearly understood at all levels. Resources were made available when required. Strong management was present at all levels. Continuing research was available to guide the strategy. Adequate international coordination supported program opera- International and national staff were highly motivated to see the program succeed. LESSONS FROM RECENT EXPERIENCES: POLIO AND MEASLES ERADICATION IN THE AMERICAS The lessons learned from smallpox eradication were subsequently ap- plied to the Pan American Health Organization (PAHO) initiatives to eracli- cate both poliomyelitis and measles from the Americas. Polio The polio eradication initiative was launched in May 1985, with the goal of interrupting transmission of the disease by the end of 1990. The strategy was based on the initial proposals of Albert Sabin, who suggested that polio transmission could be interrupted if the oral polio vaccine (OPV) were administered simultaneously to a large number of children (i.e., under five years of age) in a very short period of time (i.e., in one day or week). The effectiveness of this strategy was demonstrated in Cuba in the early 1960s, where transmission was stopped after the first two rounds of na- tional immunization days (NIDs). In 1980, Brazil initiated a similar pro- gram which had a tremendous positive impact on polio incidence after the first few rounds of NIDs. Thus, the eradication strategy in the Americas relied on biannual NIDs held at least four weeks apart. OPV was administered to all children under five years of age as a supplement to routine vaccinations administered by each country's health system infrastructure.
26 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION Surveillance was a key component of the program from day one. How- ever, countries free of poliomyelitis when the program was launched did not want to report cases of suspect poliomyelitis; they were concerned that the reports would affect tourism. So surveillance targeted acute flaccid paralysis (AFP) instead. A small network of laboratories nine for the entire region" was established for the purpose of investigating clinical cases of AFP and determining if any were due to the infection with the wild poliovirus. The labs were closely supervised and subject to routine quality control. There were four pieces of information gathered during implementation of the initiative that proved critical to the program's success. First, the surveillance network that targeted AFP was expanded from an initial 500 to over 20,000 sites, covering every district in each country. The initial network of reporting units primarily involved main hospitals and rehabili- tation clinics. But when it was learned that patients were seeking initial care in the peripheral health units before eventually being referred to the tertiary care level, the reporting unit networks were extended to include these pe- ripheral health units as well because by the time patients arrived at hospi- tals and rehabilitation clinics, it was usually too late for the appropriate collection of stools necessary for identification of the virus. Second, the analysis of epidemiological data that had accumulated over the first couple of years indicated that in the absence of wild poliovirus, cases of AFP occurred at a rate of at least one case per 100,000 persons under IS years of age. This rate became one of the primary indicators of a country's compliance with adequate surveillance. Third, as the program was winding down in Brazil, an outbreak of poliovirus type-3 was cletected. Analysis of the outbreak indicated that the composition of the trivalent vaccine did not contain adequate quantities of poliovirus type-3; therefore, the manufacturers were asked to reformulate the vaccine. This highlights the need to constantly reevaluate and improve the tools available for disease control. Fourth, despite high immunization coverage during NIDs, cases contin- ued to occur in several countries. The empiric observation that outbreaks of polio would always originate in the same areas of a given country and subsequently spread to other parts of the country indicated that the poliovi- ruses remained in certain reservoirs during periods of low incidence. This observation was confirmed by molecular epidemiology from Dr. Olen Kew and his colleagues, who determined the geographical distribution of differ- ent genotypes of the three polioviruses types in the region. These findings were applied to the program strategy and allowed for complementing NIDs with "mopping-up" operations in the main reservoirs of the disease The introduction of these operations enhanced immunity in those reservoirs and interrupted the last chains of transmission.
INTRODUCTION 27 The ways by which these four pieces of information fed back into the program strategy demonstrate the need to constantly analyze information generated in the field in orcler to adjust eradication strategies. The global polio eradication initiative is based on lessons learned from polio eradication in the Americas. However, global implementation of all of the various components of the strategy proven so effective in the Ameri- cas has been very slow. Surveillance was introduced very late in the pro- gram, and only recently have mopping-up operations been included as an essential part of program operations. These tactical mistakes, coupled with the lack of funds and civil unrest in many endemic countries, accounts for the clelay in completion of the global program. Measles After the Americas region was certified polio-free in September 1994, the PAHO Directing Council launched an initiative to eradicate measles from the Americas by the year 2000. The measles vaccine had been intro- duced in most countries of the region in the 1980s and had been used simultaneously with OPV during NIDs. It was no surprise, therefore, that by the time polio was declared eradicated, measles incidence was low. In fact, Cuba and the English-speaking Caribbean had already launched measles eradication programs. Cuba started its major campaign against measles in 1987, and the English-speaking Caribbean in 1990 both with a very high degree of success in interrupting indigenous transmission. The strategy for interrupting measles transmission was based on changes in the epidemiology of the disease after the vaccine had been intro- duced. In the pre-vaccine era, all children contracted measles at an early age; by age five, nearly 90% of all children had contracted the disease. Disease outbreaks occurred every one and a half to two years, as new cohorts of susceptible children were introduced into the population. As the outbreaks occurred, the population of susceptibles diminished and the dis- ease subsided, until a new cohort of susceptibles again fueled transmission of the infectious agent. With the introduction of vaccine, measles epidemiology changed radi- cally. Epidemics began to occur less frequently, depending on the level of coverage in a country. In some countries, several years may elapse between epidemics. As a result, some groups of children remain susceptible into adulthood, thus the incidence of disease has increased among older children and young adults. Another important criteria for developing a measles eradication strat- egy was vaccine effectiveness. Measles vaccine is only about 90-95°/O effec- tive when administered to children older than 12 months. Therefore, it was expected that even in programs achieving high vaccination coverage using
28 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION either one or two doses, many children would still fail to sero-convert to an immune status. Given these considerations, the strategy used in Cuba and the English- speaking Caribbean- and subsequently applied in all other Latin American countries aimed at interrupting the chains of transmission among those most affected by the disease. Analysis of attack rates by age group indicated that in most Latin American countries, the majority of measles cases oc- curred in children under IS years of age. The recommended PAHO strategy relied initially on four main compo- nents: 1. A one-time-only mass campaign conducted in a very short period of time during the low season for disease transmission and aimed at vacci- nating all children between one and fourteen years of age with one dose of measles-containing vaccine (either M, MR, or MMR) was recommended. These "catch-up" campaigns generally achieve 90-95% coverage of the target population. 2. Maintenance of a routine measles vaccination program aimed at vaccinating all new birth cohorts immediately after these children reach 12 months of age was recommended. These "keep-up" vaccination programs generally target 90-95 °/O coverage. 3. Since many children who are not vaccinated or fail to sero-convert remain susceptible into adulthood, mass "follow-up" campaigns targeting all children between one ant! four years of age were recommended every four years. The interval of four years was decided by taking into account the coverage achieved in most countries in the Americas: given the present 80-90% level of coverage for children between twelve and twenty-four months of age, it takes approximately four years for the susceptible popula- tion to grow to a point where it could fuel an epidemic if the virus were ever introduced into the population. 4. Surveillance shouIci be simple and sensitive enough to detect cases of fever and rash disease in all situations where health workers suspect measles. This requires that trained epidemiologists investigate suspected cases, and blood specimens be collected for laboratory testing. This activity has been supported by the establishment of a network of laboratories dedi- cated to performing serological tests and virus isolation. The results from the measles campaign have been very successful. Measles transmission is believed to be interrupter! in most countries of the Americas. Only 1,500 cases the lowest number ever reported for this region were reported during 2000. The first lesson from this initiative is that the administration of an injectable vaccine that does not immunize early after birth can be used to
INTRODUCTION 29 interrupt disease transmission. The second lesson is that while measles transmission has been curtailed in the region, most cases are now imported from the industrialized countries of Europe and Asia, for example France, Germany, Italy, and Japan. A third lesson relates to the economics of measles eradication. A recent cost-effectiveness study (Arnab et al., submitted for publication) of measles eradication in the Americas shows that while the extra expenditure to achieve interruption of transmission has been approximately $240 million over the last six years, approximately $430 million has been saved in treat- ment costs. Like the eradication of smallpox and polio, the eradication of measles will be a major cost-saving operation for the health sector. The fourth lesson refers to the impact of fever and rash surveillance on detecting the burden of other diseases. For example, as soon as measles disappeared from most countries, rubella was identified as a major public health problem. Some countries are now planning to interrupt rubella trans- mission as a first step toward eradication of rubella and its serious sequelae, congenital rubella syndrome (CRS). This has already been achieved in Cuba and several areas of the English-speaking Caribbean, and is now being attempted in Chile and Costa Rica. The strategies being used for rubella eradication are based on the lessons learned from measles eradication. Success of Polio and Measles Eradication in the Americas The efforts toward polio and measles eradication in the Americas have been possible only because the diseases meet the main preconditions for eradication outlined previously. Notably, there was a very high level of political commitment and collaboration among governments of the region and a very effective collaboration between regional governments and the international agencies involved. Intra-regional collaboration, which rose to levels never achieved previ- ously, has helped strengthen other regional initiatives, such as joint pur- chases of vaccines through a PAHO revolving fund. It has also accelerated control of other diseases, such as neo-natal tetanus, and the launching of other disease eradication initiatives. For example, at the end of the first day of polio immunizations cluring the three-day campaign to halt the vaccine- derived polio outbreak in the Dominican Republic in December 2000, the government of the Dominican Republic realized that there would be vac- cine shortage in view of the high campaign turn-out. A direct call between the ministries of health of the Dominican Republic and Haiti resulted in 400,000 doses of OPV being driven across the border from Haiti within eight hours, ensuring successful vaccination of 1.2 million children under five years of age. Subsequently, in January 2001, the Dominican Republic
30 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION lent 1,000 thermoses to Haiti to facilitate the logistics of vaccine distribu- . . . . . tlon ~ urlng t nelr po 10 CampalgIl. The availability of resources for both the polio and measles eradication initiatives was partly contingent on the establishment of an operational timeline for completion. Such operational timelines are important for all disease eradication programs to prevent the institutional fatigue that would develop within governments and collaborating partners when timely objec- tives are not met or cannot be measured for success. A final lesson from the polio and measles eradication efforts in the Americas is that the polio eradication effort in particular had a very positive impact on strengthening the health systems/services infrastructure. This is well documented by a study conducted in several countries in the Americas by the Commission on the Impact of the Expanded Program on Immuniza- tion and the Polio Eradication Initiative on Health Systems in the Americas, chaired by Dr. Car! Taylor (PAHO, 1995~. i: PROSPECTS FOR ERADICAMON OF OUR ~ DISEASES The 1998 Conference on Global Disease Elimination and Eradication as Public Health Strategies concluded that there are three viral diseases besides polio that are potentially eradicable at this time, provided that all preconditions outlined above are met. These diseases are hepatitis A, measles, and rubella. The conference participants concluded that other viral zoonotic dis- eases, such as yellow fever, rabies, and Japanese encephalitis are not eradi- cable at this time because their infectious agents all have non-human reser- voirs. Nor are influenza, mumps, and varicelia, even though they all have available vaccines. Eradication of influenza virus is impeded by its antigenic instability, frequent mutations, and regular reassortment with influenza virus circulating through birds and livestock, all of which contribute to the need for constant reformulation of the vaccine. Although mumps may be biologically eradicable, the low priority accorded to this disease makes it operationally unfeasible for eradication. Finally, the long-term carrier state among herpes zoster-infected individuals suggests that eradication of vari- celia is not feasible. Even though the disease is considered eradicable at this time, hepatitis A virus eradication efforts face considerable impeding factors. The hepatitis A vaccine is costly and cannot be used in infancy or early childhood. Further research is needed to develop a hepatitis A vaccine formulation for use in children under two years of age. The major impeding factor for rubella is the societal feasibility of ru- belia eradication. The burden of rubella, particularly of CRS, is not well known in most developing countries.
INTRODUCTION 31 As global eradication of polio nears completion, measles becomes the next target for global eradication. Eradication strategies developed in the Americas have proven effective in interrupting transmission among large geographic areas for long periods of time. Even in the presence of imported cases, transmission has not been reestablished in those countries fully imple- menting the strategy. However, a major inhibiting factor is that measles is not perceived as a priority in the industrialized world. Plus, the health infrastructure among developing countries is not strong enough to maintain high vaccination coverage in all birth cohorts, which means that the re- quired frequency of mass immunization campaigns is high and the associ- ated cost enormous. CONCLUSION The global eradication of smallpox, the eradication of poliomyelitis from the Americas and its near-global eradication, and the near-eradication of measles from the Americas demonstrate the tremendous progress achieved in disease eradication efforts. However, the recent outbreak of poliomyelitis in the Americas caused by vaccine-derived poliovirus type-1 suggests caution in determining when to launch eradication initiatives. The interruption of wild poliovirus trans- mission in the Americas and other parts of the world has relied heavily on the use of oral live-attenuated polio vaccines which have a long history of safety and effectiveness. Although it has been known for many years that live-attenuated vaccines can revert to virulence, this fact has always been considered of little epidemiological significance. In 1964, for example, Wiina Woods and Fred Robbins wrote in the American Journal of Hygiene that, "The remote possibility exists that a vaccinee, at any particular time, might be excreting a virulent strain. The large amount of evidence that has been accumulated concerning the safety of type 1 vaccine virus would indicate that this is not a matter of any great practical importance" (Woods et al., 1964~. Although the occurrence of this phenomenon in Hispaniola is a rare event and has been observed only twice before, in Egypt and China, ad- vances in sciencefrom the monkey virulence test of the 1960s to the genetic sequencing of viruses are providing newer perspectives on how to deal with these problems. Undoubtedly, the vaccine-derived outbreak in Hispaniola will make the discontinuation of control measures much more difficult, especially once wild polioviruses are eradicated from the worIcl. As previously defined, "Eradication is the absence of a disease agent in nature in a defined geographic area, and control measures can be discontin- ued once the risk of importation is no longer present." Therefore, while it is important that we accelerate activities aimed at the final interruption of
32 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION wild poliovirus transmission in the world, it is also important that we accelerate research on the optimal strategy for the final discontinuation of . . . pO 10 vaccination. By removing a major health threat, eradication of disease provides one of the greatest health benefits for humankind. It is the quintessential ex- ample of health equity, as all humankind reaps the benefits and it allows for immeasurable cost savings. In the future, the biotechnology revolution will likely yield numerous new vaccines, even for diseases considered chronic ant! degenerative, thus it is very important that we continue to search for those diseases that could eventually be eradicated. As Louis Pasteur pointed out, "It is within the power of man to eradicate infection from the earth" (Dubos and Dubos, 1953~. REFERENCES Arnab A, Diaz-Ortega JL, Tambini G. de Quadros CA, and Arita A. Cost-effectiveness of measles eradication in Latin America and the Caribbean: a prospective analysis. Submit- ted for publication, 2001. Dowdle WR and Hopkins DR, eds. 1998. The Eradication of Infectious Diseases (Report of the Dahlem Workshop on the Eradication of Infection Diseases, Berlin, March 16-22, 1997). New York: John Wiley & Sons. Dubos R and Dubos J. 1953. The White Plague: Tuberculosis, Man, and Society. London: Gollancz. Jenner E. 1801. The Origin of the Vaccine Innoculation. London: D.N. Shury. PAHO (Pan American Health Organization). 1995. The Impact of the Expanded Program on Immunization and the Polio Eradication Initiative on Health Systems in the Americas. Report of the Taylor Commission. Washington, DC: PAHO. Woods WA, Robbins FC, Weiss RA, Cashel J. and Kirschstein RL. 1964. Characteristics of sabin type 1 poliovirus after gastrointestinal passage in newborn infants. The American Journal of Hygiene 79(2):236-244.