The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health: Workshop Summary (2002)

Joshua Lederberg, Ph.D.

Nobel Laureate and Sackler Foundation Scholar

The Rockefeller University

Throughout history humans have been afflicted by zoonoses—that is, diseases transmitted to people from animals. These diseases can be acquired directly, as when a person is bitten by an infected animal. They also can be acquired indirectly, in a number of ways. For example, a person might be bitten by an arthropod vector, such as a mosquito or tick, that has picked up a pathogen from a host animal; come in contact with pathogen-bearing fluids produced by an infected animal; or consume foodstuffs contaminated with an animal-derived pathogen. Some zoonotic agents maintain an ongoing reservoir life cycle in animals or arthropods, without the permanent establishment of a new life cycle in humans. Other agents are “species jumpers” that derive from an ancient reservoir life cycle in animals but have subsequently established a new life cycle in humans that no longer involves an animal reservoir.

In recent years a number of new zoonoses have emerged, in both developing and developed countries, and a number of known zoonoses have reemerged in areas where they had been absent for decades or have spread to animal species in which the pathogens had not previously been detected. For example, beginning in the mid-1980s, cattle herds in the United Kingdom have been hit by an outbreak of bovine spongiform encephalopathy, or “mad cow disease.” After extensive study, this animal disease has now been linked to the occurrence of a progressive and often deadly neurological disorder, called new variant Creutzfeldt-Jakob disease, in humans who have presumably been exposed to diseased cattle or products therefrom. In another zoonotic outbreak, the first human cases in the Western Hemi-

sphere of West Nile encephalitis, a potentially fatal disease caused by a virus that commonly infects birds and can be transmitted by mosquitoes, were documented in the New York City metropolitan area in late summer of 1999. The West Nile virus has now been detected in a number of states along the major migratory flyways of the eastern seaboard.

Many different determinants contribute to the emergence of new zoonotic agents, and it is rare that these factors act singly. Among the forces that shape their emergence are human demographics and behavior; technology, industry, and agriculture; economic development and land use; international travel, commerce, and military expeditions; microbial adaptation and change; and breakdown of public health measures. Indeed, social and environmental changes are accelerating, in both the developed and developing worlds. The developed world has the greatest travel and transport, providing particular risks for rapid spread. Ecological change is greatest in the developing world and biodiversity is greatest in the tropics, which makes these regions potentially productive breeding grounds for new pathogens. In the final analysis, it cannot be predicted which zoonotic pathogens are likely to emerge next or cause the biggest problem. Given the obvious link between human health and pathogens that circulate in domestic animals and wildlife, we must be alert to pathogen flow in any of these areas.

Among other issues, there is concern regarding the potential “bioweaponization” of zoonotic diseases, particularly by individuals or groups either acting alone or with sponsorship by a foreign government. Many observers now consider such terrorist attacks to be the major threat, embracing biological attack against U.S. forces in peacetime deployment, as well as against private citizens in major cities. Zoonotic agents have a number of attributes, including their potentially large impact when released into a human or animal community, that make them especially suitable for use as weapons. Ironically, continued advances in biotechnology, while offering great promise for improving human health, may concomitantly make it easier for terrorists to manufacture and deploy effective biological weapons.

In addition, a number of human activities undertaken with the best of intentions may have harmful potential. For example, the food and farming industries increasingly use antimicrobial agents and other types of drugs to boost the efficiency of food-producing animals and to prevent certain troublesome organisms from reaching consumers. Use of these chemicals probably enhances the proliferation of antibiotic-resistant microbes. Some observers also suggest that xenotransplantation, broadly defined as the use of nonhuman animal cells or tissues in humans for therapeutic purposes, may inadvertently introduce new zoonotic infections to recipients of such material. This risk raises the burden of preventive responsibility on scientists and research groups conducting such trials.

The challenge taken up by participants in this workshop is to identify strategies that will help the nation, and the world, in preventing and controlling zoonotic diseases. The following sections offer some highlights of the presentations and discussions.

Many gaps remain in our understanding of zoonotic agents and the diseases they cause. More research is needed on the pathogenesis of zoonotics in relation to host biology. The transmission of an infectious agent from an animal to a human initiates a series of events that constitute the pathogenesis of the infection. The final outcome is either termination of infection (either through cure or demise of the host), chronic persistence and latency of infection, transmission to another host, or some combination of these. The zoonoses, involving two or more hosts, and often other vectors, illustrate some of the more interesting and complex patterns of virulence and pathogenesis that have evolved in nature.

Despite spectacular achievements in microbial genetics and genomics, we know relatively little about how most zoonotic agents are maintained in nature or how they respond to environmental (often anthropogenic) changes. The precise ecological factors that lead to human infection and emergence are murky, and textbook descriptions of the epidemiology of most zoonotic diseases are at best simplistic. In order to more effectively prevent or control zoonotic diseases, it will be necessary to better understand the ecology of their respective etiologic agents.

Basic research is needed to underpin vaccine discovery. The threat of emerging zoonoses will be reduced if there is preexisting knowledge of the antigens required in a vaccine and of the immune responses to be elicited. A cadre of experts in these diseases cannot be maintained, nor can steady progress be made in vaccine development, without consistent support for research. At the same time, priorities need to be set for vaccine manufacture. The cost- and time-intensive process of advanced vaccine development and licensure should be reserved for agents for which vaccines are thought to be needed soonest. Except for rapidly evolving influenza, the epitope specifications of a modern vaccine will remain relatively unchanged once discovered and well defined, as will the phenotype of a protective immune response. However, the optimal vaccine platforms by which such antigens will be constructed and delivered may change almost as rapidly as computer hardware.

In determining which zoonotic agents to study, it is possible to identify a rogues’ gallery of pathogens to receive special attention. For example, some viruses, including the West Nile virus and the yellow fever virus have been known to have major human disease potential. We should be prepared

with vector control, antiviral drugs, and prototype vaccines for when they reemerge. Of course, we also are certain to face the emergence of previously unknown pathogens. Thus, we are obliged to do basic groundwork now and not wait until we are faced with a “mystery disease” or a new, challenging pathogen. One approach would involve generic studies of certain classes of pathogens, such as filoviruses and parvoviruses, so we will not be caught without at least the basic tools to respond to new threats. Work on retroviruses that preceded the emergence of HIV greatly accelerated our response to AIDS.

To support an expanded research base, a variety of additional laboratory facilities are needed. This will mean, for example, improving in number and capacity the national Biosafety Level 3 and Level 4 laboratories, which offer the kinds of equipment and protection measures required for conducting research on exceptionally hazardous materials. Of particular note, the nation has no Biosafety Level 4 laboratories devoted to veterinary research, a situation that can impede the process of identifying unknown pathogens. These laboratories should operate multifaceted research programs, and they must be ready to deal with large episodes of disease. There also is a need to construct several small high-containment laboratories in academic institutions, yet specific federal commitment or funding for such facilities remains lacking. Also needed are facilities, located in various parts of the country, to meet such emergencies as bio-terrorism threats.

The nation’s system of veterinary diagnostic laboratories needs to be strengthened, including upgrading facilities and staffing levels. Typically located in state agencies and universities, these laboratories, which analyze specimens submitted by field practitioners, are crucial for the early identification of an emerging disease or of small outbreaks of a well-known disease. However, the laboratories are now less likely to receive specimens for diagnosis than they were in the past. This may be due, in part, to the increased burden of laboratory user fees. More funding for the laboratories to enable them to provide more free testing of diagnostic specimens may be critical in acquiring more submissions. Data sharing by and among laboratories also is a problem. At least two issues are involved: ability to share and willingness to share. First, laboratory information systems must be compatible and developed with data sharing as an objective. Standardization of variables and output formats are often lacking. Many systems are developed primarily or solely to facilitate billing-related functions. Second, cooperation among laboratories in sharing information is often absent as data are more and more often viewed as proprietary or economically threatening to trade.

Within the medical community, physicians want help in obtaining accurate determinations of the rabies status of each animal for which a human exposure has been documented. The federal Clinical Laboratory Improvement Act now requires testing human clinical specimens but not animal specimens, even when such test results may affect human therapy and outcome. The government should expand the rules to include testing of animal specimens when it impacts the treatment of humans. The government also should require laboratories performing these rabies tests to enroll in proficiency testing and quality assurance programs equivalent to those used to license laboratories that test human clinical specimens.

Many laboratories, including those maintained by the federal Centers for Disease Control and Prevention (CDC), are in short suppply of reagents for some viruses to share with all needful qualified researchers. Generic reagent production should be explicitly funded through CDC or a program similar to the one once used by the National Institutes of Health for producing arbovirus reagents.

Surveillance can provide an early-warning system for emerging zoonoses, and such monitoring must be the first link in the chain of public health action. The U.S. current surveillance systems include active systems to detect particular known pathogens and passive systems for more generalized monitoring. For example, the Animal and Plant Health Inspection Service (APHIS) of the Department of Agriculture (USDA) maintains a National Animal Health Monitoring System that collects, analyzes, and disseminates data on animal health, management, and productivity in several livestock populations, including dairy and beef cattle, swine, and poultry. Data from such national studies can be used to identify risk factors or trends associated with zoonotic pathogens. Following the emergence of the West Nile virus in New York City, the CDC launched a comprehensive program to monitor the geographic and temporal spread of the virus in states along the eastern seaboard; to develop more effective strategies for surveillance, prevention, and control; and to provide up-to-date national and regional information on West Nile encephalitis and other vectorborne diseases. More recently, CDC has expanded surveillance efforts into other states, although on a more limited basis.

Many other nations, as well as a number of international groups, also conduct surveillance programs. For example, to cope with the genetic variability of influenza, the World Health Organization (WHO) maintains a network of more than 100 laboratories that constantly survey influenza viruses, and this information is then analyzed in four reference centers. Based on these efforts, WHO makes annual recommendations for those

virus strains to be included in the current vaccine in order to stay abreast of genetic drift or, more tellingly, major shifts.

Still, improvements are needed in our ability to detect and respond to emerging zoonotic agents, particularly those that appear suddenly and are capable of spreading over large areas. The sensitivity of passive surveillance systems is one area of concern. Almost any system should find large outbreaks. Finding and assessing smaller outbreaks or scattered cases of disease, or finding large outbreaks at incipient stages, is the real challenge. Other factors may help anticipate when and where disease may be likely to occur for more targeted surveillance. In other words, we need better disease intelligence. The production of “actionable” intelligence may derive from analyses of changes in such factors as climatic conditions, vegetation, wildlife demographics, trade patterns, or vector distribution. Toward this end, APHIS is working to develop new information collection and analysis methodologies as well as relationships with intelligence groups, such as the Armed Forces Medical Intelligence Center, already collecting useful information. International surveillance will be critical in the identification of exotic diseases that would place the United States at risk. In addition, APHIS has more than 100 foreign service officers in 28 countries, and USDA’s Foreign Agricultural Service has representatives in about 100 countries. Further, APHIS offers assistance to other countries in detecting and responding to diseases on their soil, which is better than having to deal with the diseases here.

Enhancing surveillance systems may be particularly important for protecting U.S. citizens from terrorist attacks. This potential has led the government to institute the Laboratory Response Network, sponsored by CDC and managed by the Association of Public Health Laboratories, to enhance the detection of these agents in humans. Personnel in laboratories that test clinical specimens from humans will receive training in the means to rule out these agents as well as in forwarding the isolates to public health laboratories for specific identification and subsequent molecular fingerprinting. By providing a link between public and private laboratories, this network will increase the nation’s capacity to detect and prevent the spread of zoonoses, whether they are transmitted naturally or intentionally.

Of course, surveillance is of little use if not shared with other groups or individuals who can act on the information to prevent or diagnose disease. In Iowa, for example, the University Hygienic Laboratory has posted influenza surveillance data on its web site for the past several flu seasons. Data are updated automatically each night. Anyone wanting to know which viruses are circulating in their area can easily view a table that shows the numbers of Influenza A and B detected during the current week, the past week, or all year. This information may influence a decision to administer prophylactic or therapeutic drugs or to control exposures. The web site also

provides region-specific data on a variety of other diseases, including some zoonoses. Sharing data with those who participate in its reporting and accumulation will encourage timely reporting and dialogue between the private and public health care communities.

Improvements in the nation’s surveillance systems and ensuring their continued operation depend on adequate financial support. Unfortunately, waning public interest in a disease during a quiescent period often leads to reduction in political, and hence financial, support for surveillance activities. Ironically, it is during these quiescent periods that surveillance would best be conducted, to detect the appearance of an infectious agent in environmental reservoirs and eradicate the agent before it infects many humans. When surveillance is abandoned, an outbreak of human disease may be well under way before it is detected.

Perhaps the most fundamental need is for improved collaboration and cooperation among government agencies at all levels—local, state, and federal—as well as among members of the veterinary, human health, and wildlife health communities. One positive aspect of the West Nile virus outbreak may be that it is illuminating this issue and may carry over to the detection of and response to future zoonotic disease outbreaks. When staff members at the Bronx Zoo first began investigating the disease outbreak that ultimately would be linked to West Nile virus, scientific exchanges were relatively free. But the zoo staff found that as more organizations and people became involved—and, ironically, as the magnitude of the problem escalated—the situation degenerated: some states seemed unwilling to work with other states or with federal agencies; some organizations did not seem willing to work with other organizations. To help remedy this situation, CDC’s new program to provide states with funding to develop strategies and capabilities to cope with bioterrorism may provide a model. In particular, Montana, North Dakota, and South Dakota have developed what appears to be an effective regional surveillance system that integrates both veterinary and human public health.

To improve interdisciplinary collaboration, one step might be for federal agencies to develop a tripartite cooperative program to address infectious diseases in humans, in domestic animals, and in wildlife. This program can serve as a focus for regular communications through working groups to address information transfer; to improve response to disease emergencies; to establish priorities for collaborative, focused investigations; and to pursue other areas of mutual interest. The program also can serve as a model and catalyst to stimulate the development of similar cooperative programs between state agencies that would network with the federal pro-

gram. Collaborative arrangements also can be developed to integrate the emergency response capabilities within the public health, domestic animal, and wildlife conservation communities. Response to emerging infectious diseases of wildlife should be augmented as needed by the combined capabilities of the different programs to minimize the potential for establishment and spread of wildlife diseases capable of infecting other species, including humans.

Collaboration can be improved at the international level as well. Although many international activities have succeeded, often via the WHO, difficult circumstances have required the involvement of institutions outside the usual public health agency loop, such as agricultural agencies. This was true when the West Nile virus emerged in the United States in 1999, when the H5N1 influenza virus emerged in Hong Kong in 1997, and when the Hendra virus emerged in Australia in 1994. In each case, turf issues arose, and in some instances efforts to protect agricultural markets seemed to be deemed more important than efforts to protect the public health. The Hong Kong public health authorities were exemplary in their decisive actions and early involvement of international collaborators. We may have been lucky that these zoonotics did not spread to cause further harm, but who is to say what the next agent will be like? The next step in solving such turf issues will involve recognizing the primacy of prevention and control of human disease.

Some observers maintain that a number of government practices and policies have hindered the nation’s efforts to address emerging infectious diseases, including zoonoses. For example, they cite the need for better mechanisms for distributing supplementary funding for handling emergencies. This problem was particularly evident with funding for studies of the West Nile virus and of hantavirus which emerged in the U.S. Southwest in the early 1990s. Such funding today must be disbursed according to federal acquisitions regulations, and this process can lead to delays in the distribution of funds and to inflexibility in selecting funding recipients. The network of regulations surrounding the biomedical community also has been singled out for criticism, with charges that the rules often do not address real risks or abuses, but rather reflect political perceptions. Such regulations affect animal experimentation, shipping of various disease-related agents, research on certain agents, and the use of certain vaccines for occupational safety, among many other areas. Critics maintain that not only do unwarranted restrictions fail to appreciably improve public or occupational safety, but they also limit research that may indeed reduce the risk from threat diseases.

There also is a role for expanded government action. For example, some private laboratories and managed care organizations have been slow to adopt the latest technology for identifying a number of the nontraditional zoonotic agents that appeared in foodstuffs in recent years. As a result, the foodstuff that is the source of the infections cannot be identified, which means that other individuals may continue to ingest the foodborne organisms and succumb to the disease. One way to help rectify these circumstances would be for the government to specify expectations of clinicians and laboratories in the private health care setting. For example, it would be useful to clarify what circumstances dictate the performance of a culture and submission of the isolate to a public health laboratory. To help increase participation by private managed care organizations, the government, perhaps through the Health Care Financing Administration (HCFA), may at first need to offer some type of incentive. Adjustments in both reimbursement policies and quality indicator requirements are candidate incentives that HCFA might entertain, as these investments are made more to benefit the public health than improve the outcome for the individual patient.

Federal agencies can take the lead in developing a common database for disease surveillance and monitoring that can be used to track infectious diseases and the emergence of new diseases. As part of this effort, a work group should be established along with existing advisers to develop a listing of “reportable” diseases that are to be entered into the system, with standards for data entry, reporting, and utilization by collaborating agencies and institutions. CDC has proposed developing a national electronic disease surveillance network for state and federal public health information on emerging infectious diseases, and this network should be expanded to include wildlife surveillance information on emerging zoonotic diseases and should be linked to agricultural intelligence.

In addition, the government can take additional steps to increase the capacity of public health agencies to detect, diagnose, and contain infectious disease outbreaks. Many of these agencies lack the basic computer equipment to communicate data on disease outbreaks electronically, and they cannot perform simple laboratory tests to diagnose infections. Most agencies have no up-to-date assessment of their current capacities and needs. (Indeed, since this workshop, Congress has passed the Public Health Improvement Act of 2000, which establishes grant programs to enable state and local public health agencies to assess their current capacities and identify their areas of greatest need, upgrade the ability of public health laboratories to identify disease-causing microbes, improve and expand electronic communication networks, develop plans to respond to public health emergencies, and train public health personnel.)

Public education programs focused on emerging infectious diseases, including zoonoses, are critical and should be expanded. Such programs are needed both to increase awareness of the problems and to minimize undue fears. A joint approach might involve developing a better curriculum for use in schools and devising information programs to reach influential organizations and the media. One possible route would be for federal agencies to work collaboratively with an independent organization dedicated to public outreach.

There also are specific topics that might benefit from expanded public education efforts. For example, the expanding human population assures continued landscape changes, many of which can affect the emergence of zoonoses. Thus, the government and other organizations should become proactive in terms of developing and disseminating information that can help guide land development in a manner that gives greater consideration to disease prevention. Initial actions that can be considered include distributing authoritative publications, sponsoring public forums, and providing consultations on particular problems.

Many people in the United States, within government and among the public, have only minimal understanding of conditions in other countries. This is especially true regarding the developing world, where new zoonotic diseases are most likely to originate. It is critical to improve our general understanding of the various cultural, infrastructure, and other issues that will affect how the United States can best work with the world community to improve the surveillance, control, and management of disease.

Of course, improving the nation’s ability to mount an effective and comprehensive program to manage zoonoses will require national leadership. To bring all elements of such a program together, the zoonosis community, working in concert, must devise a comprehensive plan that addresses all aspects of this problem, including research needs and the needs of an effective system for disease prevention and control.

As a model, the community might look to CDC’s emerging disease plan. Strategic planning must not be biased by the most recent zoonotic disease episode, the West Nile virus. Although this virus might seem an ideal model, we would be better served by using a more complex model, one that would test all facets of candidate plans. The ultimate test of candidate plans is bovine spongiform encephalopathy and the resultant new variant Creutzfeldt-Jakob disease. Today, with the wisdom of hindsight, many observers are saying that the ministries of agriculture and health in the United Kingdom failed to react in a timely fashion and with proper scope and scale of actions to deal with what was clearly a great risk

to public health. Every aspect of the ministries’ disease prevention and control responsibilities has been called into question. This zoonosis also may be instructive in a larger historic sense, especially in its unbridled extension into the worlds of macroeconomics, international trade, national politics, and even regional governance.