5
Preparing for the Next Disease Outbreak

OVERVIEW

Although it is possible that the future will bring a more contagious, deadly form of SARS, it is certain to bring influenza and other infectious diseases, some of which may be introduced intentionally. Recognizing that it would be impossible to address the vast array of potential microbial threats individually, public health policy makers are formulating strategies to evaluate and respond to outbreaks of all kinds. Lessons learned from the recent SARS epidemic regarding surveillance and containment were described in earlier chapters; this chapter will discuss additional strategic issues, including anticipating the confluent threats of SARS and influenza, understanding the epidemiological factors that are likely to shape future epidemics, and ensuring that public health institutions and legal frameworks are appropriately designed for responding to any new outbreaks.

Like SARS and influenza, many of the microbial pathogens to come are likely to be viral zoonoses. The paper by Richard Webby and Robert Webster in this chapter argues that the trends that ushered SARS into the human population are in fact similar to those seen over a century of influenza outbreaks. As with SARS, livestock and poultry markets provide a breeding ground for influenza outbreaks, and laboratory sources appear to have sparked at least one epidemic. Although recent severe outbreaks of avian influenza have not featured viral transmission between humans, it may be only a matter of time until a highly contagious flu, such as the strain that is estimated to have caused over 20 million and perhaps as many as 40 million deaths in 1918–1919, confronts the world.

In the case of influenza, in which the virus can be anticipated to some extent, vaccines and antiviral therapies can play a significant role in containing an epi-



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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary 5 Preparing for the Next Disease Outbreak OVERVIEW Although it is possible that the future will bring a more contagious, deadly form of SARS, it is certain to bring influenza and other infectious diseases, some of which may be introduced intentionally. Recognizing that it would be impossible to address the vast array of potential microbial threats individually, public health policy makers are formulating strategies to evaluate and respond to outbreaks of all kinds. Lessons learned from the recent SARS epidemic regarding surveillance and containment were described in earlier chapters; this chapter will discuss additional strategic issues, including anticipating the confluent threats of SARS and influenza, understanding the epidemiological factors that are likely to shape future epidemics, and ensuring that public health institutions and legal frameworks are appropriately designed for responding to any new outbreaks. Like SARS and influenza, many of the microbial pathogens to come are likely to be viral zoonoses. The paper by Richard Webby and Robert Webster in this chapter argues that the trends that ushered SARS into the human population are in fact similar to those seen over a century of influenza outbreaks. As with SARS, livestock and poultry markets provide a breeding ground for influenza outbreaks, and laboratory sources appear to have sparked at least one epidemic. Although recent severe outbreaks of avian influenza have not featured viral transmission between humans, it may be only a matter of time until a highly contagious flu, such as the strain that is estimated to have caused over 20 million and perhaps as many as 40 million deaths in 1918–1919, confronts the world. In the case of influenza, in which the virus can be anticipated to some extent, vaccines and antiviral therapies can play a significant role in containing an epi-

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary demic. However, strategic actions recommended against influenza that could also inform efforts to better prepare for other viral disease outbreaks have yet to be implemented. These strategies include:1 stockpiling of broad-spectrum antiviral drugs, advanced development of pandemic strain vaccines, the establishment of surge capacity for rapid vaccine production, and the development of models to determine the most effective means of delivering therapies during an outbreak. It is evident from the experience of the late 2003 influenza season that our supply and effectiveness of antiviral drugs, capabilities to accurately predict the best viral strain for annual vaccine production, and mechanisms for surge capacity production remain inadequate (Treanor, 2004). Recognition of these vulnerabilities led numerous workshop participants to call for greater scientific and financial investments to strengthen our defenses against these certain future threats. However, most emerging infections other than influenza will represent a truly novel threat for which the world is inadequately prepared. In these cases, models based on detailed observations from previous epidemics can be used to predict demands on hospital capacity during a hypothetical epidemic and to guide the timing and nature of quarantine measures. Two papers in this chapter (Amirfar et al. and Kimball et al.) examine the modeling strategies that have been used for analyzing public health responses to epidemics as well as the particular challenges that SARS presented for international disease surveillance and alert networks. As with other public health measures, these strategies are potentially applicable not just to SARS but to any future outbreaks in which appropriate actions to protect the public’s health must be taken swiftly (and possibly even before the complete clinical profile of the new disease and the etiological agent behind it are fully understood). When containment measures such as quarantines must be put in place, establishing the trust of the public is crucial to their effectiveness. Social cohesion and compliance with SARS quarantine in Toronto, for example, have been attributed in part to a combination of clear communication and practical guidance by public health authorities. In the extreme case of mandatory quarantine, enforcement requires careful planning and a clear understanding of public health law. This is particularly true in the United States, where quarantine is likely to necessitate the coordination of federal, state, and local jurisdictions and legal authorities. As Gene Matthews’ paper elaborates, additional legal considerations include: due process, which requires proper notice; legal representation; court-reviewed decisions; and remote communications to permit a quarantined person to be heard in 1   Workshop presentation, Robert Webster, St. Jude Children’s Research Hospital, October 1, 2003.

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary court, as well as practical contingencies such as the need for law enforcement officials to serve notice of quarantine. As the world becomes more conscious of microbial threats to health, countries are increasingly recognizing the necessity of reporting outbreaks promptly and cooperating fully in international efforts to contain them. Indeed, if there is one piece of good news to be noted from last year’s epidemic, it is the fact that—as David Heymann and Guenael Rodier observe in this chapter—an array of diagnostic and surveillance tools, coordinated strategies of containment, and international collaboration among scientists and public health authorities were in this case able to control the outbreak of SARS, even in the absence of curative drugs or vaccines. Nevertheless, last year’s experiences further reinforce the lessons that HIV/AIDS, influenza, Ebola, malaria, and a host of other persistent and emerging infectious diseases have already made clear—that the health of any one nation cannot be isolated from the health of its neighbors, and that public health challenges in any locality have the potential to reverberate swiftly around the globe. Karen Monaghan’s paper for the National Intelligence Council, which concludes this chapter, summarizes the continuing threat that SARS may still pose, as well as the challenges that lie ahead for attempting to contain any further deadly outbreaks of SARS or other infectious diseases in the future. ARE WE READY FOR PANDEMIC INFLUENZA? Richard J. Webby and Robert G. Webster2 Division of Virology, Department of Infectious Diseases, St. Jude Children’s Research Hospital Reprinted with permission from Webby and Webster, 2003. Copyright 2003 AAAS. During the past year, the public has become keenly aware of the threat of emerging infectious diseases with the global spread of severe acute respiratory syndrome (SARS), the continuing threat of bioterrorism, the proliferation of West Nile virus, and the discovery of human cases of monkeypox in the United States. At the same time, an old foe has again raised its head, reminding us that our worst nightmare may not be a new one. In 2003, highly pathogenic strains of avian influenza virus, including the H5N1 and H7N7 subtypes, again crossed from birds to humans and caused fatal disease. Direct avian-to-human influenza transmission was unknown before 1997. Have we responded to these threats by better preparing for emerging disease agents, or are we continuing to act only as crises arise? Here we consider progress to date in preparedness for an influenza pan- 2   We thank W. Shea for helpful advice, S. Naron for editorial assistance, and A. Blevins for illustrations. Influenza research at St. Jude Children’s Research Hospital is supported by Public Health Service grant AI95357 and Cancer Center Support (CORE) grant CA–21765 from the National Institutes of Health and by the American Lebanese Syrian Associated Charities (ALSAC).

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary demic and review what remains to be done. We conclude by prioritizing the remaining needs and exploring the reasons for our current lack of preparedness for an influenza pandemic. In February 2003, during a family visit to mainland China, a young girl from Hong Kong died of an unidentified respiratory illness. After returning to Hong Kong, both her father and brother were hospitalized with severe respiratory disease, which proved fatal to the father. When H5N1 (avian) influenza virus was isolated from both patients, the World Health Organization (WHO) went to pandemic alert status (WHO, 2003a). At about the same time, there were rumors of rampant influenza-like disease in China. Influenza experts feared that H5N1 influenza virus had acquired the ominous capacity to pass from human to human. That outbreak is now known to have been SARS, caused by a novel coronavirus. In March 2003, another alarming situation arose on the other side of the world. A highly pathogenic H7N7 avian influenza outbreak had recently erupted in the poultry industry of the Netherlands (Koopmans et al., 2003), and workers involved in the slaughter of infected flocks contracted viral conjunctivitis. The H7N7 virus isolated from these patients had several disquieting features: Not only could it replicate in the human conjunctiva, but there was also evidence of human-to-human spread. Nearby herds of swine (which are often implicated in the adaptation of influenza viruses to humans) also showed serologic evidence of exposure (Koopmans et al., 2003). When a veterinarian died of respiratory infection (Abbott, 2003; Koopmans et al., 2003; Sheldon, 2003; van Kolfschooten, 2003), WHO again acknowledged the presence of a severe threat (WHO, 2003b). Luckily, the worst-case scenarios did not come about in either of the 2003 avian influenza virus scares. However, the year’s events eliminated any remaining doubts that global advance planning for pandemic influenza is necessary. They also highlighted how far, as a scientific community, we have come since the 1997 event: We are now much better equipped with technologies and reagents to rapidly identify and respond to pandemic influenza threats. On the other hand, the legislative and infrastructure changes needed to translate these advances into real public health benefits are alarmingly slow. The Role of WHO in Influenza Surveillance and Control In 2001, WHO initiated the development of a Global Agenda for Influenza Surveillance and Control. Its four main objectives are to strengthen influenza surveillance, improve knowledge of the disease burden, increase vaccine use, and accelerate pandemic preparedness (Stohr, 2003). In May 2002, this document was adopted after proposals and public comment were invited. The document advocates the development of methods and reagents that can be used to rapidly identify all influenza virus subtypes, thereby allowing integrated influenza surveillance in humans and in other animals. WHO, with its global influenza network of more than 100 laboratories and its distinguished record of planning for

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary yearly interpandemic influenza, is ideally situated to play a broader role in facilitating international cooperation for the rapid exchange of viruses, reagents, and information. Influenza continually evolves at the human–lower animal interface and thus can be unpredictable. As an example, within a brief period, the H7N7 virus events occurred in European poultry and humans, H5N1 viruses infected Asian poultry and humans, and novel, rapidly spreading reassortant viruses were isolated in swine in the United States (Olsen, 2002; Zhou et al., 1999). Therefore, the capacity to simultaneously manage multiple potential pandemic situations is important. The WHO global agenda document will help to prioritize areas of influenza research and facilitate national pandemic preparedness plans. Prioritization of Viral Subtypes for Surveillance and Control Influenza experts agree that another influenza pandemic is inevitable and may be imminent (Figure 5-1). A major challenge in controlling influenza is the sheer magnitude of the animal reservoirs. It is not logistically possible to prepare reagents and vaccines against all strains of influenza encountered in animal reservoirs, and therefore, virus subtypes must be prioritized for pandemic vaccine and reagent preparation. Preliminary findings have identified the H2, H5, H6, H7, and H9 subtypes of influenza A as those most likely to be transmitted to humans. (Influenza viruses are typed according to their hemagglutinin [H] and neuraminidase [N] surface glycoproteins.) The influenza A subtypes currently circulating in humans, H1 and H3, continue to experience antigenic drift. That is, their antigenic surface glycoproteins are continually modified, allowing them to escape the population’s immunity to the previous strain and thus to continue causing annual outbreaks. Although these continual modifications may lead to an increase in virulence, the mildness of the past three influenza seasons suggests that the dominance of the H1N1 and H3N2 viruses is waning as their ability to cause serious disease becomes increasingly attenuated. H2 influenza viruses are included in the high-risk category because they were the causative agent of the 1957 “Asian flu” pandemic and were the only influenza A subtype circulating in humans between 1957 and 1968. Counterparts of the 1957 H2N2 pandemic virus continue to circulate in wild and domestic duck reservoirs. Under the right conditions (which are still not completely understood), H2N2 viruses could again be transmitted to and spread among humans, none of whom under the age of 30 years now has immunity to this virus. Seroarchaeology data from the late 19th and early 20th centuries indicate that only the H1, H2, and H3 influenza virus subtypes have been successfully transmitted among humans. It is possible, but unlikely, that they are the only subtypes able to do so. Not only are the H1, H2, and H3 influenza viruses of concern, but the H5 subtype has threatened to emerge as a human pandemic pathogen since 1997, when it killed 6 of 18 infected humans. Before that event, the receptor specificity of avian influenza viruses was thought to prevent their direct transmission to hu-

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary FIGURE 5-1 Timeline of human influenza over the past 100 years. The black triangles represent documented human influenza A infections characterized by multiple cases. In each instance the species of animals implicated in the emergence of disease is highlighted. Since 1997 there has been a disproportionate increase in the number of reports of novel subtypes in humans and in the number of animal and bird species involved, suggesting that the next influenza pandemic is imminent.

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary mans. Transmission from aquatic birds to humans was hypothesized to require infection of an intermediate host, such as the pig, that has both human-specific (α-6 sialic acid) and avian-specific 2-3 sialic acid) receptors on its respiratory epithelium. The 1997 H5N1 event demonstrated that domestic poultry species may also act as intermediate hosts. H5N1 viruses continue to emerge and evolve despite heroic measures taken to break their evolutionary cycle in the live poultry markets of Hong Kong: the elimination of live ducks and geese (the original source), the elimination of quail (the source of the internal genes of H5N1/97), and the institution of monthly “clean days,” when all 1,000-plus retail markets are emptied and cleaned. Two things have become clear. Live poultry markets are potential breeding grounds for influenza and other emerging disease agents, and there is an Asian source of H5N1 influenza viruses outside of Hong Kong SAR. Between 1997 and 2003, H5N1 virus was isolated from duck meat imported from China into Korea (Tumpey et al., 2002) and Japan (ProMED-mail, 2003). These observations suggest that ducks and possibly other avian species in mainland China are a reservoir of H5N1, although there have been no official reports of H5N1 virus in China. At the beginning of the SARS outbreak, China missed an opportunity to show the world its considerable intellectual and scientific potential (Enserink, 2003a). In the case of H5N1 influenza, a pandemic in waiting, it remains to be seen whether China will show leadership in proactively addressing the problem. Concerted national and international efforts are required to deal effectively with the threat. The third virus subtype on the most wanted list is H7. The H7 and H5 viruses have a unique ability to evolve into a form highly virulent to chickens and turkeys by acquiring additional amino acids at the hemagglutinin (HA) cleavage site (HA cleavage is required for viral infectivity) (Steinhauer, 1999). The highly pathogenic H7N7 influenza viruses that were lethal to poultry infected the eyes of more than 80 humans and killed one person (Enserink, 2003b). In the case of this outbreak, the Netherlands’ policy of openness was important in reducing the potential threat and should serve as a model. When the virus was first detected at the end of February 2003, the European Community and international community, via the Office International des Epizooties, were notified so that surrounding countries, including Belgium and Germany, could immediately respond if the disease was detected. Culling of all poultry on infected farms and quarantine of surrounding farms succeeded in eradicating the virus once the etiologic agent was identified. After human infection was observed, an anti-influenza drug was given as prophylaxis, and vaccination with the current human influenza vaccine was done to reduce the likelihood that the avian virus would reassort with human H1N1 and H3N2 strains. The remaining two viral subtypes on the priority list, H6 and H9, do not share the virulent phenotypes of the H5 and H7 viruses, but still pose a considerable threat. Both of these influenza viruses have spread from a wild aquatic

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary bird reservoir to domestic poultry over the past 10 years. H9N2 viruses have also been detected in humans and in pigs (Peiris et al., 1999, 2001) and have acquired human-like receptor specificity (Matrosovich et al., 2001). Neither of these viruses was able to infect chickens before the mid-1980s. Now, for unknown reasons, H9 viruses are endemic in chickens in Eurasia and H6 viruses are becoming endemic in both Eurasia and the Americas. These facts highlight the continuing adaptation of influenza viruses in the aquatic bird reservoirs to domestic chickens. The Challenge of Developing Candidate Vaccines If the next influenza pandemic were to begin tomorrow, inactivated vaccines would offer the only immediate means of mass prophylaxis, yet their supply is limited by inadequate production capabilities and suboptimal utilization of adjuvants (Fedson, 2003; IOM, 2003). The stocks of antiviral drugs are too low to cope with an epidemic and would be quickly depleted (IOM, 2003). Tissue culture–based and live attenuated vaccines are now licensed in some countries, and could supplement the supply of inactivated vaccine. Further development of these options is urgently needed to provide alternative substrates in the face of a pandemic. Since the 1970s, influenza vaccines have been made by exploiting the tendency of the segmented influenza genome to reassort (Wood and Williams, 1998). This natural process has been used to produce vaccine strains that simultaneously contain gene segments that allow them to grow well in eggs and gene segments that produce the desired antigenicity. Natural reassortment is allowed to occur in embryonated chicken eggs, and reassortants with the desired characteristics are selected. These recombinant vaccine strains contain the hemagglutinin and neuraminidase genes of the target virus (encoding glycoproteins that induce neutralizing antibodies); their remaining six gene segments come from A/Puerto Rico/ 8/34 (H1N1), which replicates well in eggs and is safe for use in humans (Kilbourne, 1969). These “6+2” reassortants are then grown in large quantities in embryonated chicken eggs, inactivated, disrupted into subunits, and formulated for use as vaccines. Although this process creates an effective and safe influenza vaccine, it is too time-consuming and too dependent on a steady supply of eggs to be reliable in the face of a pandemic emergency. Even during interpandemic periods, 6 months is required to organize sufficient fertile chicken eggs for annual vaccine manufacture (Gerdil, 2003), and the preparation of the desired “6+2” recombinant vaccine strain can be a time-consuming process. Influenza vaccine preparation is seasonal and is a remarkable achievement, in that an essentially new vaccine is made every year. However, two of the viruses of greatest concern, those of the highly pathogenic H5 and H7 subtypes, cannot be successfully grown in eggs. Their unique ability to accumulate multiple basic amino acids at the site of hemagglutinin cleavage increases their ability to spread systemically in an in-

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary fected host and cause significant disease (Steinhauer, 1999). This feature also renders H5 and H7 viruses rapidly lethal to chicken embryos. The most promising means of expediting the response to pandemic influenza is the use of plasmid-based reverse genetic systems to construct influenza virions and vaccines. These systems also offer a successful alternative means of producing H5 and H7 vaccine seed strains. Because viable viruses can be generated from individually cloned cDNA copies of each of the eight viral RNA segments, reassortment can be prospectively defined and directed, and the extra amino acids at the HA cleavage site (which are associated with high virulence) can be removed to allow rapid generation of a vaccine seed strain in eggs. Plasmids encoding the internal genes of the base vaccine are already available. A vaccine seed strain can be created by cloning the appropriate hemagglutinin and neuraminidase genes from the target virus, altering its HA connecting peptide if necessary, and transfecting an appropriate cell line (see Figure 5-2). This technology has been shown to be effective for the production of reassortants carrying several different surface glycoprotein combinations, including those considered to have a high pandemic potential (Hoffman et al., 2002; Liu et al., 2003; Schickli et al., 2003; Subbarao et al., 2003). The next step is to take these plasmid-derived influenza vaccines through clinical trials to address crucial questions such as number and quantity of doses and the role of adjuvants. Most of the vaccines derived after the 1997 H5N1 episode by various alternative strategies induced a disappointing immune response (Wood, 2001). The optimal pandemic vaccination regimens can be anticipated only by collecting the necessary data and experience through clinical trials of vaccines against different subtypes of influenza virus. Although they are well suited to the manufacture of inactivated influenza vaccines, reverse genetic systems introduce new variables. One of the most limiting of these is the need to use cell lines. There are surprisingly few suitable accredited cell lines and cell banks available, and many of those are the property of pharmaceutical companies. The practical options are very few, in view of the technical and regulatory restrictions. Perhaps the only cell line that meets all criteria for international use at this time is the African green monkey kidney cell line, Vero. However, although Vero cell lines are in widespread laboratory use, only those that are derived from WHO-approved sources and have a detailed history are acceptable for manufacture of human pharmaceuticals. A second new variable is the use of a genetically modified virus seed strain. Because the traditional vaccine strains are made by natural reassortment, they have escaped being labeled “genetically modified.” This difference, although largely semantic, may affect the acceptance of the new vaccines. Before many of these traits can be tested, the virus must be amplified, inactivated, purified, and formulated for vaccine use (Gerdil, 2003). In preparing for a pandemic threat, collaboration between government, industry, and academia is needed to overcome the obstacles and guarantee the most rapid production of a vaccine candidate. The recent SARS episode has shown that international collaboration in the face of a truly global threat is indeed possible.

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary FIGURE 5-2 Proposed method of influenza vaccine seed virus production using the eight-plasmid reverse genetics system (Hoffman et al., 2002). The hemagglutinin (HA) and neuraminidase (NA) genes from the target strain are cloned into the bacterial plasmid vector pHW2000 in a process that allows for the alteration of the HA cleavage site when necessary (see text for explanation). These two plasmids, along with six others containing the remaining influenza A gene segments derived from the master vaccine strain A/Puerto Rico/8/34 (H1N1), are then introduced into a suitable cell line (e.g., Vero). After expression of positive- and negative-sense RNA and viral proteins from these plasmids, a productive replication cycle is initiated and viable virus particles are produced. The Safety Testing of Candidate Pandemic Vaccines and Liability Issues Unfortunately, there are only a few facilities available to carry out safety testing under the high-level biocontainment conditions required for handling highly pathogenic influenza viruses. Overcoming the technical hurdles to efficient vaccine production is only the start of a long, expensive process. Manufacturing scale-up presents its own problems, not least because plant workers will have no immunity to the pathogens they will be handling. Of prime importance is vaccine safety testing, but the need for safety testing will have to be balanced against the need for rapid mass production of a vaccine. In response to the 2003 H5N1 scare in Hong Kong, WHO has created an Interim Biosafety Risk Assessment (WHO Global Influenza Programme, in press) guideline for the safety testing of pandemic vaccines, particularly the H5 and H7 subtypes, signifying a substantial advance in preparedness for the production of a pandemic influenza vaccine.

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary A major risk for all vaccine manufacturers is the occurrence of adverse reactions in a percentage of recipients. These reactions may be attributable to the vaccine, to the host, or (most likely) to a unique combination of the vaccine and the host genetic factors. Guillain-Barré syndrome in human beings first became apparent during the U.S. swine influenza vaccination program (Roscelli et al., 1991; Safranek et al., 1991). The inevitability of adverse reactions underscores the product liability dilemma inherent in any vaccine program. The risk of devastating financial liability, and the unavailability or high cost of liability insurance, are increasingly discouraging vaccine manufacture, especially for universal use. Legislative measures can be taken to reduce the impact of liability exposure. For example, the U.S. Congress passed the National Childhood Injury Compensation Act of 1986 (the “Vaccine Act”), which created a no-fault compensation program funded by an excise tax on vaccines. Plaintiffs need only establish that their injuries were caused by the vaccine. Claimants who are not satisfied with the administrative decision may still elect to sue the manufacturer, but the legal arguments available to the claimant are limited. Although the Vaccine Act represents progress in achieving a balance between consumer and manufacturer concerns, it would not apply to vaccines given to the general population, such as those for influenza or smallpox. Congress again attempted to address these concerns in a provision of the Homeland Security Act of 2002, and an Institute of Medicine panel is currently wrestling with the problem as well; however, drug manufacturers remain hesitant. The bottom line is that unless the government authorities of every country implement mechanisms that equitably limit vaccine liability, no prospective vaccine for H5N1, H7N7, or any other threatening influenza virus is likely to be produced for universal human use. It is hoped that governments will rise to the occasion after a crisis emerges, but logic suggests that the issue should be addressed now. Antiviral Drugs A global influenza strategy would call for the stockpiling of influenza antiviral drugs for use in the event of a pandemic until vaccines can be prepared. “But,” as noted by Albert Osterhaus (Abbott, 2003b), “no country has yet started to stockpile antiviral drugs.” The potential value of antivirals was demonstrated in the recent H7N7 outbreak in poultry and humans. Further, because epidemiological modeling has suggested that it is more infectious than SARS (Ferguson et al., 2003; Lipstitch et al., 2003; Riley et al., 2003), influenza is unlikely to be controllable by SARS-like quarantine measures. The estimated US$ 10 billion cost of SARS and the societal disruption it caused in China and Toronto make a compelling case for stockpiling of antiviral drugs. Pandemic influenza has already threatened twice in 2003. The events associated with these outbreaks show that we are in a much better position to rapidly respond to an influenza threat than we were in 1997; however, much remains to be accomplished. Overall, our state of preparedness is far from optimal.

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary ernments probably would not be inclined to devote substantial resources to the fight when other diseases—such as malaria, tuberculosis, and HIV/AIDS—were claiming many more lives. The spread of SARS to countries with weak healthcare systems and vulnerable populations also is likely to make the disease appear more transmissible and lethal, heightening public fears in other parts of the world: Poor, isolated regions of Russia and China would have trouble containing an outbreak, although their governments probably could mobilize more resources to respond once infections began to climb. Even if SARS outbreaks were limited to poor countries, the persistence of the disease probably would fuel some unease around the world about a broader resurgence. The impact probably would marginally decrease demand for travel and increase demand for medical products. An outbreak of SARS in poor countries would pose particular challenges for the United States and other governments and multilateral organizations providing assistance. WHO and CDC probably would come under pressure to provide money and technical assistance to compensate for weak healthcare systems. The higher the number of infected people, the more the international community would be called on to do something. Neighboring countries are likely to press for help with disease monitoring to prevent SARS from spreading into their countries, especially if panic began generating refugee flows. Repressive regimes like North Korea might accept material assistance but block outside experts from visiting, even at the risk of putting more of their own citizens at risk. North Korea in previous years has been accused of diverting NGO assistance to the military and not allowing outsiders to monitor how it is used. Scenario Three: SARS Resurges in Major Trade Centers SARS could stage a comeback this fall in the main places it hit before—such as China, Hong Kong, Taiwan, and Canada—or gain a foothold in other places with extensive international travel and trade links like the United States, Japan, Europe, India, or Brazil. An outbreak almost certainly would spark another wave of WHO health warnings and travel advisories; Japan already has canceled an international conference on HIV/AIDS planned for this winter due to fears it would coincide with a resurgence of SARS.

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary Even if the number of infected persons were not greater in a second wave, an outbreak of SARS in major trade centers again would be likely to have significant economic and political implications. The resurgence of SARS in Asia probably would cause less disruption as citizens, companies, and governments learn to live with it, as they do with other diseases, unless the transmissibility or lethality rose substantially. Nonetheless, a second wave of SARS in Asia probably would prompt some multinationals to modestly reduce their exposure to the region if they concluded that SARS posed a long-term health challenge. Given the size of the Asian market and low wage-rates, few companies are likely to yank existing production out of China unless SARS debilitates or kills large numbers of workers. Firms probably would divert some future investments to other regions to diversify their supply chains. Disruptions due to SARS are likely to persuade some companies to loosen just-in-time production chains by creating some cushion in key inventories, increasing costs but not productivity. Global trade and investment flows could seize up if quarantines shut down factories and shipments. A substantial decline in China’s manu-facturing sector would reverberate in Southeast Asian economies that provide critical manufactured inputs, raw materials, and energy and disrupts production chains throughout East Asia. Bigger outbreaks in places such as Europe and the United States would affect new sets of business and government players. The level of public fear almost certainly would be higher in places that had not been affected by the first wave of SARS, driving up social disruption and economic costs. The economic cost of SARS probably would skyrocket if fears grew about the transmission of the disease in planes or on objects. Some buyers this spring demanded that Asian manufacturers irradiate their export goods after research indicated that SARS could survive for several days on inanimate objects. Even the health systems of rich countries could be overwhelmed if the resurgence of SARS cases coincided with the annual influenza epidemic this winter. As long as no quick and reliable test to diagnose SARS exists, people with fevers and a cough could overwhelm hospitals and clinics as healthcare workers struggled to distinguish patients with SARS and isolate them from others. A pneumonia-like illness erupted in western Canada in mid-August, raising questions among health experts about whether a milder version of SARS had returned. Surges of people seeking medical care almost certainly would increase the odds of healthcare workers missing some cases.

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary Some SARS patients have not displayed classic respiratory symptoms, suggesting some “silent” spreaders may not even know they have the disease, and some travelers with mild symptoms might lie about contact with infected persons to avoid quarantine. Given the high economic and political stakes already seen in the SARS epidemic, some jurisdictions probably would try to fudge health data in an effort to avoid official health warnings or get them lifted more quickly. Some governments might narrow the definition of “probable” SARS cases to reduce crowding in hospitals, yet such moves could spark tensions with WHO and other countries over the accuracy of data. Building Better Defenses Against Disease The emergence of SARS has sparked widespread calls for greater international surveillance and cooperation against such diseases. SARS has demonstrated to even skeptical government leaders that health matters in profound social, economic, and political ways. BOX 5-6 Influenza: Lurking Killer Influenza is an ideal virus for worldwide spread (a pandemic) and many epidemilogists argue that the world is “overdue” for a major influenza pandemic. When a new type of flu virus emerges from a reassortment of animal and human viruses to which humans have no prior immunity, a pandemic may ensue. Scientists believe the past two influenza pandemics originated in China where people live in close contact with birds and swine, the major sources of animal flu viruses. Influenza spreads even more quickly than SARS because flu can be transmitted efficiently through the air. As a result, close contact is not required for people to become infected, making it almost impossible to trace and isolate ill people who are spreading the disease. Three major flu epidemics stand out in modern U.S. history: 1918-19: “Spanish Flu” caused 20-50 million deaths worldwide, including 500,000 in the United States. 1957-58: “Asian Flu” originated in China and spread globally, killing around 70,000 Americans. 1968-69: “Hong Kong Flu,” a global pandemic, began in Hong Kong and ultimately claimed 34,000 U.S. lives.

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary The experience with SARS probably will help countries prepare for future disease outbreaks. This intense focus on SARS has opened a window of opportunity to pursue bilateral and international cooperation against infectious diseases. The United States and WHO may be able to develop new institutional channels to foster long-term cooperation on health issues. Momentum is likely to flag if SARS continues to subside and political leaders lose interest. Budget constraints and turf battles almost certainly will retard progress and agreements may fail to be implemented at the provincial, state and local levels if added responsibilities are not accompanied by additional funding. Areas of Need Several countries already are seeking assistance from the WHO and the U.S. CDC in an effort to strengthen their health systems. Some even are moving to commit more resources. Both China and Taiwan have held technical discussions with US officials exploring ways to improve their health system, and Beijing publicly has committed $1.3 billion in new funds. Surveillance Despite substantial progress in recent decades in building networks to monitor disease, the surveillance systems in most countries remain weak. Many surveillance systems have been built over the years to detect specific diseases, such as polio and guinea worm. The WHO also has created a global network of over 100 centers in 83 countries to track influenza. The longer-term challenge is to build networks throughout countries and regions and the means to issue warnings to national and international authorities. Systems focusing on specific diseases generally have been more cost effective than trying to increase surveillance for all diseases, but either approach leaves holes. International surveillance networks also must work out differences between countries over what health patterns are “normal” and which should set off alarm bells. The death of working-age pneumonia patients in the United States would be so unusual it would trigger closer examination, but this phenomenon probably was not considered abnormal in China in the early stage of SARS.

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary BOX 5-7 Health Surveillance and Biological Weapons The SARS outbreak illustrates the difficulty in distinguishing the emergence of new infectious disease from the release of a BW agent. Ongoing efforts to improve global health surveillance, however, probably will aid international monitoring for detecting the possible release of biological warfare agents, especially traditional types. As baselines for natural diseases are established in the coming years, a deliberate release of traditional BW agents could be more readily recognized. Unfortunately, many developing countries probably will not acquire domestic detection capabilities, such as tools to identify genetic sequences in disease organisms. Moreover, history suggests that some countries will not support internal disease surveillance efforts for political or economic reasons, leaving significant gaps in a global surveillance system. Even if local health workers identify worrisome developments, many medical facilities in developing countries lack communications equipment and vehicles to alert national officials and transport samples or patients. Although rapid online journal publication aided in sharing information on the new SARS virus, outbreak responders need to share data even earlier. Epidemiological Expertise Many countries lacked trained experts to map the trajectory of SARS. Such expertise was critical to understanding the transmissibility, lethality, and scope of the disease. Press reports indicate that Chinese officials have had trouble processing and sharing research information within China and with outsiders, such as WHO. Laboratory Facilities Few countries have the sophisticated laboratories or trained personnel to do the hard science of cracking mysterious new illnesses. As a result, regional or mobile labs may be the most viable prospect for speeding up diagnoses and research. WHO reports that staff in over 90 percent of developing country laboratories are not familiar with quality assurance principles, and 60 percent of the lab equipment is inoperable or outdated.

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary Equipment The cost of basic diagnostic and protective equipment is relatively modest yet still unaffordable for many countries. SARS highlighted a widespread shortage of ventilators to support patients with pneumonia. The lack of adequate sterilization equipment raises the risk of spreading disease when medical instruments are reused. The highest priority for many countries is likely to be diagnostic tests to determine which patients need to be isolated; the need for such tests would be all the more pressing if research indicates SARS can be transmitted through the blood supply. BOX 5-8 SARS and HIV/AIDS SARS has focused greater international attention on the importance of health, but the new disease probably will not lead to a significant boost in the fight against HIV/AIDS in the coming years. Indeed, many countries are likely to view spending on diseases like SARS and HIV/AIDS as a zero-sum game in the short term. SARS is generating international interest in improving health surveillance systems that could broaden screening for HIV/AIDS as well, but the interests will not always coincide on allocating limited resources. The small number of HIV/AIDS surveillance sites already in most countries is designed to gather health data on specific groups, such as young women, drug users, or prostitutes, rather than samples of the population at large. Some countries may be willing to devote more resources to improving general health and fighting HIV/AIDS within their security services. With HIV/AIDS prevalence rates running as high as 50 percent in some African militaries, a growing number of governments are working with the US on control programs. Political leaders may see it as critical and cost effective to work with outsiders for better healthcare for soldiers as well. China’s new health minister has said she plans to focus on HIV/AIDS now that SARS has subsided, according to press reports. Some AIDS activists and NGOs within China also have expressed hope that the government response to SARS will translate into more action on HIV/AIDS. A resurgence of SARS this winter could delay activity on AIDS, and some AIDS activists in China fear the government might believe the stringent controls used to fight SARS should be used against HIV/AIDS as well.

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Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary Many countries need more ventilators to support patients with pneumonia. In addition, negative pressure rooms to isolate infected patients are in shorter supply; even many hospitals in affluent countries are not likely to have enough rooms to handle a serious outbreak. Developing Countermeasures Progress in developing diagnostic tests, treatments, and vaccines would fundamentally improve prospects for combating SARS. This will take time, however, and first-generation products often are not completely effective without further research and improvement. Tracking down infected and exposed persons on airline flights also could be improved significantly if airlines retained electronic records of passenger lists. Political Hurdles Almost all countries will express support for improving international healthcare capabilities, but negotiations are likely to be contentious, and many players will see this as an opportunity to win concessions or score points with Washington. Some areas of possible contention are: Money. Many developing countries will say they cannot improve their surveillance systems and healthcare infrastructure without significant outside assistance, in the form of training, equipment, or grants. “Rich” vs. “poor” Diseases. Some developing countries may argue that they will work to improve surveillance for diseases like SARS if the United States and the international community do more to help them fight diseases which claim more lives in their countries, such as malaria and tuberculosis. Multilateral Channels. European countries are likely to use the focus on health issues to renew pressure on the United States to work through multilateral organizations such as the Global Fund for AIDS, Tuberculosis, and Malaria. Pharmaceutical Access. Any forum to discuss international health cooperation almost certainly will include some criticism of U.S. positions in the WTO on pharmaceutical sales. Research to develop tests, treatments, and vaccines is underway, but drug companies will have little incentive to bring such products to market without public sector support if SARS appears to fade away. WHO Authority. Some countries probably will argue for strengthening the authority of the WHO to sanction states that do not share health data or bar outside health experts from visiting. Other countries, such as China and Malaysia, are likely to resist any moves they see as infringing on sovereignty. Taiwan almost certainly will continue trying to use health issues to win recognition from WHO and other multilateral organizations.

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