The Unfinished Agenda of Infectious Diseases

In 1969, the U.S. surgeon general issued a now famous, if less than prescient, pronouncement: "The time has come to close the book on infectious diseases" (WHO 2000). In 2001, infectious diseases still accounted for 32 percent of the global burden of mortality and 37 percent of the global burden of disease. In Sub-Saharan Africa, they are responsible for 68 percent of deaths. The HIV/AIDS epidemic continues to spread, affecting large proportions of populations in Sub-Saharan Africa, but it is at only an early stage in Asia, when effective prevention efforts could make a difference, as they did in Thailand. AIDS is responsible for the decline in life expectancy to less than 40 years of age in five Sub-Saharan African countries. Yet recent promising results of public health efforts in Brazil, Senegal, Thailand, and Uganda demonstrate that HIV/AIDS can be prevented and controlled on a nationwide scale.

Even though the public in industrial countries often seems surprised by each new outbreak of infectious disease, the pattern of emerging infectious diseases worldwide is continuing and, at the same time, is constantly changing. Since 1970, people have been afflicted by 32 new diseases that had never previously been reported in humans, such as hepatitis C, Legionnaire's disease, Ebola, Vibrio cholerae 0139 epidemic, Nipah virus encephalitis, SARS, and the highly pathogenic avian influenza. The 1918 influenza epidemic killed 20 million to 40 million people worldwide. Precisely when human-to-human transmission of the avian influenza viruses will occur is impossible to predict, but it is likely to happen eventually. This eventuality underscores the importance of encouraging systematic collaboration on emerging and reemerging infections and strengthening global surveillance and laboratory capability. A syndromic approach to diagnosis and surveillance, as for the identification of flaccid paralysis, which accelerated the elimination of poliomyelitis in the Western hemisphere, may be crucial when laboratory diagnosis is not readily available.

Finally, the deliberate dissemination of anthrax spores in September and October 2001 in the United States has raised the specter of biological terrorism, either with pathogens natural to the environment that took years to eradicate, like smallpox, or genetically engineered pathogens of unknown capability.

Thus, the global infectious disease agenda remains unfinished. Given the continuing emergence of new infectious diseases and the increasing resistance of microbial pathogens to existing drugs and of insect vectors to pesticides, as well as low compliance with treatments, it is likely to remain so.

The Coming Epidemic: Chronic Diseases and Aging Populations

In 1998, for the first time, chronic diseases contributed more to the global burden of disease than infectious diseases, indicating the emergence of a convergence between the principal diseases of the developing countries and the industrial countries. Worldwide, cardiovascular disease is the major cause of mortality and morbidity (13.6 percent of total disability-adjusted life years) followed by cancer (6.6 percent of total disability-adjusted life years). Diabetes type 2 is increasing in most countries of the world at an alarming rate. An unanticipated finding from the global burden of disease analysis was that psychiatric illness, particularly depression, is a major cause of disability everywhere (Murray and Lopez 1996a, 1996b). Depression is now the most important disability among women in the United States, and globally it is projected to be the second largest contributor to the burden of disease by 2020.

The success of public health and childhood immunization in reducing the number of childhood deaths from infectious disease is partially responsible for the increasing burden of chronic diseases. However, part of the increase is caused by poor eating habits, lack of exercise, smoking, and other unhealthy lifestyle choices that tend to increase with a nation's income. Even though noncommunicable diseases associated with aging are increasingly contributing to the global burden of disease, the emergence of a highly virulent infectious disease pandemic could allow communicable illnesses to reassert their primacy.

The Unnecessary Epidemic: Injuries, Casualties of War, and Humanitarian Emergencies

Before the analysis of the global burden of disease, the contribution of injuries to the burden of disease and disability was unclear. The most rapidly rising category of injuries is that resulting from motor vehicle crashes. If present trends continue, by 2020 motor vehicle crashes will be the third largest contributor to the global burden of disease. Clearly public health sectors have a great deal to contribute in terms of reducing injuries from motor vehicle crashes, falls, and workplace injuries. Less amenable to intervention by public health systems will be wars and humanitarian emergencies. Obtaining accurate figures is difficult, but as Murray and others (2002) note, available statistics have greatly underestimated the burden of war and civil strife on health systems.

Genomics, Molecular Epidemiology, and Preventive Medicine

Probably the most exciting area of biomedical research for at least the next decade derives from the Human Genome Project and other efforts to sequence entire genomes of mammals, birds, insects, and microbial pathogens. Examination of these genome sequences will allow investigators to define and understand intrinsic risks for disease as well as interactions between genes and environmental threats. The sequencing of the major microbial pathogens has given rise to molecular targets for new drugs against specific pathogens that are distinct from their host counterparts and unique antigenic fragments that may become effective components of new vaccines. Researchers have sequenced the genomes of virtually all major viral, bacterial, and parasitic infectious disease agents and placed the results in databases available to everyone, a true public good (see The Institute of Genomic Research at http://www.tigr.org).

The availability of these genome sequences has catalyzed ambitious research efforts. For example, a project is under way to genetically engineer the Anopheles mosquito to render it unable to transmit malaria. Even if this effort fails, knowledge of the mosquito's genome has given new life to medical entomology and will likely help reduce vectorborne diseases in other ways. In a second example, the growing number of available influenza virus sequences will greatly aid understanding of the epidemiology and evolution of pandemic and interpandemic influenza viruses and will be a powerful tool for guiding vaccine strain selection.

The genome project has already changed the understanding of health and disease (box 4.2). Until now, epidemiology has dealt largely with external and environmental risks for disease. What the Human Genome Project offers is knowledge of the other side of the health equation—that is, the intrinsic risks for disease. Previously undreamed of molecular and cellular tools to explore gene expression and function are becoming available to provide such knowledge on a scale that was inconceivable even five years ago.

Box 4.2

Uncovering Individual Risks for Specific Diseases. Genomic information makes possible predicting individual risks for certain diseases and to certain components of the environment. One level relates (more...)

The hope is that genomics and related biomedical research on stem cells will give rise to new therapies for repairing and remodeling tissue damaged by chronic disease, from heart disease to diabetes and chronic neurological diseases. The possibility of preventive treatment has now also arisen—that is, the identification of risks for chronic disease early in life and the implementation of preventive strategies—behavioral, nutritional, or medical—to avert or overcome intrinsic risks and thereby prevent disease.

Despite the optimism and enthusiasm, a darker side of the Human Genome Project is emerging. Because individuals face different risks, the focus on "boutique medicine" will increase—that is, the focus on risks for individuals and the development of niche interventions targeting those risks, rather than the focus on populations. Identification of those intrinsic risks at birth, for example, will for some time be a luxury available to better-off children in rich countries but not to babies in poor countries or to poor populations of rich countries. Ultimately the Human Genome Project and the rapid advances in biomedical research in the industrial world have the unintended potential to increase the gap between rich and poor. If, however, most complex diseases have multigenic susceptibilities, the magic bullet approach of boutique medicine may not fulfill current expectations of rich or poor countries.

New therapies, whether they arise from genomics or from more traditional pharmacology, must be tested carefully to ensure that people in developing countries are not unfairly treated in clinical trials. Contract research organizations now carry out 60 percent of clinical trials. Many of these organizations already test products in developing countries that will have anticipated markets in rich countries but are unlikely, should they be licensed, to be available or affordable to populations in developing countries. This practice is both an ethical and a practical health problem.

Finally, in countries where testing for genetic risks becomes available, the likelihood of risk adjustment—that is, the exclusion of people with some risks from insurance and discrimination in relation to jobs, marriage, and housing—can be anticipated. In this information age, personal genetic information will certainly present an unprecedented challenge to privacy and confidentiality.

A Faint Hope: Population-based Research

The focus of future research in the rich countries will likely be on individual risks and on interventions tailored to those risks. Yet from the point of view of the world as a whole, the most effective interventions are population-based interventions, such as vaccines, insecticide-impregnated bednets, environmental modifications, antismoking campaigns, clean water, and safe sex. With knowledge derived from biomedical science and the Human Genome Project, it is hoped that some interventions will emerge that do not require knowing any individuals' intrinsic genetic risks and that may apply to entire populations at risk. The hope is that they could be comparable to existing population-based interventions—for example, vaccines recommended for all children to prevent major infectious diseases, treatment of schoolchildren once a year with ivermectin to prevent onchocerciasis, and antismoking campaigns.

In the rich countries, research has shown that aspirin and a combination of inexpensive antihypertensive drugs reduce deaths from heart attacks by 30 percent and from strokes by 50 percent. Even though they are off patent, these interventions are currently not widely used in developing countries. These findings are the products of basic research, but their effective use will depend on operational research.

The Next Frontier: Human Behavior and Social Determinants of Disease

Another revolution in research is emerging: understanding the functioning of the human brain and, ultimately, human behavior. Biomarkers for neuropsychiatric disease and environmental stresses are being sought, and with MRI and positron emission tomography technology, researchers can see areas of the brain that are thinking, remembering, or enjoying music. Within the next 50 years, science will have the technical ability to begin to untangle the processes of thinking in molecular terms, with exciting or frightening possibilities to alter or affect them. Anticipating quantifiable bio-markers for stresses and psychopathology as well as objective tools for measuring the effectiveness of new psychotropic interventions in changing behavior is not unreasonable.

Thefactors that lead people to engage in unhealthy or destructive behaviors are more complex than simple individual choices. Many of the lessons of social epidemiology—and the flourishing world of advertising—indicate that most behaviors, including risky or unhealthy behaviors, are socially patterned. Science has unfortunately not done a good job of learning how to change social patterns. For example, merely targeting individuals at high risk for HIV/AIDS without changing the social context that might reinforce stigmatization is not the best way to prevent disease. Indeed, in many developing countries that now provide free counseling, testing, and antiretroviral drugs for people with HIV/AIDS, the biggest barrier remains the social stigma of being HIV positive. Health systems must widen their view beyond individual patients to target entire communities and the media to change unhealthy socially patterned behavior. In the United States, epidemiological estimates indicate that 50 percent of the 2.3 million annual deaths are preventable or postponable. McGinnis and Foege (2004) find that in 2000, 19 percent of deaths were caused by tobacco, about 14 percent were attributable to poor diet and lack of exercise, and about 12 percent to injuries. One of the great challenges is to learn how to communicate what is known about the prevention of such conditions as heart disease, obesity, and diabetes more effectively.

Reliable and comparative analysis of health risks is key for preventing disease and injury. A recently published study (Ezzati and others 2003) reports estimates of the disease burden caused by the joint effect of 20 selected leading risk factors in 14 sub epidemiological regions of the world. In regions where high mortality persists, four risk factors—underweight in childhood, micronutrient deficiency, indoor smoke from solid fuels, and tobacco—caused 35 to 42 percent of lower respiratory infections in 2000. In the same regions, the combined risks of high blood pressure, high cholesterol, high body mass index, low fruit and vegetable intake, and physical inactivity caused 82 to 89 percent of the burden of ischemic heart disease. Important gaps in scientific evidence about the effects of multiple risk factors and risk factor interactions persist and require further exploration (Ezzati and others 2003). In this context, investigators should not underestimate social and behavioral determinants of disease, including poverty, environment, culture, and so on.

Inherent Difficulties in Setting Priorities

The first part of this chapter underscored the immense scope of health problems and the potential of global health research to make a difference. Given the complexity of the task and the multiple participants involved in the process, defining priorities for the global health research agenda is daunting.

Scientists tend to argue that more research is urgently needed on the diseases they are studying. Their research may certainly include worthwhile issues, but they may not be priorities in the wider context of global health R&D.

Some hold the view that the choice of priorities should begin with a statement defining topics that should not be priorities—for example, the development of vaccines (such as a leprosy or hookworm vaccine) when cost-effective treatments are available. Others strongly disagree, given the interconnect-edness and unpredictability of science.

The failure of the U.S. "war on cancer" offers a useful caution on the limitations of rational planning of science. In the 1960s, a group of distinguished scientists developed a set of future research priorities for the National Cancer Program. Despite the importance of the problem, the requisite scientific knowledge was not then available to develop the modern tools that have recently been successful in treating and preventing cancer. Planning for where the new innovations and discoveries will come from is hard, and planners have to be open to changing their priorities and incorporating new approaches.

A key challenge is the problematic nature of anticipating scientific connections in advance. For example, the sequencing of a mouse leukemia virus genome as part of the National Cancer Program is what enabled scientists years later to classify HIV as a related member of the retrovirus family. Indeed, who would have predicted that research on the once arcane coronavirus would become essential to control the spread of SARS? Or that the esoteric question of whether tumor cells extinguished differentiated functions of normal body cells would lead to the discovery of monoclonal antibodies? Or that the study of sex in bacteria would give rise to the entire genetic revolution of the past half century? The need to recognize the unpredictability of science and the limitations of scientists at any time is best illustrated by Oppenheimer's statement at the beginning of this chapter.

Systematic and Evidence-based Approach to Priority Setting

The process of setting priorities for the global health research agenda is complex and includes accurate or perceived assessments of the burden of disease; developed countries' threat assessments, for example, in relation to bioterrorism and epidemic potential; scientific or technical opportunities; advocacy; political commitment; ethical considerations; and funding availability.

Using a systematic and evidence-based approach to priority setting, the WHO Ad Hoc Committee for Health Research Relating to Future Intervention Options (1996) undertook the first broadly based, systematic effort to formulate "best buys" for health R&D (table 4.3). The steps included assessments of the following:

Table 4.3

R&D Best Buys.

• size of the disease burden

• reasons the disease burden persisted

• adequacy of the current scientific knowledge base

• cost-effectiveness of potential interventions and the probability of successful development of new tools

• adequacy of the current level of ongoing research and funding.

This five-step approach has been influential. The Global Forum for Health Research and the Special Programme for Research and Training in Tropical Diseases have endorsed it and further developed it. The Global Forum's combined approach matrix links the five steps with four actors or factors determining the health status (Global Forum for Health Research 2002):

• individual, family, and community

• health ministry, health research institutions, and health systems and services

• sectors other than health

• central government macroeconomic policies.

The five steps also provide the basis for the strategic emphases matrix for tropical diseases research (Remme and others 2002).

The individual disease chapters in this volume used a slightly modified version of the framework developed by the WHO Ad Hoc Committee to identify gaps and guide the formulation of research priorities on the basis of the following premise: even though the current mix of available cost-effective interventions averts a proportion of the burden of any particular disease and the remaining burden could be further reduced with improved application of existing technologies to affected populations, a fraction of disease remains that cannot be averted. Two reasons account for this fact. First, the cost for extending the existing technology to the remainder of the population would be prohibitive. Second, the existing interventions may simply not be sufficiently effective. These two categories define the magnitude of the need for new or better tools and, in essence, serve as a rationale and indicate priorities for research.

A clear example is the case of HIV/AIDS. Neither behavioral interventions, such as exhortations for abstinence and fidelity and the provision of condoms, nor antiretroviral therapy has stopped the global spread of HIV, which challenges the scientific community to undertake more research on preventive vaccines. The availability of highly active antiretroviral therapy challenges the research community to find ways of providing effective and life-saving treatment for HIV/AIDS patients in a manner that ensures proper use and compliance, averts the development of drug resistance, and thereby becomes a financially sustainable policy.

Participants and Decision Makers

Two main concerns lie at the core of most discussions of the priority-setting processes: the predominance of the industrial countries and the predominance of the scientific community in formulating research agendas. Two-thirds of respondents in a survey of researchers that was funded by the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health and was conducted in May 2004 were leading scientists from low-and middle-income developing countries and worked in the same region in which they held their citizenship. The survey highlighted their views about key factors influencing research priority setting as well as major barriers that hampered stronger participation by scientists from developing countries in global health research. According to the survey, the most important factors determining research priorities were the magnitude of disease burdens and the needs of the industrial countries. Major barriers to the success of research collaboration in global health were the lack of sustained funding; the difficulty of linking research, programs, and policy; the weak research leadership; and the absence of a science culture (Harley, Simonsen, and Breman 2004).

A more balanced participation of scientists from industrial and developing countries, a better gender mix, and the inclusion of major stakeholders are essential to the successful development of a truly global health research agenda. The challenge is to develop creative mechanisms for addressing current shortcomings.

The process for selecting the best research projects and programs within each priority area is well established and is grounded in scientific merit, based primarily on trust in peer review and expert judgment. Keeping this process independent from political pressures is extremely important. However, the peer review process has limitations, including a natural conservatism and risk aversion by scientists, given the responsibility for the allocation of public funding, their often narrow base of expertise in one discipline, and their specific cultural perspective. Alternative models of project selection from industry and other scientific, mission-oriented entities might offer interesting alternatives—for example, managerial systems or strategic planning processes, particularly for translating knowledge into successful interventions, an area that research is currently emphasizing.

Ethical considerations and pressures exerted by advocacy groups—such as public-private partnerships for targeted drug or vaccine development, fresh looks at "orphan drug" legislation, patent rules ensuring financial returns to industry as well as the affordability of new products in developing countries, and commitment before their development by the public and private sectors to subsidize their development or ensure markets for the products—are likely to counterbalance to some extent the lack of incentives for the pharmaceutical industry to develop drugs, diagnostics, and vaccines for which markets do not exist or are not profitable. In addition, one might hope that the growing pharmaceutical and vaccine industry in developing countries might place a higher priority on addressing nationally and regionally important health problems than do multinational companies.

The share of total R&D funds allocated to major causes of the disease burden in developing countries remains insufficient. As a result, the availability of funding to support global health R&D is ultimately the defining factor regarding the implementation of selected R&D priorities. Thus, the Bill & Melinda Gates Foundation has become a major driving force in defining priorities for global health R&D through its support of promising public-private partnerships. The new US$200 million it provided to finance the Grand Challenges in Global Health represents the newest large influx of funds in support of global health research (see Foundation of National Institutes of Health at http://www.grandchallengesgh.org).

Priorities Already Part of the Global Health Agenda

Priorities that are already the most prominent part of the global health agenda relate almost exclusively to the unfinished agenda of infectious diseases and to the continuous threats of emerging infectious diseases, including bioterrorism. The largest investments pertain to the development of new drugs and vaccines that are needed to reduce the burden of HIV/AIDS, malaria, and TB; to the early detection and control of new highly pathogenic viral agents (for example, SARS); and to the prevention and treatment of infectious diseases resulting from microbial terrorism (for instance, anthrax and smallpox).

In 2001, the National Institute of Allergy and Infectious Diseases developed a global research plan for HIV/AIDS, malaria, and TB. The plan outlines a comprehensive approach for fighting infectious diseases that involves building a sustainable research capability domestically and internationally and enhancing global partnerships. It comprises short-, medium-, and long-term goals for research that "will lead to prevention and treatment strategies that are effective, feasible, and realistic for individual countries struggling with the burden of numerous infectious diseases" (National Institute of Allergy and Infectious Diseases 2001).

Since the mid 1970s, the WHO Special Programme for Research and Training in Tropical Diseases and a few other institutions have been key players in strengthening research and research capacity for tropical diseases that are endemic in specific developing regions—African trypanosomiasis, Chagas disease, dengue, leishmaniasis, leprosy, lymphatic filariasis, malaria, onchocerciasis, and schistosomiasis. As a result, effective control measures are now available for Chagas disease, leprosy, lymphatic filariasis, and onchocerciasis—but questions remain regarding effective implementation strategies. The other diseases still lack effective control measures and, thus, require further research to develop better tools and effective control strategies (http://www.who.int/tdr/grants/strategic-emphases/default.htm).

The process that led to the formulation of the Grand Challenges in Global Health represents two important departures from earlier approaches to priority setting. First, the announcement of the call for ideas in May 2003 had an unprecedented dissemination worldwide and resulted in over 1,000 submissions from scientists and institutions in 75 countries. Second, the formulation of a grand challenge, described as "a call for specific scientific or technological innovation that would remove a critical barrier to solving an important health problem in the developing world with a high likelihood of global impact and feasibility" (Varmus and others 2003) was broad and had a clear goal.

The research agendas proposed in chapters 16, 18, and 21 are extensive and encompass research on basic epidemiology and risk factors and the development of new or better drugs, vaccines, diagnostics, and intervention methods. The fact that these priorities do not represent a marked departure from previous research priorities for these conditions attests to the complexity of these diseases and their importance in the poorest countries. They will require a broadly based and sustained global research effort to overcome the rapid spread of antibiotic and insecticide resistance, limited human resources, and poorly developed health systems that severely constrain the health community's ability to reduce the burden of disease.

Important Topics That Are Not Yet on the Global Research Agenda but Should Be Pursued

Cardiovascular diseases, neuropsychiatric disorders, obesity, diabetes, and cancers are causing a rapidly increasing share of the disease burden in all developing regions, with the exception of Sub-Saharan Africa; however, they do not yet figure prominently on the global health research agenda. The research priorities recommended independently by the authors of various chapters pertaining to major causes of noncommunicable diseases converge. Indeed, diet, lifestyle, obesity, tobacco, and alcohol are common risk factors for cardiovascular diseases, certain cancers, and diabetes. These diseases and risk factors represent a cluster of conditions that pose similar research challenges.

The first important cross-cutting theme emerging from this cluster of chapters is the issue of portability, or how to bring knowledge and programs from one location and define how they can become best practices elsewhere. Cost-effective preventive strategies and therapeutic approaches to reduce the burden of cardiovascular diseases, cancer, diabetes, and mental disorders have been developed and tested in industrial countries. Much of the extensive knowledge base accumulated in industrial countries to prevent the development of cardiovascular diseases, diabetes, and cancers is likely to be relevant to developing countries, yet few epidemiological studies have quantified the impact of major risk factors for chronic diseases in developing regions, and few trials have been conducted to assess the effectiveness of different intervention strategies. Research to explore the transferability of cost-effective interventions from industrial to developing countries therefore figures prominently in several chapters.

The primary prevention for noncommunicable diseases in industrial countries rests on the reduction of major risk factors—namely, diet, lifestyles, and tobacco and alcohol consumption. Research priorities include the development of epidemiological databases and of intervention studies to identify cost-effective strategies to reduce the prevalence of major risk factors in different contexts in developing countries. The transfer of personal and population-based interventions to reduce the risk of cardiovascular disease, which are based on decades of research in the industrial countries, is particularly promising. Research priorities include evaluating a range of intervention strategies, from simple dietary interventions to reduce the risk of cardiovascular disease (for example, food supplementation with folic acid and linoleic acid and reduction in the salt, saturated fat, and trans fat content of processed foods), to the hypothetical "polypill," which would combine drugs to lower cholesterol, clotting, and blood pressure. Reducing the risk of cardiovascular disease is particularly important for diabetes, which is itself an important risk factor for cardiovascular disease.

The second theme pertains to lifelong medical management of chronic conditions that cannot be cured but could be improved through the development and testing of public health prevention and treatment algorithms. This issue has been little considered in past discussions of priorities for global health research but now appears to be reasonably cost-effective. Examples include unipolar depression, bipolar disorders, schizophrenia, epilepsy, diabetes, and secondary prevention of ischemic heart disease and stroke.

The third theme pertains to crucial implementation research that combines operations research and health services and systems research. Such research is becoming central to ensuring the success of the rapid scaling-up of cost-effective interventions that is required to meet the health targets of the Millennium Development Goals, particularly in resource-poor countries with weak health systems. In this context, further research is critical to elucidate neglected areas of health system reforms, including the following (Mills 2004):

• improving public service provision

• enhancing human resources

• ensuring accountability for health outcomes, funds, and medicines

• ensuring a functioning central government

• providing evidence for policy.

Promising Research Topics Not Yet Global Priorities

Other important research topics emerge from the various chapters that are not yet global priorities but that are nevertheless worthwhile pursuing. Major themes pertain to the following:

• epidemiology of injuries and cost-effective interventions to reduce the burden resulting from both intentional and unintentional injuries, particularly motor vehicle crashes and road and vehicle safety

• major risk factors for disease in different contexts (for example, tobacco, obesity, physical activity)

• medical and surgical errors

• occupational and environmental health

• risk analysis and risk communication

• delivery of care at different levels of the health system

• performance of health systems

• management of health research

• reproductive and sexual health

• health effects of global warming.

The importance of strengthening the research agenda in those and other areas and the resultant opportunities to make a real difference have not been sufficiently recognized in the past.