Madam Chairman and members of the Committee, we are pleased
to appear before you today to discuss our programs at the
National Institutes of Health.
During the twentieth century, new vaccines diagnostic tests,
and treatments, as well as improved sanitation and control of
disease-transmitting insects have made enormous contributions to
public health by reducing the burden of many infectious diseases.
Smallpox has been eradicated from the world and polio eliminated
from the western hemisphere; diseases such as scarlet fever,
measles, typhoid fever and diphtheria, once major killers in this
country, are now rare.
Despite this progress, infectious diseases today are the
leading cause of death worldwide and the third leading, cause of
death in the United States. We remain vulnerable to new
epidemics as well as to old diseases that re-emerge, sometimes
more deadly than ever. For example, in this century alone, in
the potential lifespan of a single individual, we have
experienced two major pandemics with devastating global
consequences: the 1918 influenza pandemic that killed 20 million
people worldwide, and the ongoing epidemic of disease due to the
human immunodeficiency virus (HIV), which so far has killed
approximately 300,000 Americans.
Basic research in infectious diseases is more important than
ever and requires contributions from a wide variety of scientific
disciplines. Microbiologists, for example, study the precise
mechanisms by which microorganisms cause disease, leading to the
identification of vulnerable points to which to target
therapeutic strategies. Understanding the differences in the
disease-causing abilities of viruses as compared to bacteria or
fungi enables us to design therapies tailor-made for each class
of organism. Molecular biologists help us understand the genetic
mechanisms of microbic emergence, infection and virulence.
Immunologist delineate the factors critical to immune competence
and the protective inflammatory response. Epidemiologists
identify the mechanisms of disease transmission, including
behavioral factors that place individuals at risk for infection.
Support for these disciplines can be found in every Institute
and Center of the National Institutes of Health (NIH); they all
contribute to our efforts to prevent and treat infectious
diseases. We recognize that all tissues of the body are
susceptible to invasion by infectious organisms: neurologists
focus on brain infections, while dentists study organisms found
in the mouth. Doctors who study the digestive tract now know
that the major cause of pelvic ulcers is infection with the
organism Helicopter pylon; antibiotics, not dietary changes, cure
the disease, and a vaccine could potentially prevent this common
gastronomical disease. Diseases and treatments that suppress the
immune system, such as drugs used to treat cancer or to prevent
organ transplant rejection, can weaken the body's ability to
mount a defense against invading microbes. Thus, research in
infectious diseases cuts across all Institutes at NIH. Today we
will highlight three components of the NIH that are central to
the fight against infectious diseases, old and new, that threaten
the health of people in this country and around the world.
The National Institute of Allergy and Infectious Diseases
(NIAID) is the lead NIH agency for infectious disease research.
NIAID conducts and supports research into developing better means
of preventing and diagnosing - and treating - these illnesses. A
particular focus of the Institute is the area of emerging and
re-emerging- infectious diseases. Another Institute pivotal to
infectious disease research at NIH is the National Institute of
Child Health and Human Development (NICHD). NICHD was
established by Congress in 1962 to reduce infant mortality,
improve material health and address the causes and problems of
birth defects and mental retardation in this country, many of
which are due to infectious diseases.
Since the recognition of AIDS in 1981, the government has
marshaled these research programs to comprehensively fight HIV
and AIDS, enlisting the resources of each of the NIH Institutes
and Centers, and setting in place central leadership by
empowering the NIH Office of AIDS Research (OAR) to plan,
coordinate and evaluate the NIH AIDS research effort.
The ongoing threat of infectious diseases
The multidisciplinary research programs conducted and
supported by each of the Institutes of NIH, from basic studies of
pathogens and how they cause disease, through clinical research
and product development, are central to the Nation's ability to
effectively meet the continuing challenges of infectious
diseases. The importance of NIH-sponsored infectious disease
research is underscored by the re-emergence in recent years of
ancient diseases such as tuberculosis, cholera, malaria and
plague. In addition, the United States has experienced the
emergence and re-emergence of previously poorly recognized
diseases such as Lyme disease, caused by the bacterium Borrelia
burgdorferi; the often lethal respiratory distress syndrome
caused by a new form of hantavirus; gastrointestinal disease
caused by the foodborne Escherichia coli 0157:H7 bacteria and
cryptosporidium in municipal water supplies; and the increasing
incidence of a particularly invasive form of Group A
streptococcus referred to in the lay press as " flesh-eating
bacteria."
The emergence and re-emergence of infectious diseases are a
result of many factors. Microbes have the capacity to adapt
rapidly to changes in their environment, through genetic change
and environmental selection. These genetic changes often result
in increased infectivity, virulence and resistance to drugs and
the body's immune defense system.
A familiar example of how microbial changes can influence
disease transmission is the annual occurrence of influenza
outbreaks. New versions of the virus are constantly appearing
due to the remarkable ability of genes from different types of
influenza to recombine. People who have been infected with one
strain become resistant to reinfection; when confronted with a
new form, however, they are as susceptible as if they had never
before seen the virus. Another example of the influence of
microbial changes is seen with cholera. For the first time in
more than 100 years, cholera was reintroduced to the western
hemisphere in 1991. The newly introduced organism, the 01 El Tor
strain of Vibrio cholerae imported from Asia, has become endemic
in many areas of South and Central America, including areas of
Mexico adjoining the southern U.S. border; almost 300,000 cases
were reported in South America in 1993. More recently, another
new variant has emerged in Asia that threatens to become the
cause of the world's next pandemic. This 0139 strain is so
different from the 01 strain that individuals who have developed
a protective immune response to the 01 strain remain susceptible
to the new 0139 strain. This new cholera strain has already
spread widely in Asia, the Middle East and Russia.
Through mutation and evolution, microorganisms that had
previously been controlled by antibiotics and other drugs have
re-emerged. Widespread and often suboptimal treatment set up
the perfect conditions to select for drug-resistant mutant
organisms. For example, the availability of a relatively
inexpensive drug, chloroquine, contributed to the emergence of
chloroquine-resistant malaria seen in most parts of the world.
The global situation for treatment and prophylaxis of the most
severe type of malaria, caused by Plasmodium falciparum, has
become desperate. According to WHO, by 1994 the only
malaria-endemic countries that did not report some level of
resistance to chloroquine were in Central America. Moreover,
resistance to newer alternative drugs is increasingly common, and
sensitivity to the old stand-by quinine also appears to be
diminishing.
Hospitals in this country and worldwide are facing
unprecedented crises from the rapid emergence and dissemination
of antibiotic-resistant microorganisms. Strains of
Staphylococcus aureus resistant to many common antibiotics are
endemic in hospitals and chronic-care facilities, leaving only
one drug (vancomycin) as an effective treatment for these
infections. As a result, increasing reliance on vancomycin has
led to the emergence of vancomycin-resistant enterococci. Until
1989, vancomycin resistance had not been reported in U.S.
hospitals; by 1993, more than 10 percent of hospital-acquired
enterococci reported to the CDC were resistant. Some
enterococcal strains are now untreatable because of simultaneous
resistance to several different families of drugs.
Tuberculosis (TB) also has become increasingly problematic
because of the development of resistance to currently used drugs.
Globally, approximately 8 million people develop active TB every
year, and 3 million die. In the United States, TB cases
increased dramatically in the mid 1980's, with many people
infected by TB strains resistant to two or more drugs. Failure
to complete a lengthy treatment regimen, combined with the
immunosuppression associated with the developing HIV epidemic,
contributed to the emergence of multidrug-resistant tuberculosis.
In 1992 in New York City, more than one third of the strains
tested were resistant to one drug and nearly one fifth were
resistant to two front-line drugs. These drug-resistant strains
are as contagious as those that cause drug susceptible TB.
Drug-resistant TB is more difficult and vastly more expensive to
treat that drug-sensitive TB, and patients with drug-resistant
TB may remain infectious longer due to inadequate treatment.
Ecological or environmental changes also lead to the
emergence or re-emergence of disease. A recent example is the
1993 emergence of hantavirus in the Southwestern U.S. Scientists
now think that the virus emerged in part as a result of climatic
and environmental conditions which favored an increase in native
rodent populations harboring the virus. Altered land-use
influenced the appearance of Lyme disease, which has become the
most reported tick-borne disease in the United States.
Reforestation and suburban residential expansion into wooded
areas have created optimal conditions for transmission of this
organism to man.
These and other infectious diseases will continue to threaten
the United States, not only because of changes in the microbes
themselves and in the environment, but also because of chances in
human behavior and advances in technology. Most cities in this
country can be reached by commercial flights from any area of the
world within 36 hours. The world is truly a global village, and
infectious disease problems of other countries are very much on
the minds of the American public, as illustrated by the extensive
media coverage of the recent outbreaks of Ebola hemorrhagic fever
in Africa.
The importance of research
In preparing our country to respond to the threat of emerging
and re-emerging infectious diseases, early detection through
disease surveillance, a function primarily of the Centers for
Disease Control and Prevention (CDC), is important. Equally
crucial, however, is the role of biomedical and behavioral
research. These research programs, which range from basic
research in microbiology and immunology, to product development
in the areas of diagnostics, vaccines, and therapeutics, to and
clinical trials that evaluate these products, are being actively
pursued by NIH. Continued investment in these programs leads to
the creation and refinement of new tools for intervention and are
critical to our ability to respond to the ever-present threat of
emerging and re-emerging microbes.
An excellent example of the public health threat of a
decreasing investment in research is the recent re-emergence of
TB. In the 1970's the Public Health Service developed a
comprehensive plan for the elimination of TB by the year 2000.
The program was initially successful and the incidence of TB
steadily declined. As a result, scientists thought TB was cured
or at least well-controlled; the research community became
complacent and investment in TB research and the health care
delivery infrastructure declined. The changing social ecology in
this country, including increasing numbers of homeless
individuals often housed in crowded shelters, greater numbers of
immigrants from TB-endemic countries, and rising numbers of
immune-compromised HIV-infected individuals, in combination with
the decaying, public health infrastructure resulted in the
re-emergence of TB in the early 1980's. With the recognition of
this renewed epidemic, the NIH made a major commitment to TB
research, recruiting new investigators, initiating training
programs, and increasing financial support for investigator-initiated research. Now, within the NIH, multiple Institutes
contribute to TB research. For instance, NIAID-supported
researchers have developed a new class of anti-TB drugs that
appears to be effective against some strains of TB that are
resistant to existing-drugs; the National Heart, Lung and Blood
Institute (NHLBI) has focused a complementary effort on research
aimed at developing drug delivery systems that would be optimally
effective in delivering TB drugs to the lung. The stabilization
in the number of new TB cases in the United States over the last
two years, likely a result of increased surveillance and early
and aggressive therapy, demonstrates the ability of a rejuvenated
infrastructure to respond to a known problem, i.e.,
drug-sensitive TB. It is NIH's increased investment in basic
research and product development that should result in an
improved ability to respond to new global challenges, such as
drug-resistant TB.
Lyme disease is an emerging problem that also has benefited
greatly from a multidisciplinary research effort. Not only did
an NIH investigator identify the causative organism, but
NIH-supported research has delineated the mechanisms of
transmission and how disease results. Research in vector biology
identified the tick vector and traced the life cycle of the
bacterium through deer and rodent hosts. This has allowed us to
predict regions where Lyme disease is likely to pose the greatest
threat, and has led to improved prevention based on public
information about the dangers of tick-borne infection. Basic
research has identified bacterial antigens that form the basis of
experimental vaccines and improved diagnostic assays.
Complementary research on the immune response, sponsored by NIAID
and the National Institute of Arthritis and Musculoskeletal and
Skin Disease (NIAMS), has contributed insights into the way the
bacteria cause arthritis and other long-term health problems.
Thus, the multidisciplinary effort of NIH has resulted in our
ability to successfully treat and prevent many diseases. A
continued commitment to research is necessary to prepare us for
the challenge of new infectious diseases that are certain to
appear.
The challenge of HIV and AIDS
HIV is the prototype of a new and emerging pathogen. No
other disease so thoroughly transcends every area of clinical
medicine and scientific investigation, crossing the boundaries of
every NIH institute.
Approximately one million Americans are currently infected
with HIV. Worldwide, the World Health Organization (V;HO)
estimates that 18.5 million adults and 1.5 million children and
infants have become infected with HIV since the beginning of the
epidemic. More than 2.5 million of these individuals have died.
Estimates of the number of infected individuals worldwide
expected by the year 2000 range from 40 to I 10 million people.
In the United States and many other countries, AIDS is the
leading cause of death among young adults.
The HIV/AIDS epidemic in the United States is shifting into
new populations, disproportionately affecting women, young adults
and people from racial and ethnic minorities. Additionally, the
proportion of newly reported AIDS cases resulting from
heterosexual transmission has increased dramatically.
A commitment to HIV/AIDS research
The United States government and NIH have made a remarkable
research commitment to confront the health emergency of HIV and
AIDS. Research on HIV infection and AIDS has reached an
important juncture, as the Nation's investment in AIDS research
is reaping tangible benefits and opening new and exciting
scientific avenues. To plot the course through the many research
opportunities in AIDS, the OAR has spearheaded two important
initiatives: the development of an annual trans-NIH research plan
and budget, and a nearly completed evaluation of the entire NIH
AIDS research program. A unique and inclusive process was
utilized to formulate the AIDS research plan, involving the NIH
Institute and Center Directors; NIH intramural and extramural
scientists and program managers; distinguished scientists and
researchers from other government agencies, academia,
foundations, and industry; and community representatives. This
plan sets the scientific priorities and objectives for NIH AIDS
research and is used to guide scientific and budgetary decisions
about the research portfolio. The goal of the current evaluation
process is to determine whether each of the components of the
AIDS research program is appropriately designed and coordinated
to answer the critical scientific questions to lead to better
treatments, prevention, and a cure for AIDS. These activities
have provided a frank assessment of the successes and
shortcomings of NIH-sponsored AIDS research based on a broad
consensus of the scientific community. Utilizing the legislative
authorities of the OAR, NIH is refocusing scientific priorities
and redirecting resources to meet new scientific opportunities.
The fundamental basic knowledge that we have developed in
infectious diseases, molecular biology, microbiology and
immunology has allowed us to make significant progress in
understanding the pathogenesis of HIV disease, that is, how the
virus destroys the immune system and causes disease. Indeed, the
identification of HIV so soon after recognition of the epidemic
was possible because of the earlier discovery of the existence of
other human retroviruses. NIH-sponsored scientists first
identified these types of viruses when studying cancer and all
retrovirology; researchers were thus poised to look for a
retrovirus when they recognized that the agent causing this new
syndrome was transmitted in a manner similar to the malignancy-associated retroviruses.
Since that early discovery, NIH-supported research has
provided a wealth of information on the molecular virology of
HIV. However, our understanding of the virus itself is not yet
matched by our understanding of how HIV infection leads to
disease and how it induces inunune deficiency. The complexity of
the immune system has proven to be a formidable obstacle for
rapid research progress in elucidating the pathogenesis of AIDS.
A significant challenge facing, AIDS researchers is to understand
the normal functioning of the immune system while at the same
time defining the mechanisms by which HIV infection disrupts it.
To meet this challenge, NIH has intensified its efforts
toward fundamental research, the foundation that supports the
entire AIDS research enterprise. Animal models, particularly
macaque monkeys that can understanding the details of
pathogenesis and in establishing the nature of protective with
weakened HIV mutants can studying, how the immune responses
elicited by vaccination w of from infection with fully virulent
HIV. As these so-called "correlates of immunity" protect animal
Scientists are determining whether attenuated viruses can be
developed that are sufficiently safe to be considered as human
vaccine candidates.
Understanding HIV disease
A broad NIH effort, consisting of the contributions of
individual Institutes Centers, each with unique areas Of
expertise, has greatly advanced our understanding of how HIV
causes disease in the body. For instance, HIV, NIH-supported
investigators have shown that the levels of HIV RNA in a
patient's plasma are predictive of progression to AIDS. NIH
intramural investigators have further demonstrated that the
levels of HIV in plasma reflect HIV replication in the lymph
nodes, which are the major reservoirs of virus in the body of an
infected person. These and other studies support the concept
that the level of virus in the plasma is the most useful
parameter on which to base therapeutic decisions regarding the
initiation and modification of anti-retroviral therapy.
Progress in HIV therapy
The largest proportion of NIH AIDS research spending is
devoted to studies of therapies to improve and prolong the lives
of HIV-infected individuals. The NIH sponsors intramural and
extramural clinical trials of potential anti-HIV agents, in
single or multidrug regimens, for the prevention of HIV
infection, intervention early in disease, and treatment of HIV
infection and its accompanying opportunistic infections (Ols) and
malignancies in children and adults.
Several important advances were reported this year in the
search for effective antiretroviral therapies for HIV-infected
individuals. In a large NIH-supported clinical trial known as
ACTG i75, the combinations of AZT plus ddl or AZT plus ddC, used
during early - to intermediate - stage disease, resulted in delayed
disease progression and improved survival as compared to standard
therapy. This study provided the first conclusive evidence that
anti-retroviral therapy could result in clinically measurable
benefits, such as reduced risk of death in individuals who had
not yet advanced to the symptomatic stage of disease.
The concept of combination anti-retroviral therapy first
tested in studies performed by NIH intramural scientists in the
mid-1980's, is now being expanded to include combinations that
use a newly developed class of drugs called protease inhibitors.
These powerful drugs block the HIV protease enzyme that is
critical for the later staues of the virus life cycle. Other
anti-HIV drugs such as AZT work at an earlier stage of the viral
life cycle by blocking another enzyme.
Collaboration between the biotechnology and pharmaceutical
industries, the federal ,government, and academia in the AIDS
research effort is an important priority of NIH. An excellent
example of such collaboration is the development of protease
inhibitors. Basic research initiated and supported by NIH was
instrumental in identifying the importance of the HIV protease
enzyme, developing the concept of blocking this enzyme,
crystallizing the protease enzyme so that protease-blocking drugs
could be developed, and developing an assay to test these drugs.
National Cancer Institute (NCI) investigators were pivotal in the
actual crystallization of the protease enzyme; the substantial
body of crystallization research supported by the National
Institute of General Medical Sciences (NIGMS) was key to the
crystallization of another HIV enzyme and provided a base of
knowledge that allowed the protease work to go forward. In
addition, early work on discovery of protease inhibitors at one
pharmaceutical company was partially supported through NIAID's
National Cooperative Drug Discovery Groups for Treatment of HIV
(NCDDG-HIV).
Recent results of clinical trials conducted by pharmaceutical
companies assessing protease inhibitors in combination with other
anti-retroviral drugs have shown the greatest effect noted to
date in decreasing the amount of virus in patients' blood and
increasing their CD4+ T cell counts. In addition, one study
demonstrated an impressive improvement in survival and delay in
the onset of the symptoms of AIDS in patients receiving a
combination of a protease inhibitor and other drugs. NIH is now
initiating further clinical studies to evaluate the effects of
the newer protease inhibitors in combination with other
anti-retroviral agents, and in patients at various stages of
disease.
Our therapeutic successes against HIV have been substantial.
Five reverse transcriptase inhibitors and one protease inhibitor
are currently approved by the U.S. Food and Drug Administration
for the treatment of people with HIV infection, based in large
part on data from NIH-supported clinical trials. An important
task before us is to improve upon the magnitude of viral
suppression we have achieved thus far, to build on the
improvements seen in immunologic parameters such as CD4+ T cell
counts, and determine if the limited clinical efficacy of
anti-retroviral agents currently available can be prolonged.
Because infection with HIV results in a damaged immune
system, investigators are emphasizing new innovative therapies to
restore immune function, including cell replacement therapies and
the use of naturally occurring, immune-boosting proteins. In
addition, investigators are actively developing a variety of gene
therapy approaches to render cells resistant to HIV.
Treatment of opportunistic infections
Because of advances in the treatment and prevention of Ols
associated with HIV, HIV-infected individuals are living longer
and with a better quality of life now than they did a decade ago.
At least twenty-five drugs are currently licensed for the
treatment of HIV associated opportunistic infections and
malignancies. However, HIV-associated infections, including
cryptosporidium and microsporidium, continue to present new
challenges in the care of HIV-infected people. Furthermore, in
the current era of increasing antibiotic resistance, many common
microbes once thought vanquished now plague HIV-infected people,
as well as those in the general population. Multi-drug-resistant
TB, discussed above, is a good example of this.
To address the need to develop new anti-infectives, NIH is
intensifying efforts in drug discovery. Additional biomedical
and clinical research is needed to better understand dosing, drug
formulations, pharmacokinetics, drug interactions, and toxicity
issues associated with compounds administered singly as well as
in the multi-drug combinations often required in the treatment
of HIV-infected individuals.
AIDS-associated malignancies
A dramatic increase in the incidence of several malignancies
has been observed in HIV-infected individuals. These include
Kaposi's sarcoma, Hodgkin's lymphoma, nonHodgkin's lymphoma, and
ano-genital cancers, particularly cancer of the cervix in HIV
infected women. Treatment of these malignancies in patients who
are already severely immunocompromised is complex, as these
cancers are frequently more resistant to standard anti-cancer
drugs, and patients tolerate treatment less well. NIH supports a
large research effort in the area of AIDS-associated
malignancies, with particular emphasis on the development of
novel and improved cancer therapies.
Research into Pediatric AIDS
The increasing numbers of HIV-infected women, usually
infected through injection drug use or heterosexual contact
(often with HIV-infected injection-drug users), have resulted in
more infants becoming infected. HIV-infected women give birth to
about 7,000 babies each year in the United States; until
recently, approximately 25 percent of these infants became
infected with the virus.
Investigators supported by NIAID and NICHD have found that
the drug zidovudine (AZT) can reduce by two-thirds the rate of
HIV transmission from mother to infant when given to HIV-infected
women during the last 20 weeks of pregnancy and during, labor and
delivery, and to their infants during the first six weeks of
life. Scientists anticipated that the use of AZT in HIV-infected
pregnant women could prevent the infection of 1200 infants each
year in this country, with a Potential savings to the U.S. health
care system of as much as $170 million annually. In fact, two
recent studies have shown that the use of AZT in pregnant women
has increased dramatically in several states since the
dissemination of the results of the above study. This has
resulted in marked reductions in perinatal transmission of
infection, from 19 percent to 6 to 8 percent.
A collaborative approach to research into HIV disease in
children and adolescents, coordinated by OAR and carried out
within several NIH Institutes, has resulted in other significant
advances. For example, an early NICHD study of HIV infection in
children demonstrated that intravenous administration of
immunoglobulin effectively reduced secondary infections in
children whose immune systems were weakened by the virus.
A diverse portfolio of pediatric HIV research continues to be
a high priority of NIH. The major components of this portfolio
include the intramural research program of the NCI and the
collaborations of NICHD and NIAID through the pediatric ACTG
network. Recently, NHLBI joined the ACTG collaboration in trials
designed to determine whether HIV-hyperimmune immunoglobulin
(HIVIG) added to the AZT regimen can further reduce HIV
transmission from mother to baby. These and other studies are
central to our goal of bringing an end to pediatric AIDS.
A vaccine against HIV
The development of an effective anti-HIV vaccine is a high
priority for NIH investigators. A vaccine to completely prevent
HIV infection, our greatest hope for the eradication of HIV,
remains a challenge. A more realistic goal may be to develop a
vaccine to prevent disease caused by infection with HIV. To
achieve this goal, scientists must have a much better
understanding of the mechanisms of transmission of HIV between
individuals, the processes by which the infection becomes
established and persists, and the nature of the immune response
to the virus. NIH is the major sponsor of research in these
important areas worldwide and a continued strong commitment to
basic research into these questions is critical for success.
Despite significant challenges, a number of promising
vaccines are in the "pipeline" at various stages of development.
To further the development of promising HIV vaccine candidates, a
strategic plan for research and development in HIV vaccinology
was recently announced. Government/industry partnerships are
being prospectively formed to develop specific vaccine concepts,
and these collaborations also involve the HIV community. In
addition, NIAID has established a large infrastructure for
eventual efficacy trials of HIV vaccines and has supported many
early phase trials. These trials have shown the feasibility of
developing a safe vaccine that can induce effective immune
responses.
Behavioral and social science research
While vaccines represent one approach to disease prevention,
another critical prevention strategy involves behavioral and
social science research. NIH AIDS research in these sciences
focuses on three key areas: improving primary prevention of HIV
infection through interventions to change behavior; developing
the basic science that underlies these behavior chance
interventions; and addressing the individual and societal
consequences of HIV and AIDS. Cutting across these areas is a
continued commitment to improving the methodologies employed in
behavioral and social sciences research, and to better link
research with communities most affected by HIV and AIDS . NIH-supported researchers have made significant advances in this
area, but much more remains to be learned.
AIDS research benefits other areas
In the last 15 years, the investment in AIDS research has led
to scientific advances that will benefit people with many other
diseases as well. Extensive study of the human immune system
has contributed to insights and advances in understanding cancer
and such autoimmnune diseases as type I diabetes mellitus,
rheumatoid arthritis, and multiple sclerosis. The design of
drugs for all disorders will benefit from the development,
through HIV research, of methods of rational drug design using
sophisticated techniques of structural biology and advanced
computer imaging methods. Advances in the treatment and
prevention of HIV-associated opportunistic infections have
enhanced the care of patients with other immunodeficiency states
such as cancer patients and organ transplant recipients.
Infectious agents that may be responsible for malignancies have
been identified through HIV research, such as the recent
discovery of the agent that causes Kaposi's sarcoma. HIV
research has led to a better understanding of the mechanisms by
which infectious agents and inflammatory cells gain access to the
brain, thereby contributing to the study of Alzheimer's disease,
dementia, multiple sclerosis, neuropsychological disorders,
encephalitis, and meningitis. Research on HIV-related wasting
has provided important information for research on nutritional
disorders, metabolic abnormalities and gastrointestinal
dysfunctions.
HIV research: the future
Clearly, important progress has been made in our fight
against HIV disease. However, the long-term effectiveness of
newly developed therapies is still uncertain and a preventive
vaccine against infection has proven elusive. The most important
scientific opportunities lie in our insight into the virus and
the disease that it causes. Through the legislated authorities
provided to the OAR, NIH is refocusing efforts and redirecting
resources to guide research that will lead to the ultimate goal
of eliminating AIDS worldwide. A strong collaboration with
Industry will be critical for these efforts.
STD research
Other sexually transmitted diseases (STDs), in addition to
HIV infection, remain a significant problem. Each year, an
estimated 10 to 12 million Americans acquire an STD other than
HIV disease. Approximately 65 percent of these infections occur
in people under 25 years of age, with 3 million cases among
teenagers. These infections may be present without symptoms and
often are unknowingly passed to others causing serious
complications, particularly in women and their offspring. In
addition, the risk of becoming infected with HIV is much higher
in an individual with another STD such as herpes, syphilis,
gonorrhea or chlamydial infection.
Because of the urgency of the STD epidemic, initiatives to
prevent and control urge are a key priority of NIH. Scientists
are making, important progress in the areas of vaccines,
diagnostics, therapy, behavioral interventions and other methods
that promise to facilitate the prevention of STDs and HIV
infection.
Recently, NIH-funded research has led to simple tests for
vaginitis and chlamydial infection. NIH scientists also have
developed an experimental vaccine to prevent chlamydial
infections that shows promise in laboratory tests. Such a vaccine
has the potential to reduce the more than 4 million chlamydial
infections that occur each year and the associated costs, which
exceed $2.4 billion annually.
NIAID and NICHD are funding, research to test the potential
of microbe-killing chemicals that could be used topically in the
vagina to protect women from STDS, including HIV, and prevent the
spread of STDs to their partners. A three-pronged strategy to
develop these topical microbicides has been developed. The first
part of this strategy consists of basic research to delineate the
precise mechanisms by which STD organisms infect the host vaginal
surfaces. The second arm is pre-clinical product development,
including in vitro screening against STD organisms, animal
toxicity studies and the development of specific drug,
formulations for topical use. Finally, clinical trials are being
initiated using the NIAID large international trials network to
study both safety and efficacy of therapies. The development of
these agents is important in that it may provide women with a
method by which they can control, independently of their partner,
their exposure to and risk of infection with STDS, including HIV.
We have long known that infections such as rubella or cytome-alovirus can result in miscarriage or otherwise harm the fetus.
Recently, NIH research has taught us more about the role played
by other infections in causing adverse outcomes of pregnancy. A
recent large-scale study supported by NICHD and NIAID
demonstrated that many women have an asymptomatic vaginal
infection during pregnancy called bacterial vauinosis; this
condition is associated with premature labor and low-birth-weight
delivery. Low-birth-weight infants are at high risk for mental
retardation, respiratory disorders and other adverse effects, and
for death. Studies indicate that screening pregnant women for
bacterial vaginosis and, if they are infected, treating them with
an appropriate antibiotic, markedly reduces premature delivery.
Thus, for the first time, we may have an effective intervention
to prevent this persistent and unyielding problem of prematurity.
New and improved vaccines
Prevention research is a central component to NIH efforts
against all infectious diseases and includes both behavioral and
biomedical approaches. At a minimum, behavioral research can
result in reduction of risk of transmission and prevention of
progression of disease, while biomedical research may elucidate
mechanisms of transmission and disease progression. The ultimate
prevention goal is the development of effective vaccines. NIH
has made many important contributions to the improved management
and prevention of infectious diseases. In this regard,
development of new and improved vaccines is an extremely high
priority. Vaccines provide safe, cost-effective, and efficient
means of preventing illness, disability and death from infectious
diseases. In addition to vastly improving the health and
well-being of our citizens, vaccines can markedly decrease both
direct and indirect health care costs. For example, experts have
calculated that $14 are saved for every dollar spent on measles,
mumps, and rubella immunization in this country. Considering
that infectious diseases account for 25 percent of all visits to
physicians each year, at a total annual cost to society that may
exceed $120 billion, the importance of research into disease
prevention by vaccination cannot be overstated.
NIH efforts have contributed to the development or
improvement of many vaccines. Recent successes include the
development and licensure of hepatitis A vaccines and Haemophilus
influenza type B (Hib) conjugate vaccines.
Hepatitis A virus, transmitted by contaminated food and
water, affects more than 130,000 individuals each year in the
U.S. Protection of persons at high risk for infection, such as
travelers to countries where the disease is endemic, promises
substantial reduction of the $300 million in annual hepatitis
A-associated costs in this country.
In the 1960's the leading cause of acquired mental
retardation in the U.S. was brain damage from meningitis caused
by Hib. Despite the availability of antibiotic therapy, children
who contracted Hib meningitis often had brain damage or deafness,
and many died. At that time, NICHD intramural investigators and
NIAID-funded grantees developed a vaccine composed of the
polysaccharide surface coat of Hib. Investigators determined
that the purified polysaccharide was safe and stimulated
protective levels of antibody, first in animals, then in adults,
and finally in children. With the added involvement of industry,
three Hib polysaccharide vaccines were produced and licensed in
1985.
The polysaccharide vaccines by themselves had limitations
because they did not stimulate protective antibody levels in
infants and very young children, the age group with the highest
incidence of serious disease. Over several years, NIH
investigators developed a new concept, a "conjugate vaccine,"
linking the "weak" polysaccharide to a carrier protein that
improved the protective properties of the Hib vaccine for
infants. These researchers demonstrated that the conjugate
vaccines were effective in both infants and adults.
Since 1987, four Hib conjugate vaccines have been licensed
and marketed. These vaccines have become part of the routine
pediatric immunization series that is given babies starting at
age 2 months. Since routine use of Hib conjugate vaccines began
in the U.S., the number of cases of Hib meningitis or sepsis has
fallen from 15-20,000 per year to less than 100. Hib conjugate
vaccines are also now used routinely in Canada, Chile, Iceland,
western Europe, and other parts of the world. Wherever these
vaccines have been used, Hib meningitis and other serious effects
caused by this pathogen have virtually disappeared. This
accomplishment is one of the most important recent contributions
of the NIH that directly benefits the public health. The
introduction of vaccination against Hib in this country has
virtually eliminated this disease, saving more than $400 million
each year in direct and indirect costs. Today there is every
expectation that this organism, which is found only in humans,
will, like smallpox, be eliminated.
More recently, NIAID and NICHD have supported research toward
the development of safe and effective pertussis (whooping cough)
vaccines, which are expected to be licensed shortly. The
pertussis vaccine currently used in the United States is composed
of whole bacteria cells. While safe and effective, this vaccine
sometimes causes side effects that caused concern among parents
to the point where some were reluctant to have their children
immunized. Scientists at NICHD and NIAID responded to this
serious public health problem using two approaches. NICHD's
scientists developed a new, single-component vaccine using a
unique method of inactivating the pertussis toxin to make it a
safe toxoid, but still preserving its immunizing properties. As
an excellent example of the inter-Institute collaboration within
NIH, NIAID's Vaccine Evaluation Units were used for NICHD's Phase
1 studies of their toxoid vaccine in children. Results from
Phase III field trials show a good protective effect for the
vaccine with far fewer side effects, and the approval and
licensing process with FDA is moving ahead expeditiously. The
NICHD pertussis toxoid vaccine is L acceptable for vaccination of
adults, and thus can be used to eliminate the remaining reservoir
of whooping cough in the entire population.
At the same time, NIAID-supported scientists developed and
evaluated acellular pertussis vaccines that contain only portions
of the pertussis organism, thus avoiding the toxicity observed
with the licensed whole-cell vaccine. In two landmark studies,
these vaccines have proven to be efficacious and better tolerated
than the current whole-cell vaccines. The availability of these
improved and better-tolerated acellular pertussis vaccines
should revitalize worldwide public acceptance of this important
public health tool. Of additional importance, the acellular
vaccines hold promise as a potential component of new combination
vaccines, which may enable physicians to reduce the number of
immunizations required for prevention of childhood infections.
NIH scientists also have demonstrated that a single component
vaccine using the Vi antigen protects against typhoid fever.
This Vi vaccine is now licensed in the U.S. and at least 30 other
countries and provides one-shot, side-effect-free inexpensive
protection against typhoid, not only for residents of areas of
the world with poor sanitation, but for U.S. travelers and
military personnel in those areas as well.
Other studies suggest that a conjugate vaccine developed by
NIH researchers can prevent the diarrhea and dysentery caused by
shigella, a major cause of death in infants worldwide.
Preliminary clinical evaluation of a vaccine to prevent infection
with E. coli 0157:H7, often responsible for serious intestinal
infections in children, is now being completed. In addition, a
pharmaceutical manufacturer is evaluating a NICHD-developed
conjugate vaccine for Staphylococcus aureus, a leading cause of
hospital-acquired infections, and an organism that is becoming,
resistant to most antibiotics.
Major and original contributions to vaccines for
pneumococcus, Group B streptococcus and hepatitis B have resulted
from NIH-supported research. NIH has also had a critical role in
both fundamental and early clinical research currently ongoing
for vaccines against gonococcal and herpes infections.
NIH-supported scientists also are studying a new approach to
developing a vaccine for tuberculosis.
The future of vaccine technology is exciting. New biomedical
advances in various areas are being applied to the development of
methods to prevent diseases that have not previously yielded to
immunization, such as Lyme disease, certain pneumonias, malaria,
rotavirus, respiratory syncytial virus, and many others.
Conclusion
We are currently in the midst of the HIV pandemic and have
within this century experienced pandemics or epidemics of
influenza, cholera, malaria and other infections. Clearly, we
remain vulnerable to infectious diseases, which must be fought on
many fronts.
The continued support of basic research in microbiology and
immunology, as well as clinical research in infectious diseases,
are critical to prepare the Nation against newly emerging and
re-emerging microbes. Continued biomedical and behavioral
research will equip us with the tools to effectively combat
future threats of infectious diseases to the health of people in
this country and around the world.
This concludes our remarks. We would be pleased to answer
any questions you may have.
