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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Page 10
Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Page 26
Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Page 27
Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Page 28
Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Page 29
Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Page 30
Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Page 31
Suggested Citation:"1 Summary and Assessment." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Page 32

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Summary and Assessment Joshua Lederberg, Ph.D. Nobel Laureate and Sackler Foundation Scholar The Rockefeller University, New York, NY The successful smallpox campaign demonstrates that global eradica- tion of a disease is possible, given the necessary technical base, political commitment, and economic resources for immunization and continued sur- veillance. Currently, there are three infectious viral disease candidates for global eradication—polio, measles, and rubella—each of which closely sat- isfies necessary preconditions for eradication as outlined by the 1997 Dahlem Conference on Disease Eradication: (1) no animal reservoir for the virus is known or suspected; (2) sensitive and specific tools are available for diagnosis and surveil- lance; (3) transmission from one individual to another can be interrupted; (4) non-lethal infection or vaccination confers life-long immunity; (5) the burden of disease is important to international public health; and (6) political commitment to eradication efforts exists. Of the three diseases, poliomyelitis is likely the next candidate for global eradication. In the Americas, polio was eradicated in the early 1990s, and less than 3,000 cases were reported worldwide in 2000. The current goal is certification of global eradication by 2005. Measles stands next in line after polio, although no global goal has been set. In 2000, there were only 1,500 reported cases of measles in the Americas; however, measles still causes 900,000 deaths each year worldwide and accounts for some 30% of 1

2 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION all deaths due to vaccine-preventable diseases. Rubella, which generates 100,000 cases of congenital rubella syndrome, is the furthest from global eradication. Many attributes of the disease uniquely favored smallpox eradication. Its characteristic clinical features made diagnosis and surveillance for infec- tion much easier than they are for polio, measles, and particularly rubella. Every infected person had a characteristic rash; thus, the presence of the virus in a geographic area could be readily determined. Containment was easy since transmission was by droplets spread by face-to-face contact, and the virus survived outside the human host for only a limited period of time (in contrast to poliovirus, for example, which spreads through a fecal-oral route and may remain viable in feces for six weeks or longer). Smallpox had a higher average age at infection prior to wide-scale vaccination and thus was less transmissible than either polio or measles. A safe, heat-stable vaccine assured protection with only a single inoculation and could be administered from the time of birth (in contrast to oral polio vaccine [OPV], for example, which requires a three-dose regimen and special storage re- quirements). Finally, an extraordinary international cooperative effort sup- ported the campaign. Despite these ideal criteria for disease eradication, the smallpox cam- paign was not without technical, financial, and political challenges. Ex- pected voluntary contributions to the program were sparse in fulfillment. A number of endemic countries needed persuasion to undertake vaccination and surveillance activities, and political and social upheaval seriously de- layed or threatened the campaign. It was difficult to achieve sustained interest and support for continued disease surveillance and immunization after a nil incidence was achieved locally, even in light of rumors of spo- radic cases and the threat of possible reintroduction. These challenges show that eradication can be extremely difficult even when eradication is techni- cally and operationally feasible and political commitment is strong. The success of the smallpox eradication campaign and the title of this meeting hint at future success. Indeed, the regional eradication and near- eradication, respectively, of polio and measles in the Americas illustrate tremendous progress. However, it is far from clear that success is just around the corner. Interruption of the final chains of transmission faces several difficult challenges, including high transmissibility in densely popu- lated areas and public and professional complacency regarding continued vaccination due to dwindling first-hand experience with the consequences of infection and the increasing publicity on adverse reactions to vaccina- tion. Even in developed countries where infections have been eradicated or near-eradicated, mass vaccination will probably have to be maintained at very high levels for an extended time in order to protect against reintroduc-

SUMMARY AND ASSESSMENT 3 tion from areas where poverty, civil unrest, or lack of political will impede high vaccination coverage and sustain endemicity. There is much concern that the sixth precondition for eradication as outlined at Dahlem—political commitment—is not being fully met with respect to measles and rubella. This is evident by recent discussions among members of the international public health community which reflect seri- ous reservations about the feasibility and cost of attempting to eradicate these two diseases. Indeed, operational feasibility, particularly with re- gards to maintaining a strong routine immunization program, is consid- ered by many to be an important additional criterion that was omitted from the Dahlem list of preconditions for eradication. As was learned from the Dominican Republic/Haiti polio outbreak, low routine coverage is a critical problem that can lead to the circulation of a virus for several years. Yet, in the case of measles, in many countries the feasibility of delivering routine immunizations is too often ignored by those who advocate eradica- tion. Thus, it is important to note that the current World Health Organiza- tion (WHO) strategy for measles is “mortality reduction” and not “eradi- cation”. The failure to address the operational aspects of routine coverage seriously threatens our ability to achieve mortality reduction and certainly eradication. As the title of this report suggests, the focus of this workshop was post-eradication challenges. However, certification of eradication for other infectious diseases besides smallpox may be years off. Eradication efforts against polio, measles, and rubella represent a broad spectrum of achieve- ment. The current status of and particular challenges to each were also discussed during the workshop, the highlights of which are presented below. POLIO The main challenges confronting global eradication of polio are main- taining high levels of immunization in the population at large (the global polio eradication initiative relies on national immunization days (NIDs) with OPV offered two or more times annually for all children under five years of age) and targeting high-risk areas with “mopping up” operations in order to interrupt the last chains of transmission. A major lesson from the regional polio eradication effort in the Ameri- cas is the need for ongoing analysis of information gathered from the field and for the flexibility to change eradication strategies as necessary. For example, based on information gathered during the campaign, surveillance units were increased and moved to match where patients were seeking initial care. As another example, when it was discovered that a poliovirus

4 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION type 3 outbreak in Brazil could not be contained by the available vaccine, the manufacturers were led to reformulate the vaccine. However, as fewer cases are reported, intensified surveillance efforts and immunization programs compete for limited resources with other pub- lic health programs, even though laboratory surveillance is critical to the success of the polio global eradication effort. Infection with enteroviruses, echoviruses, and coxsackieviruses can cause an illness whose clinical fea- tures emulate paralytic polio, and the OPV vaccine itself can (rarely) cause paralysis. Differentiating OPV-derived viruses and these other causes of paralysis from the wild-type polio virus requires a relatively specialized laboratory technology not readily available in many lesser developed coun- tries. These difficulties confound true incidence rates, encumber surveil- lance efforts, and consume valuable resources. Although intensified mopping-up and surveillance have proven to be successful means of interrupting the last chains of polio transmission in the Americas, they were introduced very late in the global program and their implementation elsewhere has been slow. How well we address the chal- lenges of continuing surveillance for poliovirus and in maintaining polio vaccination in polio-free areas until global eradication is achieved will de- termine whether the goal of certifying the world as polio-free by the year 2005 will be met. MEASLES Mathematical models predict that 95% population immunity is needed to interrupt transmission of the measles virus. This is best achieved through a two-dose immunization strategy: once at nine months of age and then again in the second year of life. Major success in prolonged interruption of measles transmission in the Americas using this two-dose immunization strategy, supplemented with nationwide “catch-up” and “follow-up” cam- paigns targeting susceptible populations and geographic reservoirs, pro- vides evidence for the feasibility of global eradication. However, several impediments to global measles eradication remain. First, large birth cohorts stay seronegative to measles, resulting in subse- quent transmission among a susceptible adult population. Second, virus transmissibility is high in densely populated urban areas where susceptible children and immigrants serve as a source of outbreaks. Third, HIV-in- fected persons could become chronic carriers of the measles virus and con- tinue to shed the virus long after initial infection. Fourth, more than a million travellers use the skies every day, making it very difficult to contain spread. Fifth, the currently available vaccine is not 100% protective and leaves a pocket of susceptibility that enables transmission. To address these concerns, research is being done on aerosolization

SUMMARY AND ASSESSMENT 5 administration and a mucosal route of immunization (versus by injection); however, there is concern about whether the pharmaceutical industry would invest funds in a new vaccine that would entail new manufacturing plants and regulatory compliance and introduction into an unknown market. Also, even if an improved vaccine were developed, the focus of prevention efforts should still be comprehensive immunization of all children. Sixth, the greatest obstacle to measles eradication may be lack of politi- cal will. Indeed, data from the Americas show that measles transmission can be interrupted on entire continents, which means that interruption is technically possible, given the necessary political commitment. While the United States has made measles eradication a public health priority, some of the lowest measles vaccine coverage rates are found among the world’s richest countries, where measles is not seen as a problem. These countries need to be encouraged to maintain continued immunization and surveil- lance as protection against reintroduction via immigration and transconti- nental travel. This may require legal mandates. It may also be helpful to compile known risks of vaccination versus disease in some format that is accessible to the public in an effort to assuage concerns about the risks of vaccination. Equally important, health authorities in the developing world need to be confident that embarking on measles eradication will not detract from delivery of other health services and will lead to benefits for overall health care. As with polio, an important lesson learned from the measles eradica- tion campaign in the Americas is the importance of learning by doing and adjusting strategies based on newly acquired knowledge. For example, measles epidemiology changed radically when immunization was intro- duced; in particular, its relative incidence increased in older children and young adults. This was particularly true in countries like the United States, where older populations accounted for a greater percentage of cases be- cause of continued susceptibility due either to a lack of vaccination or vaccine failure, coupled with decreased exposure to the wild virus as infants and young children. In response, mass “follow-up” campaigns targeting all children between one and fourteen years of age were recommended every four years in order to remove remaining susceptibility in this older age group and achieve complete interruption of measles transmission. CONGENITAL RUBELLA SYNDROME Congenital rubella syndrome (CRS) is a serious disease caused by infec- tion of the fetus with the rubella virus during early pregnancy. Although CRS mortality is not as high as that of measles, the large number of CRS cases (approximately 100,000 worldwide) results in a large population of disabled individuals.

6 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION In developed countries, the current strategy of immunization is univer- sal measles-mumps-rubella (MMR) immunization at twelve to eighteen months of age and again at four to twelve years. This strategy has proven successful and should continue. The Pan American Health Organization (PAHO) has recommended that developing countries add rubella to the measles vaccine; increase universal immunization of children between nine and twelve years of age with the combination measles-rubella (MR) vac- cine; and repeat mass vaccinations directed at children nine to fourteen years of age. Vaccine manufacturers need to be provided incentives to both decrease the per dose cost and increase the overall supply to meet the demands of increased immunization. One of the most important challenges to rubella eradication is that clinical diagnosis of rubella is often inaccurate, unlike measles, since rubella can occur without a rash or be completely subclinical. The most sensitive laboratory tools currently available for diagnosis and surveillance are either not suitable for use in the field, can only be used in the most sophisticated laboratories, or are not commercially available. Improved diagnostic capa- bilities must be developed to accompany rubella eradication. Another major impediment to CRS eradication is that failure to achieve high immunization coverage in children could lead to increased susceptibil- ity among adult women who have grown up without contact with the virus and thus are more susceptible to infection, which they can then pass on to their fetuses during pregnancy. Ironically, this could potentially lead to more cases of CRS than occurred prior to the implementation of a vaccina- tion program and suggests that it would be prudent to decrease susceptibil- ity in adult women. But this poses a difficult challenge since adult women have an increased risk of reactogenicity and contraindication for use (e.g., possible transmission of live virus to the fetus from vaccination during pregnancy). Experimental work with vector genes and DNA vaccines sug- gests that maternal immunity could be overcome with the appropriate vac- cine. However, there is currently no financial incentive for the pharmaceu- tical industry to develop a new vaccine or even a new route of administration. As with measles, garnering broad financial and political support is perhaps the greatest challenge to CRS eradication. Although many years have passed since Australian epidemiologists confirmed CRS, the disabling consequences of CRS are not well publicized, and policymakers in devel- oped countries—where eradication priorities tend to be set—are not as aware of CRS as they are of, for example, polio and measles. POST-ERADICATION CHALLENGES Eradication must not beget complacency, but it almost certainly will.

SUMMARY AND ASSESSMENT 7 As has been learned from past control or eradication attempts with a vari- ety of viral diseases, from yellow fever to influenza, accidental or inten- tional reintroduction is a real threat—one that could strike anywhere and for which we need to be fully prepared. This is especially true as immunity wanes in the post-eradication era and the population at large grows more susceptible to infection. Even after immunization ceases, it is crucial that enough vaccine be stockpiled (or provision made for emergency replenish- ment) to cope with potential outbreaks; that surveillance continues in order to identify and stamp out local outbreaks quickly and before they spread to other regions; that vaccine manufacture be continuously improved to keep up with changing regulatory requirements and new technology; that vital research on vaccine technology and viral biology continue; and that viruses certified as eradicated in the wild be safely contained to minimize the risk of either accidental or intentional reintroduction. Post-eradication strategies need to be carefully developed and implemented in order to secure the full health, human welfare, and economic benefits of the eradication of a viral disease. Discontinuing immunization in the post-eradication era can yield large cost savings, freeing health care resources for other interventions. However, knowing if, how, and when to stop immunization in the post-eradication era is a major challenge, especially for the polio eradication campaign. Although the use of OPV has been crucial to the success of the polio eradication effort thus far, unique properties of the vaccine complicate decisions regarding if and when to cease vaccination. OPV-derived viruses can revert to pathogenicity during replication in the gut and, if shed, can circulate through the population. The problem of OPV persistence is fur- ther complicated by the fact that immunocompromised individuals who are vaccinated with OPV can excrete the virus for unknown, extended lengths of time. Although there is a non-pathogenic alternative to OPV—the inac- tivated IPV—several practical advantages to OPV make it the vaccine for choice for polio prevention. OPV confers substantial immunity; because it is transmissible, OPV can spread immunity, not just disease; and OPV is much less expensive. Ideally, a new, non-infectious vaccine that produces mucosal immunity like OPV would be developed as an end-strategy for immunization against polio—perhaps a DNA or some other vectored vaccine—although it is unrealistic to expect either the private or public sector to invest in the development and production of such a vaccine this close to eradication. Different ways of combining OPV and IPV strategies have been considered for use in the post-eradication era, but no decision has been reached about which strategy would offer the best protection against OPV-derived viral disease. For example, one suggested strategy is using an OPV-IPV combina- tion vaccine initially and then eventually removing OPV so that only a

8 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION “protective IPV layer” remains. However, it is not at all clear that this strategy would ever stop OPV transmission, thus raising the question, should we continue with the cheaper OPV vaccine indefinitely? Even if IPV could stop OPV transmission, a major disadvantage to relying on IPV as an end-strategy is the enormous cost, considerable tech- nology transfer, and several years that would be required to prepare an adequate supply of IPV to meet the world’s needs. With regards to the greater cost of IPV in comparison to OPV, it could be argued that as more new vaccines are introduced into the developing world, the added cost of adding an IPV component may become trivial. One argument for relying on IPV as an end-strategy is that because IPV still allows some intestinal excre- tion of the poliovirus, the excretion of wild-type virus could be detected in situations where it was believed to have been eradicated. This would facili- tate surveillance and detection of outbreaks. The time is ripe for a decision about how to proceed with vaccine production in the post-eradication era. Will there be an end game, or are we going to vaccinate against polio for the indefinite future? Key to answering this question is knowing whether IPV stops transmission of OPV-derived viruses. It will be ironic if it becomes necessary to continue vaccination in the post-eradication era as protection, not against wild polio, but against polio vaccine-derived disease. The post-eradication era is one for which we have no historical prece- dent. We have no experience with the consequences of a reintroduction or reemergence of previously eradicated organisms. We do not know how viruses will evolve in the future; if and how current vaccines would be able to protect us from disease caused by newly evolved viral variants; and if and how our immune system may change as the selective pressures previously imposed by eradicated viruses are lifted or altered. We have no experience on which to base predictions about the rate or extent of spread of disease in a population with zero immunity, especially as increased transcontinental travel and movement of people across borders make containment increas- ingly difficult. For the first time in human history we have a herd that, for more than twenty years, has never been exposed to epitopes that could potentially reappear in circulation. We need a better understanding of the long-term biological implications of altering the host-virus interaction through eradication and cessation of immunization in the post-eradication era. Post-eradication strategies need to be developed well before certifica- tion of eradication. During the smallpox campaign, post-eradication strat- egies were developed only after it became clear that the applied vaccine technology had proven successful and that eradication was practical and attainable. That all available resources were devoted towards the goal of interrupting smallpox transmission reflected the strong belief that any strat-

SUMMARY AND ASSESSMENT 9 egies that diverted resources away from achieving full eradication would be pointless if the eradication campaign failed. At risk was the loss of billions of dollars invested and gradual reversion to a pre-eradication status as special funds and interest withered. More importantly, a failed eradication effort would have undermined other global initiatives and confidence in expert public health advice. We tend to worry more about the inability to consummate eradication than the consequences of having done so. How- ever, as we have learned, focusing too much on the immediate goal of interrupting transmission without considering the consequences of having done so can leave the population very vulnerable to future public health crises of unpredictable, potentially catastrophic, magnitude. It has been over 20 years since the global eradication of smallpox. However, several post-eradication challenges remain, including: safely con- taining virus stocks still being stored in laboratories; renewing abandoned smallpox surveillance efforts; producing a potent vaccine should an out- break occur; and developing antiviral chemotherapy that might be appli- cable to smallpox. The risk of reintroduction—especially via biowarfare or bioterrorism—highlights the threat of reversion to a pre-eradication status and the need for developing post-eradication strategies early on during an eradication campaign in order to avoid the need for costly catch-up efforts. Following eradication, the consequences of reintroduction become in- creasingly grave over time due to the decline of herd immunity and in- creased susceptibility of the population to a pandemic, complacency in surveillance and maintenance and improvement of diagnostic laboratories, reduced medical awareness, and decreased research activity. REINTRODUCTION OF DISEASE IN THE POST-ERADICATION ERA Reintroduction could strike anywhere, at any time. Bioterrorism is generally considered the greatest risk of smallpox reintroduction, even though it was initially dismissed as a possibility since all countries had actively participated in eradication efforts. By the mid-1990s, however, U.S. intelligence had learned of several countries that were considering using smallpox as a potential bioweapons agent and that, in fact, smallpox was widely considered the bioweapon agent of choice for some terrorist activities. And, importantly, it is not the only choice. Both the measles and polioviruses could be used as bioweapons, for example, as aerosols, the pathogenicity and transmission about which we know very little. Impor- tantly, with the increasing accessibility of sophisticated molecular and bioengineering technology, all of these viruses could be genetically altered in ways that pose a tremendous challenge to post-eradication diagnosis and surveillance which, in order to be effective, must be able to detect novel

10 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION viral variants; and to the vaccine industry which must be encouraged to continue research and development of new vaccines that offer protection against a constantly changing viral genome. Accidental reintroduction from a stasis reservoir is also an important threat, as illlustrated by the 1977 re-emergence imputedly from frozen stock of a major variant of an influenza virus that had disappeared from circulation in the 1950s. Safe and secure biocontainment of the virus is essential for protecting both the environment and workers from accidental infection or contamination. Ensuring good biomanagement practices while simultaneously allowing legitimate and necessary viral research to continue presents a major challenge to post-eradication strategizing. Although laboratory escape and the use of viruses for bioterrorism or biowarfare may be the most obvious sources of reintroduction in the post- eradication era, the evolution of new viral variants, reemergence from un- known zoonotic reservoirs, and reactivation from chronic carriers are equally important to consider. The rise of megacities and increasingly dense human populations and high-density animal feed lots provide favorable milieus for rapid microbial evolution. The creation of new reservoir hosts, cross-species transfer of infectious agents, rise of antimicrobial resistance, and immune evasion are all potential sources for the emergence of novel viral variants. Important and often overlooked, mass vaccination itself can also exert tremendous selective pressures and lead to the evolution of new infectious agents. Even though no non-human reservoir has been identified for smallpox, polio, measles, or rubella, unknown non-human reservoirs may exist. The HIV pandemic is testament to the extraordinary clinical impact that a single zoonotic transmission event can have. In 2000, HIV-1 was estimated to have caused over 50 million infections worldwide. Data show that humans are routinely exposed to a plethora of primate lentiviruses (SIVs) from which HIV is derived. Multiple incidents of zoonotic transmission of a virus create the potential for recombination between the human virus (e.g., HIV) and the newly introduced zoonotic virus (e.g., SIVs). If unknown non-human reservoirs are harboring variants or ances- tors of the viruses responsible for disease, zoonotic transmissions may be a potential source for other viral diseases as well. Theoretical concerns about a non-human reservoir of measles, for example, raise questions about our assurance that the smallpox virus no longer resides in the natural environ- ment. Given the rapid evolvability of viruses and the rapidly changing evolutionary pressures in a 21st-century world, it would not be surprising to see the gradual evolution of new, previously enzootic, diseases with human-to-human transmission properties. Chronic carriers—HIV-infected persons, malnourished children, and other immunocompromised individuals—who can harbor and shed unde-

SUMMARY AND ASSESSMENT 11 tected virus for extended lengths of time are another important potential source of reemergence. More information is needed to better understand how long immunocompromised carriers continue to shed virus into the environment and what proportion of immunocompromised individuals shed virus for prolonged periods of time. This information is crucial to planning post-eradication vaccine production strategies, especially for polio. Because of its ability to revert to pathogenicity during replication in the gut, the oral, live-attenuated polio vaccine (OPV) used to prevent polio creates a serious challenge. OPV is usually shed from immunocompromised carriers for weeks to months but can be shed for as long as 10 years, compared to less than 3 months for immunocompetent carriers. Indeed, the probability of genetic reversion from attenuation to patho- genicity must always be considered in the application of live-attenuated vaccines. As disease due to wild-type virus is eliminated, vaccine-associated cases become of increasing concern. Since 1973, the number of vaccine- associated paralytic poliomyelitis (VAPP) cases has exceeded the number of wild polio cases in the United States. Worldwide, there have been several epidemics caused by reversion of the polio vaccine to virulence, the most recent in 2000 in Hispaniola. DETECTION AND SURVEILLANCE Continued surveillance, improved surveillance methods, and assistance to lesser developed countries in their efforts to implement national surveil- lance campaigns are essential for the rapid detection of disease outbreaks. Given the biological variability of vaccine strains, and the innumerable array of samples in frozen storage, it is not a question of whether disease outbreaks will occur in the post-eradication era, but, rather, when and where. Surveillance laboratory capacity must be strengthened, especially in areas where eradication has proven difficult to achieve or variants are likely to emerge. Surveillance tools must be sophisticated enough to detect differ- ent and new viral variants. To this end, global laboratory networks cur- rently in place need to be further developed, especially for measles surveil- lance efforts. Measles surveillance is complicated by the fact that measles cases can be mistaken for dengue, rubella, scarlet fever, and roseola; thus, differential diagnosis based on clinical symptoms can be difficult, and labo- ratory surveillance is very important for detecting and reporting all cases. The measles laboratory network in the Americas is by far the most highly developed and should serve as a model for networks in other parts of the world. National leaders must be convinced of the importance of strengthening surveillance capacity—not only to monitor the increasing likelihood of viral

12 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION surprises as we enter a post-eradication era but also to more readily detect pockets of low immunity as eradication campaigns near completion. Na- tional surveillance programs must be strengthened and the WHO and able countries encouraged to provide support, as needed, to countries who do not already have national surveillance networks in place. To aid in this effort, revised International Health Regulations (IHR) will provide a tem- plate for core requirements for national surveillance systems in countries where they do not already exist. Ideally, the IHR revision process should involve broad consensus with all WHO member states; better working relationships among WHO, member states, and other international agen- cies whose work is related to the IHR need to be established. The IHR are a set of global regulatory guidelines for how to respond to international disease threats and are currently the only binding set of regu- lations established on global surveillance for infectious diseases by WHO member states. They are designed to ensure maximum security against international spread of disease with minimum interference of world traffic and trade. However, the current IHR are limited in several ways; thus, the call for revision. Most importantly, they stipulate regulations for only three diseases, none of which are currently slated for eradication. The revised IHR will be more comprehensive and will apply to all “events of urgent international importance related to public health.” An algorithm—or “de- cision tree”—is being developed for use in determining whether an event is of urgent, international public health importance. Additionally, the current IHR regulations do not provide any mecha- nism for collaboration between member states and WHO. Even though the best way to prevent international spread of disease is to identify and stop local outbreaks before they begin to spread, national efforts often require international assistance. Such a conclusion recognizes the advantage of a single international entity (e.g., WHO) coordinating and overseeing global surveillance. Equally important, even local events can have international impact, especially if unauthorized information is disseminated in such a way that it causes overreaction and gratuitously damages tourism, traffic, or trade. Indeed, one of the motivations for revising IHR was the increasing threat of cross-border transmission due to increased transcontinental move- ment of people. The new IHR will require mechanisms to assure rapid communication between member states and WHO in the case of an out- break; they will involve more collaboration between WHO and member states; and they will ensure the quick dissemination of information to ap- propriate sources. Knowing if and when to discontinue surveillance in the post-eradica- tion, post-immunization era poses a great challenge. With the continued threat of bioterrorism and reemergence of disease from unknown natural reservoirs or new viral variants, in combination with a decreased immunity

SUMMARY AND ASSESSMENT 13 and increased susceptibility in the population at large, it is likely that sur- veillance will need to be continued and strengthened even after immuniza- tion ceases, perhaps indefinitely. The potential usefulness of immunological surveillance—perhaps using a saliva antibody test to detect declining vacci- nation rates and pockets of susceptibility—as a supplement to disease sur- veillance needs to be further examined. CONTINUED VIRAL RESEARCH IN THE POST-ERADICATION ERA Although it may not seem worth arguing over whether a virus that only spreads among humans and has severe adverse health effects should be completely eliminated to the point of extinction, even in the laboratory, it may be necessary to retain samples for future study, especially given the rapid pace of viral evolution, the loss of immunity as infection disappears and immunization ceases, and the likelihood that new viral variants with altered pathogenicities or routes of transmission will emerge at some point in the post-eradication era. Too often, success or near-success at eliminat- ing an infectious agent results in languished research efforts toward advanc- ing knowledge of that agent. In anticipation of polio eradication in the early 1990s, for example, polio research laboratories were told they would be soon required to cease poliovirus research and destroy all virus and infectious DNA stocks. The unfortunate consequence was that many research programs that could have contributed valuable information on new vaccines, new antiviral drugs, and animal models for virus transmission were shut down. If new vaccines or antiviral therapies are to be developed to cope with unforeseen viral chal- lenges, basic scientific research on viral-host biology must continue even after eradication. Maintaining research programs that address important scientific questions about viral biology and pathogenesis will require an increased investment in containment laboratories and improved communi- cation between the public health sector and research community. Before viral stocks and samples can be safely contained, they need to be located. Inventories must include not only vials clearly labeled “measles” and “polio,” for example, but also any biological samples, such as stool samples from patients who have had suspected enterovirus infections, that carry the risk of contamination. This is a daunting challenge. To complicate matters, many laboratories or clinics do not even realize that they have virus specimens until somebody stumbles upon them inadvertently. Once identified, all viral stocks and samples should be transferred to biorepositories demonstrating well-developed and documented procedures for safe handling and security. This will ensure that the viruses are available for ongoing research, as needed, with a minimal risk of accidental reintro-

14 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION duction. Established standards, such as Biosafety Level 3 (BSL-3) and the more stringent BSL-4, have generally proven very successsful at protecting both workers and the environment from infection or contamination, where they have been in force. However, intermediate systems that incorporate more controls than BSL-3 but are not as stringent as BSL-4 often rely on ambiguous language and ill-defined protocol. Virus-specific standards need to be clearly established, based on known risks and properties unique to each virus. Not only must virus stocks be safely contained in order to prevent accidental reintroduction, but precautions need to be taken to protect against intentional reintroduction as well. Internal security measures at biorepositories where the virus is housed should insure restricted physical access to the viruses (e.g., by securing freezers with locks that require two people to open), and freezer inventories should be designed in such a way that a locator code is needed to find the material. All movement of material should be tracked to verify authorized access. Only qualified end-users should be allowed access to the virus, and it must be assured that the receiving laboratory is capable of controlling access. End-users should dem- onstrate knowledge of the material and its potential hazards. Potential recipients should be screened by appropriate authorities, e.g., the depart- ments of Commerce, State, and Treasury. Undue proliferation of many regulations will hinder important scien- tific research. Restrictions may be necessary to prevent samples from falling into the “wrong hands,” but the regime must acknowledge the need for scientific progress. It is imperative that the scientific and research commu- nity be proactive in presenting a reasonable framework for viral research to policy makers and legislators. Physical containment of laboratory virus stock may become irrelevant with the advent of advanced recombinant and synthetic molecular tech- nologies. Viral genes could readily be synthesized from nucleic acid se- quences, and viruses themselves could probably be reconstituted from se- quences or clones, thus precluding the need for continued storage of intact viruses. Importantly, however, individuals or organizations with bioterrorist intentions could do this just as well as legitimate research labs. And, as bioengineering technology advances, it becomes more possible to construct new, chimeric viruses. Although this would require greater planning, re- sources, and scientific expertise than simply removing intact stocks from a freezer, it may be an attractive alternative for persons or institutions with bioterrorist or biowarfare intentions. Although unlikely, the threat of a bioterrorist or biowarfare attack with an infectious agent of unknown properties reinforces the need to continue viral and antiviral research in support of improved vaccine and drug development.

SUMMARY AND ASSESSMENT 15 VACCINES AND ANTIVIRAL THERAPIES FOR USE IN THE POST-ERADICATION ERA Following eradication, smallpox vaccine production ceased in 1982. By the time it was realized that malevolent use of the smallpox virus posed a serious bioweapons threat and the Centers for Disease Control and Preven- tion (CDC) issued a contract for the production of a new national vaccine stockpile in 2000, the vaccine reserve was not only deficient but had de- cayed over time. The vaccine program infrastructure had deteriorated; vac- cine technology used previously for smallpox vaccine production was out- dated; and standards of vaccine production had changed. In order for other disease post-eradication initiatives to avoid the type of catch-up campaign that production of the smallpox vaccine currently faces, vaccine production and research must continue even after immuniza- tion has ceased. This poses a tremendous challenge, as the financial incen- tives to develop and produce new vaccines are weak, and research leader- ship in this area is lacking. An in-date supply of vaccine must be made available for use in the event of an outbreak. Vaccine development must keep up with changing regulatory requirements, and improved vaccines must be able to protect against newly evolved or bioengineered viral strains with altered pathogenesis or routes of transmission. Stockpiles should be replenished regularly; expertise and experience of the manufacturing and control personnel should be maintained; and facilities, equipment, and the production process should be continually validated, as well as reliable means of storage. The size of vaccine stockpiles should correspond, at minimum, to the threshold immunity required to break transmission. New methods for rapid large-scale vaccine administration need to be developed and their immunogenicity demonstrated. Given the tremendous success of vaccination in the prevention of infec- tious disease, one might question the necessity to develop other antiviral therapeutics. However, given the risk of reintroduction of disease, the evolvability of viruses, and the unknown changes that the human immune system will undergo against the background of zero immunity in the post- eradication era, other potentially useful antiviral strategies must be consid- ered as means to strengthen the immune system or serve as adjuvant or prophylactic therapies. Although diseases currently slated for eradication have never been con- sidered targets for antiviral drug development, our knowledge of molecular biology and viral-host interactions has advanced to a point where selective, specific antiviral agents could be developed. Although broader-spectrum antiviral drugs, like interferon, would probably be more applicable (and more likely to attract investors) than narrowly focused drugs that only target specific viruses, they are notorious for their toxicity and many side

16 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION effects; also, more research would be needed to identify host cell functions that could be targeted with a broader-spectrum antiviral drug. Although treatment with antivirals should never serve as a substitute for the preven- tion of disease, they can impact public health, as evident by their ability to reduce viral load in HIV-infected individuals. However, there are few in- centives for manufacturers to invest in antiviral research, especially for vaccine-preventable diseases. If antiviral chemotherapy could be developed for a broad range of viral infections, it would drastically alter our assess- ment of risk of resurgence post-eradication. Immunoprophylactics are another option. Although nonspecific immunoprophylactics (e.g., interferon) have been developed for treatment of a wide variety of diseases, experienced knowledge of toxicity and effec- tiveness of general prophylaxis against chronic infections in humans is very limited and would require extensive research before being considered for widespread use. Plus, given the readiness with which wild-type viruses evolve ways to escape host cell antiviral activities, it is unlikely that a universal prophylactic agent will be identified. More promising are prophy- lactic agents that target specific viruses. As with antivirals, the technology is now available to develop specific prophylactic agents against chronic infec- tions like polio, measles, and rubella, but this has not been done. Our approaches to disease prevention, mainly vaccination, rest upon the presumption that the human immune response has not changed for centuries and will remain strong for centuries to come, even as immunity changes in the post-eradication era. However, we do not know how true this is. In light of the possibility that our immune system may weaken in the post-eradication era—for example, from changing selective pressures—it would be a good idea to do all that we can to strengthen the immune response. Probiotic bacteria—living microbes introduced into the body to improve intestinal microbial balance—have great potential to sustain an immune response in the post-vaccine era and may prove useful in strength- ening the immune response in immunocompromised individuals who are at risk for chronic infection. For example, recent studies have shown that probiotic lactobacilli can have a beneficial effect on the immune response in HIV-infected children. It has long been understood that our human body space is shared with a multitude of microbial species, inhabiting our skin and mucous mem- branes. On the presumption that these may have varying effects on our health—from mutualistic enhancement through every grade of pathogenic- ity—we have been wont to regard them as a “microbiome”, a collective set of genomes to be compared with our own intrinsic “human genome”. As this is written, the day’s headlines refer to studies regarding a protective effect of coinfection with the GBV-C, a relative of hepatitis-C virus, on the course of AIDS (Xiang et al., 2001; Tillmann et al., 2001). Proof is hard to

SUMMARY AND ASSESSMENT 17 find, but it makes evolutionary sense that any chronically infecting member of the microbiome would enhance its fitness by excluding the extinction of the host by more virulent competitors. In similar vein, we should not be surprised that Helicobacter secretes peptide antibiotics active against chol- era, though there is not yet direct evidence that this has any clinical signifi- cance. After eradication, the natural tendency is for vaccine and other relevant research funding—both public and private—to wither away. However, ba- sic research on the immunological basis of protection will be vital to devel- opment of new vaccines and other antiviral therapeutics. A strong federally supported research program will be crucial to advancing our knowledge of viral genomics and pathogenesis in support of vaccine and antiviral drug development. Strong commitment is needed from both the public and pri- vate sectors to share the costs and risks associated with developing products which may have only a very short product life cycle. Research on non- vaccine antiviral therapies must be continued and strengthened in light of the fact that the post-eradication era may, ironically, pose even greater challenges to the immune system as immunity wanes and viruses evolve. INSTITUTIONAL AND SYSTEMS PREPAREDNESS FOR DISEASE OUTBREAK When discussing disease outbreaks in the post-eradication era, small- pox is of foremost concern since it is the only disease that has already been eradicated, plus we have a precedent for it. In 1946, in response to a new outbreak of smallpox and a single import from Mexico, six million New Yorkers were vaccinated. The question is, what would the situation be like if there were a recurrence of that same event today? First and foremost, would there be enough vaccine to vaccinate everyone who would need to be vaccinated? Who would need to be vaccinated? Where would the vaccine come from? And how would it be released? To complicate matters, today’s population is much more susceptible to infection than it was in 1946, and emergency vaccination measures taken at that time were probably to some extent supererogatory since at least half of all New Yorkers were probably already vaccinated. It is likely that a newly introduced case would spread much more rapidly today than it would have done several decades ago. Drawing on the lessons learned from smallpox eradication and as summarized above and discussed in detail throughout this report, a re- sponsible post-eradication strategy must include provisions for vaccine reserves and contingency planning in case the disease re-emerges; contin- ued surveillance and diagnostic activities; and research on and develop- ment of new vaccines and antiviral therapeutic drugs. The federal govern- ment will play a key role in supplying these provisions in the

18 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION post-eradication era. With regard to vaccine production, for example, vac- cines will become much less profitable to market after certification of eradication. Plus, over time, regulatory guidelines for vaccine manufacture are likely to become more troublesome as unforeseen safety issues arise (e.g., the risk of prion-mediated diseases resulting from incorporation of bovine derivatives into vaccines). Because of the increased cost of produc- tion and stricter regulatory guidelines, the private sector will likely lose interest in vaccine manufacture, and government-sponsored production may be necessary to maintain adequate vaccine supply. The security consequences of a post-eradication oubreak should be assessed and prepared for from the outset of any eradication effort. Agents with biowarfare potential should be included in formal biological control negotiations, and information gathered to help determine if any nations or groups have sought to develop the agent as a bioweapon. The intelligence, arms control, law enforcement, and defense communities must be ad- equately prepared since they are all likely to be involved in the event of a disease outbreak with national security consequences. Intelligence informa- tion may be required to help determine if the outbreak was a natural or deliberate occurrence; evidence may need to be collected for legal or arms control issues; recurrence of disease outbreak will need to be prevented; and those responsible will need to be held accountable. Hospitals serve as a major hub in the U.S. health care system and can and should play a major role in an outbreak response. However, at present, the U.S. health care system is not prepared to handle either a natural or intentional disease outbreak. It lacks the capacity and infrastructure; has neither incentives nor mandates that require preparedness; has no networks in place to aid in the coordination of response among different health care communities; and is plagued by unresolved staffing and legal policy issues. In order to effectively confront the demands of an outbreak, including the mass surge of people, the health care system must at least be operating effectively prior to the outbreak. However, U.S. hospitals are currently facing tremendous economic pressures, and current staff levels are insuffi- cient to cope even with small and predictable influenza epidemics. Without funding incentives or mandates in place, it is unreasonable to expect that hospitals will take the necessary measures to prepare for disease outbreaks in the face of other, more pressing and immediate concerns. Substantial communications barriers exist among and between public health agencies, emergency and first response communities, and medical care delivery communities. These barriers, combined with a climate of competition among hospitals and distrust across the public/private sector divide, prevent coordinated regional responses. Effective regional networks will require adequate funding, designation of an in-charge organization and individual, and development of a regional response plan.

SUMMARY AND ASSESSMENT 19 The consequences of a disease outbreak in a post-eradication era will entail more than public health and security implications: the psychological response—particularly fear and panic—could hinder intervention and con- trol. The media, government, and medical communities will play large roles in determining how the public will respond to an outbreak. While develop- ing outbreak policies, the emotional and physical impact on leaders of these communities will need to be taken into account. Over-dedication, sleep deprivation, and the intensity of their roles during a crisis can lead to sub- optimal decision-making and other manifestations of poor judgement. Pro- tocols need to be developed for decision-making processes in the event of an outbreak. Research is needed on how to address the psychological and behavioral consequences of an outbreak, and the behavioral and societal effects of past infectious disease outbreaks should be studied in order to identify effects of different responses. Research is also needed on how best to enlist media support in the management of outbreaks, and risk commu- nication programs need to be developed. By definition, post-eradication outbreaks would involve infections rarely, if ever, seen in medical practice. Primary health care workers may have limited knowledge of the pathogen in question, making disease diffi- cult to diagnose and treat. Untrained or mistrained responders could con- tribute to institutional breakdown. Poor medical knowledge can lead to conflicting messages and confusion regarding an appropriate course of ac- tion. While it is the nature of scientific discourse to debate and criticize, this will not instill confidence in a time of crisis and can lead to an undermining of authority. We need a better understanding of how the public should be trained to anticipate and cope with the diverse, and often conflicting, infor- mation that may be disseminated in the wake of an outbreak. CONCLUSION The current state of the U.S. health care system reveals a weakness in the United States’ capacity to control outbreaks in a post-eradication era. However, this capacity is even weaker or even non-existent in poor coun- tries who do not have any health infrastructure or resources to cope with an outbreak. Too often in the developing world, global eradication priorities override local health priorities. In the polio eradication effort, for example, countries have been pressured to focus on global priorities (to immunize everyone, for example, even if polio is not a disease that the people have witnessed) at the expense of eliminating other diseases that are killing their children but for which there is no global eradication effort. Recent reports indicate, however, that efforts to strengthen local health service infrastruc- tures can operate synergistically with efforts to address global priorities— the two need not be mutually exclusive. In particular, evidence indicates

20 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION that eradication efforts are more successful in countries with a strong health infrastructure in place. Focusing on building local health infrastructures and empowering communities with the resources to address their own prob- lems in a self-reliant way is the best framework for dealing with disease outbreaks in a post-eradication era. However, building local health infrastructure does not necessarily mean implementing the “doc-in-the-box” western model of primary health care centers. An important lesson learned from smallpox eradication was that vaccination could not be achieved by waiting for people to show up at a primary health care center. Rather, the vaccinators had to go out into the field and contact the people. Furthermore, what works in one locality may not work in another. Priorities for action must be based on an assessment of local resources and capabilities. That so many countries still lack basic health services to prevent and cope with current public health crises, let alone capabilities to respond to a major disease outbreak in a post-eradication era, is indicative of the reality that even though post-eradication challenges need to be considered and prepared for concurrently with eradication efforts, still, except for small- pox, the post-eradication era may not be foreseeable in the near future. This is true even of polio, which is considered next in line for eradication. However optimistic we are about global eradication of polio, measles, rubella, or any other disease, current conditions in many parts of the world still pose significant challenges to eradication, let alone post-eradication strategizing. There is some concern that too much focus on eradication, rather than on control, could divert resources and effort away from more pressing and serious public health crises. After all, the practice of good public health is based on the judicious and wise use of limited resources to achieve maxi- mum public benefit; neither the international public health community nor any single nation has unlimited funds to support public health programs. Eradication is expensive, thus the decision to eradicate must be based on an in-depth review of all available funds and resources. Equally important, it must also be based on a thorough evaluation of the opportunities that may be lost by prioritizing actions and making decisions for the sake of eradica- tion. For example, although polio is generally considered next in line for eradication, some participants in this workshop questioned the wisdom of focusing too much on polio eradication when there remain nearly a million people dying each year from measles. This high opportunity cost of polio eradication (i.e., lives lost) leads one to wonder if polio and measles eradi- cation efforts should be conducted concurrently with more emphasis placed on controlling both, rather than eradicating one or the other. Another advantage to emphasizing control rather than eradication is that the former keeps us on guard that there might be still—somewhere on the planet—a

SUMMARY AND ASSESSMENT 21 threat great enough to motivate continued surveillance, vaccination, and research. The information contained in this report provides important insights that can and should be incorporated into the decision-making process about whether to enter into future eradication efforts. With respect to polio eradi- cation efforts, for example, a major selling point to political leaders was the potential post-eradication cost savings. But if we had known that immuni- zation would likely need to be continued even in the post-eradication era, would the level of political commitment have been the same? If we had been more aware of the post-eradication challenges, would we have favored disease control rather than eradication and would development of the health infrastructure have been a better overall investment? These are difficult questions to ask. Many would contend that the eradication of smallpox is one of public health’s greatest victories, a feat worthy of being emulated. Yet we must be cautious about embracing the ideology of eradication at the expense of sound, rational judgement. Given the challenges of managing the many post-eradication issues raised during this workshop, the public health community must consider all available evidence when deciding whether to launch similar efforts in the future. Once a major disease has been eradicated, too much is at stake to return to a pre-eradication era. Post-eradication strategies need to be con- sidered early on during an eradication campaign and developed when the possibility of eradication is certain. As population immunity wanes, viruses evolve, and complacency sets in, the catastrophic potential of a disease outbreak in the post-eradication era increases. It is crucial that we ad- equately prepare for recurrence of an outbreak, no matter how improbable. The issues raised in this workshop provide a framework for thinking about post-eradication policy and research needs that must be addressed now, before eradication of any other disease is certified and while there is still time to prepare and conduct crucial research that can influence how well we will meet the challenges of the post-eradication era. REFERENCES Tillmann HL, Heiken H, Knapik-Botor A, Heringlake S, Ockenga J, Wilber JC, Goergen B, Detmer J, McMorrow M, Stoll M, Schmidt RE, and Manns MP. 2001. Infection with GB virus C and reduced mortality among HIV-infected patients. New England Journal of Medicine 345(10):715–724. Xiang J, Wunschmann S, Diekema DJ, Klinzman D, Patrick KD, George SL, and Stapleton JT. 2001. Effect of coinfection with GB virus C on survival among patients with HIV infection. New England Journal of Medicine 345(10):707–714.

1 Introduction Ciro A. de Quadros, M.D., 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 Jenner inoculated James 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. Jenner concluded, “This practice would wipe out this scourge from the face of the earth” (Jenner, 1801). Since then, eradication has been defined in many different ways. In 1997, the Dahlem Workshop on the Eradication of Infectious Diseases defined several levels of deliberate efforts of disease control, including eradi- cation, as follows (Dowdle and Hopkins, 1998): • 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 and/or 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:1 • Control: the reduction of disease in a defined geographic area; intervention 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 Dahlem 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-long immunity. • There must be a tool 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 eradication: 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 Smallpox (Global) 1911 William Gorgas Yellow Fever (Americas) 1915 Rockefeller Commission Yellow Fever (Global) 1950 Fred Soper Smallpox (Americas) 1954 WHO Yaws (Regional) 1955 WHO Malaria (Global) 1958 Viktor Zhdanov Smallpox (Global) 1985 PAHO Polio (Americas) 1986 WHO Guinea Worm (Global) 1988 WHO Polio (Global) 1994 PAHO Measles (Americas)

INTRODUCTION 25 a two-pronged 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 tool available for interrupting the chains of transmission (i.e., an effective heat-stable vaccine easily administered with a bifurcated needle). • 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- tions. • 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 eradi- 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 15 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 detected. 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 order 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 delay 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% 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 15 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% 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 and 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 should 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 interrupted 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 during 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- tion during their polio campaign. 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. Carl Taylor (PAHO, 1995). PROSPECTS FOR ERADICATION OF OTHER VIRAL 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 varicella, 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- cella 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- bella 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, Wilna 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 science—from 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 world. 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 polio 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 and 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.

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Since smallpox eradication, the science of eradication has changed and with it, our definitions of what diseases are possible to eradicate. However, eradication must not beget complacency. As has been learned from past control or eradication attempts with a variety of viral diseases, from yellow fever to influenza, accidental or intentional reintroduction is a real threat—one that could strike anywhere and for which we need to be fully prepared. The criteria for assessing eradicability of polio, measles, and other viral infections have been debated extensively. With the elimination and eradication of several viral diseases on the horizon, issues surrounding the cessation of immunization activities become exceedingly important. In an effort to better understand the dynamics of disease eradication and post—immunization policies, the Institute of Medicine Forum on Emerging Infections hosted a two-day workshop (February 1—2, 2001) on The Consequences of Viral Disease Eradication. This book explores the principles underlying the biological challenges, medical interventions, the continuing research agenda, and operational considerations for post—immunization strategies for vaccine—preventable viral diseases, and highlights important efforts that may facilitate wise decision making.

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