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4 Operational and Institutional Challenges to Post-Eradication OVERVIEW The greatest impediment to eradication is the accidental or intentional reintroduction or re-emergence of infection. Non-human reservoirs of in- fection, accidental reintroduction from a stasis reservoir, reversion of the vaccine strain virus to virulence, recombination between vaccine and wild- type virus, the evolution of new viruses, ecological niches left vacant after vaccination, and malevolent intent are all potential sources of reintroduc- tion for which we need to be fully prepared. Reintroduction could strike anywhere. Increased movement of people across international borders complicates the challenge of combating unex- pected disease outbreaks and preventing global spread. Prevention of rein- troduction requires detecting infection while outbreaks are still locally confined, which means that a national surveillance system supported by accurate laboratory-based diagnosis must be firmly established. In addition to serving as a regulatory framework for global surveillance, the proposed revision of the International Health Regulations (IHR) provides a func- tional and effective template for national surveillance in countries that do not already have an effective system in place. One of the greatest challenges in the IHR revision process is ensuring that reporting of public health risk expands to all urgent international public health events, instead of focusing only on specific diseases. Countries and institutions need to be able to act as a network of networks in order to identify and limit the damage caused by new outbreaks, while simulta- 98

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OPERATIONAL/INSTITUTIONAL CHALLENGES TO POST-ERADICATION 99 neously minimizing unnecessary overreaction, economic hardship, and so- cial instability. In many countries, global eradication priorities override local health priorities. In the past, this has been justified by cost-effectiveness analyses demonstrating the enormous savings expected when an infectious agent is declared eradicated. Now, however, we are beginning to realize that strengthening local health service infrastructures can operate synergistically with global priorities. Indeed, empowering communities with the resources to manage their public health problems in a self-reliant way is the best framework for dealing with disease outbreaks. Finally, prevention of reintroduction requires the safe containment of post-eradication agents in order to protect against accidental or intentional transmission of eradicated agents. Good practices are needed for the acqui- sition, preservation, authentication, and `distribution of infectious materials for legitimate research and clinical purposes. Heightened laboratory con- tainment and security will be an increasingly essential part of the biological research infrastructure in the post-immunization era. REVISION OF THE ~ERNATIONAL HEALTH REGULATIONS: PROGRESS REPORT Mario Libel, M.D., M.P.H. Epidemiologist, Communicable Diseases Program Division of Disease Prevention and Control Pan American Health Organization, Washington, D.C. a: The International Health Regulations (IHR) were the first multilateral initiative for the surveillance of cross-border transmission of infectious diseases. They are currently the only binding set of regulations on global surveillance for infectious diseases by WorId Health Organization (WHO) member states. In response to the threat of cross-border transmission posed by substantial increases in international travel, the World Health Assembly (WHA) requested the revision of the IHR in 1995. The original public health protection measures for international travelers, conveyances, goods, and cargoes will remain in the revised IHR, but they will be subject to review and consultation. The fundamental principle of the IHR is to ensure maximum security against international spread of disease with minimum interference with world traffic and trade. To achieve this purpose, the present IHR oblige member states to notify WHO of cholera, plague, and yellow fever out- breaks in their territories, list the maximum measures applicable during such outbreaks (based on evidence-based information), and make rules for

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100 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION international traffic. Listing maximum allowable measures is essential for preventing overreaction which could damage tourism, traffic, and trade and lead to unnecessarily harsh economic consequences. During the early l990s, for example, a cholera epidemic in the Americas cost Andean coun- tries more than $1 billion because maximum allowable measures had not been defined. These measures should be based on evidence-based informa- tion. Although the IHR are the only international, legally binding too! for public health, they have limited use for the following reasons: They stipulate regulations for only three diseases (i.e., cholera plague, and yellow fever). They render WHO wholly dependent upon the country suffering the outbreak to make the official notification. They do not provide a mechanism for collaboration between mem- ber states and WHO. They lack event-specific measures and incentives for compliance. . With these major constraints in mind, key changes have been proposed to develop an IHR that would adapt to emerging trends in 21st-century epiclemiology and global travel. Revised Core Concepts Although there are some new core concepts proposed for the revised IHR, most of the changes involve developing and fine-tuning already extant rules: Surveiliance The new IHR will neither contain a list of notifiable diseases nor de- pend solely on the use of syndromes for notification. Instead, they will require the reporting of all "events of urgent international importance re- lated to public health." The reason for this is two-fold. First, in the present world of new and re-emerging diseases, any disease list could immediately become obsolete. Second, a case of a disease in and of itself does not always pose a danger of international spread or impact. The disease must be coupled to circumstances, such as place, time, size of outbreak, closeness to an international border or airport, speed of spread, mode of transmission, and so on. Thus, routine occurrence of endemic diseases will not be notifiable under the revised IHR, and countries will not be able to send off reports about diagnosed cases in an automatic fashion. When there is an event with

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OPERATIONAL/INSTITUTIONAL CHA FLENGES TO POST-ERADICATION 1 01 possible international consequences, the national administration must quickly decide if the event fulfills the WHO criteria and should be reported to WHO. The new IHR will contain a test to help administrators decide if an event is both urgent and international. An early draft of the algorithm, which was tested during the Syndrome Pilot Study, contained the following parameters: High potential for spread outside the community/country, Unexpectedly high case fatality ratio, Unusual or unexpected event, Country capacity to control and contain the event, High international media profile, Potential for imposition of trade/traffic barriers by other countries, Occurring in a high-density/urban area, Significant possibility of international transport of infected persons or contaminated goods/conveyances, and Significant possibility of vector transport. Communication Because the new IHR will cover a much wider span of public health events and outbreaks, and because these events may happen very quickly, 24-hour communication with WHO is critical. Information may need to be distributed nationally to hospitals, health officials, ports, and airports very quickly. Each member state should have a single, focal e-mail address that leads to someone who is available at all times. This requires a reliable electronic communication and back-up system within each member state. Reporting Capaciry a: In order to ensure the quick dissemination of information regarding urgent national events of potential international importance, each country must have the capacity to quickly report, analyze, and determine the poten- tial effect of national disease events on other member states. This will require surveillance systems that allow for rapid analysis and transfer of information on unusual and unexpected events from the periphery to the center. The revised IHR will contain a recommended template for core require- ments for a national surveillance system. In many countries, this surveil- lance/analysis capacity may already be in place. Others may need a grace period to fulfill this IHR requirement, and external assistance and funding may be necessary; the template could be used for defining core surveillance needs to national health sectors and external donors.

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102 Notification CONSIDERATIONS FOR VIRAL DISEASE ERADICATION Member states will have the option to make confidential, provisional notifications to WHO. Currently, the IHR automatically lists notified cases in the Weekly Epidemiological Record (WER). However, in the early days of an event, it is often unclear if the criteria for an urgent international event are fulfilled. With this proposed change, member states will have the option to contact WHO on a provisional basis before any information is made public. The member state and WHO can work together to assess the extent and potential impact of the event anal issue a joint statement. By collaborating with WHO before making a statement, the member state would gain credibility ant! reduce the likelihood of overreaction. Information Other information in addition to official notifications will be used by WHO to help identify and control urgent international events, and member states will respond to requests from WHO to verify the reliability of this information. Urgent international events often reach the global information super-highway and become news even before the most efficient administra- tion has had time to react to the events and make any sort of official notification. To prevent threatened countries from responding to unverified news by restricting cross-border traffic and trade, WHO will need to in- form member states and issue recommendations on appropriate measures. Economic Considerations In order for a global surveillance system to function well, the economic consequences of reporting disease events must be considered. If the WHO notification and response system cannot help to reduce tourism and trade losses to what is strictly required from a public health perspective, compli- ance with IHR reporting and notification obligations will likely be ignored by member states. Thus, the new IHR will establish a template for measures to protect other member states from unnecessary economic losses. These measures will be based on the actual public health threat or impact of the event, as determined by all available evidence. Establishing these guidelines will require input from all WHO departments involved in goods, such as Food Safety, Environment, Pharmaceuticals, as well as a plethora of exter- nal stakeholders. Assistance Many countries may neecl external assistance after provisional notifica- tion or a request from WHO for further information. Under the new gu~de-

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OPERATIONAL/INSTITUTIONAL CHALLENGES TO POST-ERADICATION 1 03 lines, WHO will be obligated to assist member states in rapidly assessing and controlling outbreaks. If the extent and potential threat of the outbreak is unclear, WHO will offer to send a response team to collaborate with the member state government in controlling disease spread and minimizing economic damage. By working with ~IO, the affected country would receive interna- tional recognition for its effort to prevent international spread, which should reduce unnecessary economic hardship. The capacity of WHO to react and assist in outbreaks, even when there are multiple outbreaks occurring si- multaneously, must be improved. Recommendations A transparent, decision-making process will be established within WHO to issue recommendations for member state action in case of imminent risk of international disease spread. These recommendations could be ctirectect either at the affected country, at all other member states, or both. This will require a quick gathering of wide, representative consensus. Preventive Measures lust as it is impossible to list diseases, there is no way to describe appropriate measures for each event in advance. However, the revised IHR will contain a list of all key measures that could potentially be used in a WHO recommendation to prevent international disease spread at embarka- tion, during travel, and at point of entry. Some examples of measures potentially applicable at point of entry into non-affected member states from an affected member state are shown in Table 4-1. During an urgent health event, TRIO would use appropriate measures from the complete list as a basis for a recommendation to member states. The recommendation wouIct be time-limited for the event, so a clear proto- co! for ending the measures would need to be included. To create the flexibility required to adapt to each major international threat, non-binding recommendations will have to replace the fixed, binding measures in the current IHR. Review Process A permanent IHR review body will be established in order to build continuity within the IHR process. Lack of a mandatory review process has rendered the existing IHR out-of-date. Plus, the new IHR will have much broader provisions and will require continuous interpretation and prece- dents setting.

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104 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION TABLE 4-1 Measures Potentially Applicable at Point of Entry into Non-affected Member States from an Affected Member State Travelers Goods and Conveyances -require travel history in affected country -require inspection of conveyance, cargo, -require proof of medical examination or goods -require medical examination on entry -require treatment of conveyance, cargo, or -require proof of vaccination or prophylaxis -require vaccination or other prophylaxis goods for entry -require destruction of cargo or goods -require protective measures for suspected -refuse entry of conveyance, cargo, or cases -active or passive medical surveillance if travel from affected area -isolation of traveler for incubation period of disease -refuse entry of persons from affected area goods -require isolation of conveyance, cargo, or goods The Role of WHO The new IHR will provide global regulatory guidelines for how to respond to international disease threats, the implementation of which WHO will coordinate. Even though the best way to prevent international spread of disease is to detect public health threats early and stamp them out when they are still a small, local problem, national efforts often require interna- tional coordination. Many countries need assistance from multilateral insti- tutions for their national surveillance systems. Plus, even localized national events can quickly affect international traffic. Thus, an international coor- dinator is critical for standardizing notifications, responses from other coun- tries, and the global exchange of epidemiological information. Effective notification of disease events to WHO will be facilitated by an assurance of how this information will affect member states' economic interests. All of the various functions that TRIO would serve as international coordinator in response to a disease event are included in Figure 4-1. IHR Benefits to Member States The new IHR will benefit member states in a variety of ways: National surveillance systems will need to be improved. Modern communication systems for detecting and responding to

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OPERATIONAL/INSTITUTIONAL CHALLENGES TO POST-ERADICATION 1 05 1. Media scans, media reports 2. Provisional notification to WR, RO, HO 3. Official _ notification from Member State _ country c oes Contact country to not verify verify Potential urgent international event verified Offer assistance work with Member Provisional State; possibly status ending sending team Yes, urgent international event 1 ' . 1 . Together with affected MS notify all others . , Recommendations issued 1 Continuing reappraisal of evidence of situation Event controlled; measures ended If verified - FIGURE 4-1 Possible framework for IHR response. SOURCE: PAHO/WHO. ..~ potential international health events will need to be developed in countries where they are not already available. Disturbances to free traffic, which constitute an obstacle to report- ing, will need to be thwarted. . . A set of generic rules to handle different kinds of urgent events and a rapid mechanism to agree on appropriate levels of national protection within this set of rules will be clevelopect by the IHR for implementation in member countries. Ideally, the IHR revision process should involve broad consensus with all member states. The current collaboration between the Secretariat and

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106 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION interested member states is designed to test proposed changes and seek suggestions on how the member states want the new IHR to operate. An electronic virtual discussion forum has been set up between the IHR team and representatives of WHO member states, and the revision team has written to all member states asking them to nominate individuals who will provide input to the revision process. In Latin America, the Pan American Health Organization (PAHO) has been working with Mexico, Peru, Brazil, and signatory states of the Mercado Comun del Sur (MERCOSUR) to establish formal collaboration partnerships for the IHR revision process, and MERCOSUR has listed IHR revision follow-up as an agenda topic for its health sector committee. The next stage of consensus-building involves steering working rela- tionships among WHO country representatives, member states, WHO re- gional offices, and international agencies and institutions whose work is related to the IHR. These international agencies include the Food and Agriculture Organization (FAO), International Air and Transport Associa- tion (IATA), International Civil Aviation Organization (ICAO), World Trade Organization (~110), and International Maritime Organization (IMO). DISEASE SURVEILLANCE, PROGRAM MANAGEMENT, AND SUSTAINMENT OF IMMUNIZATION PROGRAMS Donald S. Burke, M.D. Professor of International Health Director, Center for Immunization Research lohns Hopkins School of Hygiene and Public Health, Baltimore, MD A major challenge to post-eradication is knowing how long disease surveillance should be continued, both during immunization and after it. Surveillance is also an important control issue for other viral diseases, such as yellow fever, that are not currently slated for eradication but for which vaccines are available and in various stages of implementation worldwide. Following is a review of several disease control programs and lessons to be learned from their historical examples. Polio Surveillance and Program Management Laboratory surveillance has been crucial to the success of the polio eradication campaigns. Surveillance measures include: . detection and reporting of all cases of acute flaccid paralysis (AFP),

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OPERATIONAL/INSTITUTIONAL CHALLENGES TO POST-ERADICATION 107 . collection of two stood specimens within the first 14 days after the onset of paralysis, isolation and characterization of enteroviruses in cell cultures with particular attention to the polioviruses, and . differentiation between the wild type and polio vaccine virus strains. Differentiating the oral polio vaccine strains is a major challenge to laboratory surveillance because it requires a relatively cumbersome cell culture technique. This is true despite a global network of functional polio eradication laboratories; most small country laboratories experience diffi- culties performing the specialized technique. An example of a typical surveillance caseload is Mongolia, where there are about 1,000 reporting districts throughout the country that participate in ongoing surveillance. Over the past three years, these reporting districts have detected 90 cases of AFP. All 80% of the cases for which specimens were available for laboratory differentiation were confirmed not to be po- lio. The other 20%, for which specimens were unavailable or inadequate for laboratory analysis, were confirmed not to be polio based on clinical evaluation: either there was no residual paralysis on long-term follow-up or, if there was, expert clinical review of the case confirmed that it was not polio. The last confirmed case of polio in Mongolia was in 1993. Measles Surveillance and Program Management Measles cases can be mistaken for dengue, rubella, scarlet fever, and roseola, the clinical manifestations of which overlap and make differential diagnosis difficult. Consequently, as for polio, laboratory surveillance for measles is very important, especially if eradication requires detecting and reporting all compatible cases. In contrast to polio, measles diagnosis is made by detection of IgM antibodies, not virus isolation. Measles infection usually occurs 14 days before the onset of rash, and anti-measles IgM typically appears within the first few days after the rash. The sensitivity of the IgM assay in the first few days after rash is 60 or 70/O, and nearly 100% by the fourth day. Diagnos- tic accuracy relies on the proper timing of specimen collection. As with polio, routine diagnosis is usually done in one of the many eradication network laboratories currently being developed worldwide. Lessons from Yellow Fever Program Management The first attempts at yellow fever eradication were the early campaigns sponsored by the Rockefeller Foundation. In 1915, Wickliffe Rose, the Director of the International Health Commission of the Rockefeller Foun-

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108 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION cation, said that the "international commission was prepared to give aid to eradication of this disease in those areas where the infection is endemic and where conditions would seem to invite cooperation for its control." One of the major reasons these early yellow fever eradication efforts failed was the presence of jungle yellow fever: a cycle of disease that existed in non-human primates and was transmitted by vectors other than Aedes aegypti. During his investigations of epidemics near Muzo, Columbia, in 1907, Colombian scientist Dr. Franco macle several observations that led him to believe that jungle yellow fever existed: the disease could be con- tracted in the forest as well as urban neighborhoods; it was transmitted by other culicine vectors in addition to Ae. aegypti; and its transmission oc- curred during daylight hours. After the 1915 declaration to eradicate yellow fever, William Crawford Gorgas famous for eradicating yellow fever from Cuba and the Panama Canal Zone led a commission into Muzo, Colombia, to investigate re- ports of yellow fever. The existence of jungle yellow fever was not recog- nized at the time, and the commission believed that Ae. aegypti had to be present in order for yellow fever to be transmitted. So when they found no evidence of Ae. aegypti, they concluded that the reported disease could not be yellow fever. Thus, the eradication campaign proceeded in the face of what was most certainly unrecognized jungle yellow fever. It was not until 1935 that Dr. Fred Soper, Regional Director of the Rockefeller Foundation's International Health Division in Rio de Taneiro, acknowledged Franco's contribution and finally agreed that jungle yellow fever existed. The Rockefeller yellow fever program extended into Africa as well, where a yellow fever research laboratory was built in Entebbe, Uganda, in 1936. Although its primary focus initially was yellow fever, over the years this laboratory has been involved with a variety of other viral diseases as well. For example, the West Nile virus was first isolated there in 1938, and studies conducted at the laboratory in the 1930s provided an early under- standing of the ecology and epidemiology of this virus. The facility now houses a major AIDS laboratory, as well as polio and measles surveillance laboratories. Thus, the initial yellow fever investment has resulted in a number of positive spin-offs. The lessons to be learned from yellow fever eradication and control initiatives are, first, that field research is essential to making sound policy decisions. We need to beware of false epidemiological dogma. Second, even a "failed" program can leave a strong legacy on which to build. Influenza Although influenza has never been eradicated, major variants of influ- enza virus, such as HlN1, have spontaneously disappeared. By using

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110 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION vaccine, suggesting that adeno 7 had moved into a vacant niche previously occupied by adeno 4. These findings may have relevance for other immunization programs, such as polio. For example, sequence analysis of the RNA polymerase of the enteroviruses shows that the phylogenies of the Coxsackie A viruses and the polioviruses are intertwined. It has been hypothesized that the only difference between these viruses is the host recognition receptor: poliovi- ruses use the CD155, and the Coxsackie viruses use the ICAM 1. It is possible that a simple receptor switch would provide variants of Coxsackie viruses with properties more like polioviruses. The question is, will Cox- sackie A viruses fill the vacated poliovirus niche? Poliovirus es Detailed discussion about polio revertants and recombinants is pro- vided elsewhere in this report. For example, known instances of reversions of polio vaccines, including the Poland USOL and several Sabin strains, that have led to vaccine-associated paralytic polio (VAPP) epidemics are pre- sented in Table 4-2. Also, a natural recombinant polio wild type Sabin-1 circulated in China for several years; and toward the end of the polio epidemic and the eradication of polio in China, a recombinant strain con- taining sequences from the Sabin vaccine strain spread from person to person, infecting thousands of Chinese. Early lessons learned from the poliovirus are that viral evo~va~oiiity can introduce unexpected wild cards. Viral evolvability raises concerns about all forms of live attenuated vaccines with a proven capacity to efficiently swap genes between humans and animals. Of particular concern are live attenuated vaccines with seg- mented genomes, such as influenza and rotavirus, for which we can almost certainly expect recombinant variants of wilct type and vaccine type to emerge. Hopefully, none will be more virulent or more transmissible than the wild type parent. TABLE 4-2 Reversion of Polio Vaccine to Virulence with Epidemic Spread Year Country Virus (Vaccine) # Cases 1968 Poland Polio-3 (USOL) 464 1988-1993 Egypt Polio-2 (Sabin) 32 Mid-1990s China Polio-2 (Sabin) NR Late-199Os Israel Polio-2 (Sabin) (0) Dominican 2000 Republic/Haiti Polio-1 (Sabin) 19

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OPERA TIONAL/INSTITUTIONAL CHA ~ rENGES TO POST-ERADICA TION 111 Hepatitis B Virus All current hepatitis B virus (HBV) vaccines are either inactivated or not capable of replication. Immunity is directed largely against a particular immunodominant hydrophilic loop of the surface antigen of hepatitis B. In many inqmunized persons, the loop has significant amino acid substitutions that substantially change immunogenicity. These variants are the predomi- nant type of virus present in as many as 20-30% of vaccinees who become infected. Long-term models predict that it will take 30 or 40 years for these escape variants to predominate worldwide. The early lesson learned from HBV is that virus variants may emerge, particularly for vaccines targeting a single major epitope. Virus variants of live attenuated vaccines or complex antigens are less likely to emerge. Conclusion . Several lessons can be learned from our past efforts to control or eradi- cate viral diseases: Yellow fever: The presence of a non-human reservoir (i.e., jungle yellow fever) creates the likelihood for continued reintroduction. Influenza: Accidental reintroduction can result from a stasis reser- vo~r. Smallpox: Malevolent reintroduction poses a serious threat. Polio: A vaccine strain can revert to virulence anchor recombina- tion between vaccine and natural virus. Hepatitis B: "Immune escape" mutants of wild-type virus can . .. . . .. .. evolve and eventually predominate worldwide. HIV: Natural viruses are actively emerging (see Chapter 2~. Francois-Joseph Broussais (1772-1839), one of Napoleon's personal physicians, referred to the "genius of the epidemic." Given the already proven cleverness of the viruses in their ability to frustrate our immuniza- tion strategies, we should carefully consider how viruses might thwart our eradication efforts and how we can detect and promptly counter those moves. Surveillance is crucial to successful eradication. As eradication cam- paigns near completion, the potential for viral surprises will increase, not decrease. "Forward" laboratories are a vital part of surveillance. Labora- tory capacity should be strengthened, especially in regions where eradica- tion is difficult and/or variants are likely to emerge.

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112 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION THE CAPACITY OF PUBLIC HEALTH SERVICES TO RESPOND TO AN OUTBREAK IN THE POST-ERADICA~ON EM Car! E. Taylor, M.D., M.P.H. Professor Emeritus, Department of International Health Johns Hopkins School of Hygiene and Public Health, Baltimore, MD During global eradication initiatives, global priorities tend to override local priorities. Evidence suggests, however, that there are cost-effective, synergistic ways to meet both objectives simultaneously. Indeed, empower- ing local communities with strong primary health care infrastructures which they can rely on to solve their own problems is the best way to prevent emerging disease outbreaks. New advances in Community-Based Primary Health Care (CBPHC) provide new hope for building synergisms between competing goals in order to cope with emerging infections. In accordance with the World Health Assembly resolution in 1988, nations made a commitment to pursue polio eradication "in ways which strengthen the development of immunization programmer as a whole, fos- tering its contribution, in turn, to the development of the health infrastruc- ture and of primary health care." Recently, this level of commitment has been evaluated in several ways. Recent Reports A 1993 PAHO commission involving a detailed qualitative assessment of polio eradication (PE) in six Latin American countries concluded that PE strengthened health systems in countries that already had a basic health infrastructure. This success could not, however, be extrapolated to coun- tries with weak health systems. The greatest positive impact of PE was on social mobilization and intersectoral cooperation, two of the three main goals of the Alma Ata World Conference on Primary Health Care in 1978. However, negative effects were also seen, mainly competition between com- ponents of the health infrastructure as a result of aggressive targeting. Other recent evaluations of the great progress in worldwide PE call for a greater awareness of the fact that the eradication experience will be different in places where health services are weak or nonexistent compared to places with well-established health systems, as was shown in malaria eradication efforts in the 1960s. Comprehensive recommendations have been made about the many "missed opportunities" and the need for a new organizational framework to strengthen the health service infrastructure. Recommendations from a WHO meeting in December 1999 include:

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OPERATIONAL/INSTITUTIONA ~ CHALLENGES TO POST-ERADICATION 1 13 Monitor "key indicators" of impact on health systems. Compile existing documentation, especially gaps in equity, com- munity ownership, political will, public-private partnership, peace build- ing, Vitamin A supplements, laboratory capacity, and opportunity costs. Establish an oversight committee for the health systems-strength- ening aspect of the PE goal. Engage broader participation of those with expertise in health sys- tems to ensure action on "missed opportunities." . The WHO report warned that "as polio eradication enters its most difficult stages, many health experts express their concerns that the ARIA promise ... will not be achieved, unless greater efforts are made. Intensive, accelerated, polio activities are underway ... and the fear, expressed by some, is that there will not be enough staff time or energy to take on the broader agenda of strengthening routine immunization and health systems. . . . Today, routine immunization coverage is at the lowest it has been in a decade in many countries and health systems have not effectively responded to decentralization, particularly in the provision of preventive services." Finally, the report suggests that help will be needed from GAVI (Global Alliance for Vaccines and Immunization), presumably because the amount of money needed has dramatically increased. Dilemma Or In the past, the costs of focusing only on direct eradication services have been justified by cost-effectiveness calculations indicating that when PE is declared there will be a savings of at least $1.5 billion per year per country. Thus, countries where wild virus still occurs are pressured to pay more attention to the global priority for PE rather than the diseases killing their own children. Now, however, we are beginning to realize the impor- tance of strengthening local health systems. Deficiencies in diagnostic and treatment capacity decrease surveillance capacity and can create a long time lag between the occurrence and identi- fication of outbreaks. Identification of outbreaks will be especially impor- tant after eradication is declared complete, and it is critical that local health systems be strengthened in order to meet this demand. Stronger local health systems are also needed to increase child immunization rates. UNICEF is now using independent surveys for the State of the World's Children Report and is changing some of its earlier claims about child immunization patterns of the past decade. In India, between 1999 and 2000, the percentage of children reported as fully immunized dropped on average 20 points, from the 80s to the 60s. In China, at the same time immunization rates dropped on average 10 percentage points.

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114 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION There are tremendous differences in immunization rates within coun- tries, as shown by data from the USAID-funded Demographic and Health Surveys in India. The Pulse Polio National Immunization Days (NIDs) that began in 1995 have resulted in the greatest public health events in history with reports of having reached more than 100 million children. Rates in the advanced southwestern states of India were already good, and the NIDs raised them to over 90%. However, in the north central states of India where the rates were low, they remain low. Twenty-nine percent of children in two Indian north central states (Uttar Pradesh and Arunachal Pradesh) still had no reported immunizations. Uttar Pradesh's population is equiva- lent to the 10th largest country in the world. Similar reports are emerging from Africa. 3: Need for Cooperation for Adequate Surveillance There is abundant evidence that PE efforts and actions to strengthen local health systems can produce powerful synergisms. PE depends on both NIDs and surveillance, both of which in turn depend on technological mobilization and research on the changing nature of health services. They also depend on flexible methods of social mobilization to bring vaccines and children together and ways to identify and diagnose acute flaccid pa- ralysis (AFP). The technological mobilization is straightforward, especially when outside funding for campaigns is available. However, the reality is that equipment lasts only about 10 years in developing countries and vac- cines have to be paid for annually. There is great uncertainty about the sustainability of social mobiliza- tion. In the past, social mobilization has been based on a passive and unsustainable model. However, there is an alternative model which relies on community empowerment that works amazingly rapidly if programs are organized to promote community self-reliance rather than dependency. In recent years, there has been great progress in understanding the process of community empowerment. It is no longer necessary to assume, as we did earlier, that community empowerment happens by chance. It has, for many of us, been baffling and contrary to other experience to see the success of social mobilization for polio. Everyone, and especially the bureaucrats doing the implementation, have been amazed at the response. Even the poorest countries can generate a local commitment that brings together immunizations and mothers and children in the most massive health events of all time. Global pressure has made leaders of the poorest countries feel ashamed if they do not cooperate and mobilize all govern- ment resources for this global priority. The local commitment was under- standable for vaccine campaigns targeted at one of the main causes of child death. But it is unclear why the commmitment persists for a disease that is

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OPERATIONAL/INSTI~TIONAL CHALLENGES TO POST-ERADICATION 1 15 so rare that local peoples have no name for it and, in some places, efforts to educate the people about the disease involve searching for relatively rare cases with residual paralysis to use as audiovisual aids. Why do the local people think that there is so much official concern for these diseases? Do they think that the vaccinations have some special power? Do they think the oral drops will make it less necessary for their children to receive the painful injections that make them cry? How long will poor countries con- tinue to let global priorities completely override local priorities? And, most importantly, what can we do so that the remarkable public enthusiasm for PE social mobilization enhances other immunization programs and pro- motes interventions for the main infections that cause death in each local- ity, thereby truly balancing global and local priorities? Although the amazing and highly publicized advances in technical and social mobilization for PE are impressive, there have also been parallel but not publicized advances in community-based primary health care. It is time to bring the two streams of progress together. Evidence shows that building primary health care infrastructure is not necessarily expensive and slow. After the Alma Ata Conference, the claim was made by donors that com- prehensive primary health care does not go to scale and only selective approaches can be extended. However, we now know that sustainable services can be expanded remarkably rapidly to cover whole regions. The key issue is whether the social mobilization necessary for NIDs and surveillance can be accomplished using an approach that will not collapse when outside funding and expatriates are gone. Great effort is already being directed toward building capacity and mobilizing volunteers, so it will only take a little more patience to build a self-reliant community. Top- down processes create dependency, not self-reliance. A remarkable feature of the new process is that it includes the best hope for long term financing. International Monetary Fund (IMP) economic reforms cut health budgets in Africa by a third to a half in the 1980s. Donors dumped responsibility for public health back onto countries, except for the few diseases that could be attacked by campaigns, and countries dumped responsibility onto communities. It is clear that communities will eventually have to assume responsibility for self-financing, except for the very poor who will need subsidization and for whom sustainable financing must be found. Talk about insurance is relevant only for people with re- sources. Now, with worldwide privatization of health care and pharmaceu- ticals, the prospects for care for the poor seem even more jeopardized unless . . . . . ll:lternatlOna~ . equity IS ta ten serious Y. Condusion Objective research is needed to determine if scientific and technical

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116 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION improvements in immunization strategies better control infectious diseases. Research is also needed to gain a better understanding of the role of social mobilization in successful immunization programs. How can this amazing phenomenon be used to build a sustainable local capacity for solving a nation's own public health problems? Strong local health services and em- powered communities are the best framework for preventing the disease outbreaks that this conference is addressing. LABORATORY SECURITY AND REGULATIONS GOVERNING VIRAL PATHOGENS IN A POST-IMMUNIZATION ERA Raymond H. Cypess, D.V.M., Ph.D., President and CEO Frank P. Simione, M.S., Vice President, Safety and Regulatory Affairs American Type Culture Collection (ATCC), Manassas, VA Managing virus stocks under good laboratory security and in compli- ance with current regulations can best be accomplished by applying prac- tices currently in place at Biological Resource Centers (BRCs) (Table 4-3~. BRCs play an essential role in the biological research infrastructure by coordinating the shared use of validated biomaterial and data among gov- ernment agencies, industry, academia, and the public. They serve as reposi- tories, service providers, and knowledge managers. They authenticate, pre- serve, and distribute living cells, genomes, model organisms, research tools, and information relating to heredity and functions of living systems. Of particular relevance to public health and infectious disease pro- grams are BRCs that specialize in microbiology. These are collections of culturable organisms, viable but not yet culturable organisms, replicable parts of these materials, and associated data. BRCs relieve storage and distribution burdens for investigators and institutions, and they provide controlled on-site biosecurity and access to their holdings. Types of BRCs included 1Key to abbreviations: ATCC, American Type Culture Collection; BDSC, Bloomington Drosophila Stock Center, Indiana University; CBS, Centraalbureau voor Schimmelcultures; CDC, Centers for Disease Control and Prevention; CGC, Caenorhabditis Genetics Center; Coriell Institute for Medical Research, New Jersey; DSMZ, Deutsche Sammlung van Mikroorganismen und Zellkulturen GmbH; IFO, Institute for Fermentation, Osaka; JCM, Japan Collection of Microorganisms; NRCC, National Resource Center for Cephalopods, University of Texas; RPRC, Regional Primate Research Center; RSMAS, Rosenstiel School of Marine and Atmospheric Science; USDA, U.S. Department of Agriculture

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OPERATIONAL/INSTITUTIONAL CHALLENGES TO POST-ERADICATION 117 Microorganisms (e.g., ATCC, CBS, CDC, DSMZ, ~CM), Plant germplasm, i.e., seeds, clones, cells, and tissue (e.g., ATCC, DSMZ, USDA), Animal cells and tissue (e.g., ATCC, Coriell, IFO), Vertebrate models (e.g., rodents at Jackson Laboratories, primates at RPRC, zebrafish at University of Oregon), and . Invertebrate models (e.g., Drosophila at BDSC, nematodes at CGC, Aplysia at RSMAS, cephalopods at NRCC). A challenge to eradication is identifying where viral stocks are currently housed, which requires a systematic inventory of existing biorepository holdings. Persons responsible for the materials must be forthcoming in complying with requests for this information. As laboratories are identified, an attempt should be made to transfer all specimens to those biorepositories that demonstrate well-developed and documented procedures for safe handling and security. Good biorepository management practice requires documenting, managing and securing strain data, ensuring safe handling in the laboratory and in the biorepository, and strict management of access to and distribution of the agent. Storage in select biorepository holdings will ensure that the agents are available for ongoing laboratory studies, as needed, with minimal risk of reintroducing the disease into the general population and environment. Agents that present a grave cianger to a post-immunization community TABLE 4-3 The Role of Biological Resource Centers Provide central source and controlled access to standard biomaterials, reagents, and data Provide controlled conditions for on-site biosecurity Provide central source of technical support Minimize redundancy of biomaterials Relieve storage and distribution burdens for investigators Coordinate regulatory compliance Provide safety deposit for essential germplasm Support equitable sharing of biomaterials Provide intellectual property management and services Provide knowledge management and distribution Promote translation of research discoveries into practical applications Facilitate industrialization of technologies in medicine, public health, pharmacy, agriculture, food, and environment

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118 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION should be stored in facilities with Biosafety Level 4 (BSL-4) containment capability. Admittance to material can be restricted by providing secure, con- trolled access to the viral agents. Levels of access should be established so that the most dangerous strains have the greatest restrictions for access and use. End-users should be qualified to work with the agent, and their institu- tions capable of ensuring adequate biocontainment and security. BRC Lab Security Acceptable acquisition practices start with a sound demonstrated knowledge of the material and its potential hazards. Acquisition is usually accompanied by material acquisition agreements which can be used to record information on the agent, its potential laboratory risk, and condi- tions under which the material is being provided to the biorepository. In order to ensure that the agent is safely and securely maintained in a viable unchanged state, low-temperature storage with redundant controls on equipment should be used to maintain cryopreserved stocks, and multi- response alarm monitoring should be available. All work performed on the virus stocks in the laboratory must be conducted under good biosafety practices. Potential hazards should be iden- tified through risk assessments and, where appropriate, laboratory workers should be immunized. However, live viral vaccines such as those available for poliovirus may present a risk if immunized laboratory staff shed the virus outside the laboratory and potentially expose a non-immunized com- munity. Those agents posing serious risk to the community should be handled under BSL-3 containment and practices, and some agents may require BSL-4 containment. Disposal must avoid risks associated with handling of infectious mate- rials. The best practice is inactivation of biological materials in the labora- tory, as required for BSL-3 and BSL-4 containment. Even in a BSL-2 labo- ratory, accommodations should be made for destruction of biohazardous agents within the laboratory area. Internal security is especially important for stocks that cause disease for which immunization has been discontinued or that create a high risk of life- threatening disease. Physical access to the virus stocks can be controlled by securing freezers with combination or key locks that require two people to unlock the freezer and by controlling access to the area of the facility where the freezers are housed. Physical access to the biorepository can also be controlled by using key-card or other individual access identifiers. Acldi- tiona! safeguards include denying individuals access to both the

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OPERATIONALnNSTITUTIONAL CHALLENGES TO POST-ERADICATION 119 biorepository and freezer, thus requiring two people to obtain or deposit biohazardous agents. Freezer inventories should be designed so that a locator code is needed to find the desires! material. Locator codes can be kept in strictly controlled, secure databases. Access to freezers wouict be denied to those who also have access to the locator codes, again requiring two people to retrieve or deposit material. Chain of custody documentation a system of sign-offs that tracks the movement of materials should be established to verify authorized access to the material. Evidence of the disposition of all material released to a laboratory, including destruction of records, should also be documented. Access and Transfer of BRC Materials to Outside Sources A mechanism for verifying a recipient's legitimate need for the material must be established and controlled independently of the biorepository. The recipient should be located at an institution where work with the agent is approved and all necessary safety and security policies and practices are in place. A mechanism such as that used by the Centers for Disease Control and Prevention (CDC) for controlling the transfer of designated select agents should be used for agents for which immunization has ceased (Code of Federal Regulations 42, Part 72.6~. The greatest risk of transferring viral agents to an outside laboratory is the potential for an unqualified end-user to gain access to the virus. There- fore, there must be some way to ensure that the receiving laboratory is capable of controlling access and preventing the release of restricted etio- logical agents to known or suspected persons, institutions, or countries that represent a proliferation risk for biowarfare or bioterrorism. With the aid of appropriate federal authorities, including the departments of Commerce, State, and Treasury, the biorepository must be able to screen potential recipients. Distribution of disease-causing viral agents requires strict adherence to the permit and licensing requirements of local, state, federal, and interna- tional agencies. End-users should process requests for their material through an institutionally controlled system that identifies materials needing special permits and licenses. The biorepository should be familiar with the regula- tions on packaging, shipping, and tracking to ensure safe and controlled transfer of material. For example, the release of any biological material from ATCC- re- gardless of risk category requires that the requester provide an organiza- tional profile and documented assurance that the facility is equipped to handle the material safely and securely. In addition, all requests for biologi- cal materials from ATCC are screened against U.S. government lists of

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120 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION denied individuals, entities, and embargoed countries, and all required per- mits and licenses are applied where appropriate. Conclusion Assuring the security of post-eradication viral agents is critical to suc- cessful eradication. But it is only achievable if good practices for the acqui- sition, preservation, authentication, and distribution of the materials are applied. BRCs can continue to provide safe and secure management and control stocks of post-eraclication viral agents. It is critical, however, that access to potentially dangerous microbial agents be controlled uncler strict guidelines and regulations mandated outside the BRCs, and that BRCs function solely as a means of ensuring compliance with these requirements.