April 28, 2004
Mr. Chairman and Members of the Committee, thank you for the opportunity to discuss with you the role of the National Institute of Allergy and Infectious Diseases (NIAID) in combating infectious diseases worldwide. Infectious diseases pose a major global public health challenge. These diseases are the second leading cause of death worldwide, accounting for 26 percent of all deaths. Furthermore, because infectious diseases strike the young disproportionately, causing approximately two thirds of deaths among children less than five years of age, the situation is even worse in terms of years of healthy life lost. Infectious diseases also seriously undermine economic development, especially in developing countries, and can cause serious political instability. Infectious diseases are both a cause and consequence of poverty.
Infectious diseases have afflicted humanity throughout history, and will continue to do so for the indefinite future. Moreover, the viruses, bacteria, and parasites that cause infectious diseases continually and dramatically change over time as new pathogens emerge and familiar ones re-emerge with either new properties or in unfamiliar settings. For example, since the Acquired Immunodeficiency Syndrome (AIDS) was first recognized in 1981, this emerging disease has spread relentlessly throughout the world. It now threatens to surpass in total fatalities both the "Black Death" of the 14th century and the influenza pandemic of 1918-1919—two other emerging infections that each killed tens of millions of people. In the past five years alone, we have seen the appearance of the West Nile and monkeypox viruses in the United States, an unprecedented number of human infections with avian influenza viruses, as well as the emergence of a new infectious disease, Severe Acute Respiratory Syndrome (SARS). Finally, the anthrax bioterrorist attacks of 2001 confronted us with a disease resulting from the deliberate release of an infectious agent.
Effective national and global responses to infectious disease threats, whether they are emerging, re-emerging, or deliberately introduced, involve many different types of activities and many different organizations. NIAID, a component of the National Institutes of Health (NIH), is the lead Federal agency for conducting, supporting, and coordinating research on infectious diseases. NIAID's research activities include the basic and clinical research needed to understand these diseases, as well as the application of knowledge gained to develop the relevant diagnostics, therapeutics, and vaccines. Today, I will briefly highlight NIAID research activities on the three infectious diseases with highest global death toll—malaria, tuberculosis, and HIV/AIDS, as well as three other emerging and re-emerging infections—SARS, West Nile Virus, and influenza. I will close with a short discussion of NIAID biodefense research to counter deliberately-emerging disease threats.
Malaria is one of the major killers of humans worldwide, threatening the lives of more than one-third of the world's population. Caused by a single-celled parasite and transmitted by mosquitoes, malaria causes an estimated 300 million acute illnesses each year, with more than 1 million deaths. It is a substantial impediment to economic and social development in regions where it is endemic, especially in sub-Saharan Africa. The threat posed by malaria is growing, primarily because of the spread of drug-resistant strains and insecticide-resistant mosquitoes, changing weather patterns, and limitations of the medical and public health infrastructure in many endemic areas.
The sequencing of the complete genomes of all three organisms involved in the malaria parasite's life cycle—human beings, Plasmodium falciparum, the most lethal malaria-causing parasite, and Anopheles gambiae, a mosquito that transmits the parasite to humans—were recently completed. Scientists are now mining this wealth of genomic data to gain new insights into malaria pathogenesis, and to uncover new molecular targets for both drugs and vaccines. For example, genomic data have allowed scientists to discover new parasite enzymes that are very promising targets for drug intervention; NIAID and the pharmaceutical industry are currently collaborating in the development of drug candidates against these enzymes. In addition, in 2003, NIAID launched its first clinical trial of a malaria vaccine in a malaria endemic country: Mali, in west Africa.
The bacterium that causes tuberculosis (TB) currently infects about 2 billion people, or about one-third of the world's population; five to ten percent of infected people will develop active TB disease sometime in their lifetime. Each year, approximately 8 million new cases of active TB occur, and approximately 2 million people die of the disease. The problem is currently being exacerbated by two major factors. First, the alarming global prevalence of HIV/AIDS has created a situation whereby many more people today have a compromised immune system, which allows a latent TB infection to become active and spread more easily. Second, drug resistant strains of the TB bacterium develop readily when an infected individual does not take the entire course of standard antibiotic treatment, which typically lasts for six to nine months. Strains of the TB bacterium that are resistant to the least expensive and most effective anti-TB antibiotics have spread widely.
To address this problem, NIAID scientists are working to develop more effective drugs that would allow for shorter and less complex drug treatments. A promising drug candidate developed by public and private partners with contributions by NIAID is completing preclinical evaluation, and is expected to undergo review by the U.S. Food and Drug Administration (FDA) later this year for approval to be tested in humans. This candidate is a new member of a class of chemicals known as nitroimidazoles, which have the potential to be effective against both the drug-resistant and drug-sensitive forms of TB.
The development of a new TB vaccine is also critical because the currently available TB vaccine only offers protection against disseminated TB in infants and children, with limited effectiveness against TB of the lung, the most contagious form of the disease among adults and children. This year, two new engineered TB vaccines developed with NIAID support entered clinical trials in the United States, the first to do so in 60 years. These studies also offer an opportunity to learn more about the protective immune responses against the TB bacterium, which are currently not completely understood. In addition, NIAID is supporting development of several promising TB diagnostic tests.
HIV/AIDS is taking a terrible toll worldwide. Approximately 40 million people worldwide are infected with the virus. In 2003 alone, 5 million new infections occurred—about 14,000 each day—and an estimated 3 million people with HIV/AIDS died, 500,000 of whom were children. In the United States, nearly one million people are living with HIV/AIDS, and by the end of 2002, more than 500,000 Americans with HIV/AIDS had died. As sobering as these numbers are, however, they do not adequately convey the physical and emotional devastation to individuals, families, and communities coping with HIV/AIDS, nor do they capture the devastating impact of the pandemic on national economies and political stability.
Although the burden of HIV/AIDS continues to grow, biomedical research provides optimism that those already infected can lead healthy lives and that improved prevention approaches to stop the spread of HIV can be developed. Two decades of basic research into the mechanisms by which the virus propagates itself and evades and destroys the immune system have led to the development of more than 20 antiretroviral drugs, which can reduce the level of virus in an infected person, maintain the health of the person for many years, and prevent mother-to-infant transmission of HIV. Four new antiretroviral drugs were licensed in 2003 by the FDA, each of which was developed on the basis of NIAID-sponsored research or tested in NIAID clinical trials networks. Many other new anti-HIV drug candidates are in clinical trials.
A vaccine that prevents HIV infection, or at least slows the progression of disease, would be an enormously powerful tool to control the pandemic, and is, therefore, a critical NIAID priority. Development of such a vaccine presents many difficulties, including the genetic diversity of the virus and the lack of a clear understanding of the immune responses that might protect against HIV infection. Nonetheless, NIAID and its academic, industrial, international and philanthropic partners have made significant progress, and several HIV vaccine candidates are in preclinical and clinical development.
Because of the international character of the AIDS pandemic, the President's budget request for FY 2005 includes approximately $355 million for NIH HIV/AIDS research conducted at international sites. The NIAID international HIV/AIDS research agenda includes development of vaccines, microbicides and other prevention strategies to interrupt transmission of HIV, testing of therapeutic approaches for HIV and common co-infections such as tuberculosis and malaria, and discovery of new ways to prevent HIV transmission at birth and through breast-feeding. Furthermore, the President's Emergency Plan for AIDS Relief (PEPFAR)—a $15 billion initiative to treat, prevent, and care for HIV infection in areas hardest hit by the pandemic—and the activities of the Global Fund to Fight HIV/AIDS, Tuberculosis, and Malaria—an international effort organized with U.S. leadership and currently chaired by HHS Secretary Tommy Thompson—will provide treatment, care, and prevention services to those who need them most, and, together with continued advances in the biomedical research arena, will help address the devastation caused by HIV/AIDS.
SARS is the first severe, newly emergent infectious disease of the 21st century. The prompt recognition in the Spring of 2003 that SARS is caused by a new type of coronavirus and the rapid progress in SARS research that followed reflect the dedication of and collaboration by the world's medical researchers and public health experts, including NIAID-sponsored scientists in the United States and abroad. Although only very few cases of SARS have occurred over the past several months, we must remain vigilant to prevent another global outbreak. NIAID supports research to understand the epidemiology and biology of the SARS virus and how it spreads, and to develop vaccines, diagnostic tests and therapeutic agents to effectively address any future SARS outbreaks.
NIAID scientists and grantees are pursuing several parallel approaches to develop candidate SARS vaccines. NIAID intramural scientists recently made two advances in SARS vaccine development. In one study, they showed that the mouse immune system develops antibodies capable of neutralizing the SARS virus. In a second study, NIAID researchers demonstrated that a DNA vaccine based on a gene for a viral protein protected mice challenged with the virus by inducing the appropriate antibody responses. A Phase I clinical trial of this candidate DNA vaccine is planned for August, 2004. Although a great deal of work remains to translate these findings into a safe and effective human vaccine, these studies indicate that SARS vaccines that trigger antibodies to the SARS virus are a promising avenue to pursue.
West Nile Virus
West Nile virus (WNV) first appeared in the Western Hemisphere in 1999, and by 2003 had spread to 46 states in the United States. NIAID has moved quickly to address this threat by expanding basic research into how the virus causes diseases and how it is maintained in nature. NIAID also embarked on the development of vaccines and treatments, and acted to provide reagents and other resources to the research community. Several promising vaccine candidates against WNV are under development. Two are genetically engineered combinations of WNV proteins added to a highly attenuated strain of another virus. One candidate is based on the attenuated virus used in the Yellow Fever vaccine, the other on the attenuated Dengue virus used in a Dengue vaccine. Both have been shown to be 100 percent protective in primates, and both will shortly enter Phase I human safety and immunogenicity testing. Another vaccine candidate is DNA-based. A Phase I clinical trial is planned for late 2004 to assess the safety and immunogenicity of this vaccine candidate in healthy volunteers.
The influenza virus constantly changes, and therefore can be considered a classic example of a re-emerging disease. In the United States, influenza infections cause an average of 36,000 deaths and 114,000 hospitalizations each year; the World Health Organization (WHO) estimates that the annual average number of influenza-related deaths worldwide is approximately 500,000.
In most years, human influenza viruses undergo gradual changes in their antigenicity so that over time viruses emerge that are no longer neutralized by the anti-influenza immune responses of most people. This process is called antigenic drift and is the reason influenza vaccines must be re-evaluated and usually updated every year. Influenza viruses are common in nature and infect many different animal species especially migratory water fowl, pigs and horses. Occasionally, one of these animal influenza viruses acquires the ability to infect other hosts and jumps from its normal host into humans, as has occurred in the past months with avian influenza. Humans that become infected with avian influenza viruses do not appear to transmit these animal viruses to other humans. However, if the animal virus mutates sufficiently and/or recombines with a human virus and thereby acquires the capability to spread efficiently from person to person, the result can be a fast-moving and deadly pandemic. For example, the influenza pandemic that occurred in 1918-1919 after such a viral evolution killed 20-40 million people worldwide, including more than half a million individuals in the United States. Influenza pandemics that occurred following other such shifts in 1957 and 1968 killed approximately 2 million and 700,000 people worldwide, respectively. These figures explain our current high level of concern about the appearance of new forms of virulent H5N1 avian influenza viruses in Asia, which could subsequently mutate or recombine with human influenza viruses to cause a pandemic. Given the poor condition of public health systems in many underdeveloped regions and the speed of modern air travel, the consequences of such an event, should it result in an influenza pandemic, would be severe.
The NIAID has responded to this situation with a comprehensive research program. The overall goal of the NIAID Influenza Program is to support research that leads to more effective approaches for controlling influenza virus infections. The program has two major components. The first component reflects longstanding programs for interpandemic influenza—research to understand the pathogenesis, transmissibility, evolution, epidemiology, and the immune response to influenza viruses, and to develop new drugs and vaccines to combat it. The second component specifies NIAID's several roles after the emergence of influenza viruses with pandemic potential in humans. Foremost among these is to help develop and produce an effective vaccine as rapidly as possible. NIAID also would work with industry to produce and clinically test candidates at different doses and in different populations in our vaccine clinical trials sites, and would coordinate closely with the Centers for Disease Control and Prevention (CDC), FDA, and WHO to ensure that a safe and effective vaccine is available to the public as soon as possible.
The use of reverse genetics—a genetic tool developed by NIAID-supported scientists—holds great promise for rapid generation of vaccine candidates that could be used against a newly-emerged pandemic strain. Laboratories around the world are using this technique to prepare vaccine candidates against the H5N1 viruses emerging in Asia; NIAID is currently conducting negotiations for the production of a 2004 H5N1 inactivated influenza vaccine for clinical trials.
Since the anthrax attacks of 2001 and the growing understanding of the serious threat posed by the possibility of bioterrorist attacks with deadly pathogens, NIAID has significantly strengthened, accelerated, and expanded its biodefense research program. NIAID-supported biodefense research includes basic research into the disease-causing mechanisms of microbes that could be used by bioterrorists, as well as translational research to turn this knowledge into safe and effective treatments, diagnostics, and vaccines. Biodefense research on potential agents of bioterror promises to enhance not only our preparedness for bioterrorism, but also for other naturally-occurring endemic, emerging, and re-emerging infectious diseases.
Recent progress in biodefense research has been rapid. More than 50 major NIAID initiatives involving intramural, academic and industrial partners have been undertaken. NIAID has also implemented a large program to expand the infrastructure necessary for biodefense research. This includes funding of eight Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Research, and the construction of two National Biocontainment Laboratories (NBLs) and nine Regional Biocontainment Laboratories (RBLs). These high-level biosafety facilities will speed the development of effective therapies, vaccines and diagnostics for infectious diseases.
The ultimate goal of all NIAID biodefense research is the development of medical countermeasures. With respect to drug treatments, NIAID-supported scientists have recently identified antivirals that may help treat smallpox or the complications of smallpox vaccination, and have identified several approaches to blocking the toxins of the anthrax bacterium. New and improved vaccines against smallpox, anthrax and other potential agents also are being developed. For example, NIAID has sponsored the development of a next-generation anthrax vaccine known as rPA. Clinical trials of rPA are under way; results to date suggest that the vaccine is safe and capable of evoking a robust immune response. Researchers also will test whether the currently recommended course of antibiotic therapy for individuals exposed to anthrax spores could be shortened by vaccinating with rPA after exposure.
NIAID-supported researchers also are testing several new smallpox vaccine candidates that may have fewer side effects than the traditional Dryvax vaccinia virus. One of these, modified vaccinia Ankara (MVA), is based on a strain of the vaccinia virus that replicates far less robustly than Dryvax in humans, and is known to cause fewer side effects. Human trials of the potential efficacy of MVA vaccines are under way at NIH and elsewhere; recent studies by NIAID intramural scientists and their colleagues have shown that MVA protects monkeys and mice from smallpox-like viruses.
NIAID has launched the first human trial of a vaccine designed to prevent infection with Ebola virus. The trial vaccine is made from parts of the viral DNA, and is similar in design to other investigational vaccines that hold promise for controlling such diseases as AIDS, West Nile, and SARS.
Emerging, re-emerging, and deliberately emerging diseases pose a global public health challenge. NIAID, the federal agency charged with the responsibility for conducting and coordinating basic and clinical research to cope with infectious disease, plays a major role in our national response to these serious global health issues.
I would be pleased to answer any questions you may have.
Last Revised: April 29, 2004