Testimony
Before the Committee
on Appropriations, Subcommittee on Labor, HHS, Education
and Related Agencies
United States Senate
Bioterrorism Preparedness:
NIH Smallpox Research Efforts
Statement of
Anthony S. Fauci, M.D.
Director
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Department of Health and Human Services
For Release
on Delivery
Expected
at 9:00 am
on
Friday, November 2, 2001
Mr. Chairman and
Members of the Committee, thank you for inviting me here
today to discuss the threat of smallpox as a weapon of
bioterrorism and the current efforts by the National Institutes
of Health (NIH) to accelerate basic and clinical research
related to the prevention and treatment of smallpox.
Recent events,
notably the attacks on the World Trade Center and Pentagon
and numerous incidents involving the intentional spread
of anthrax spores, have highlighted our Nation's vulnerability
to attack by bioterrorists. In addition to anthrax, other
potential agents of bioterrorism include smallpox virus,
the bacteria that cause plague and tularemia, botulinum
toxin, filoviruses (e.g. Ebola virus) and arenaviruses
(e.g. Lassa virus), and other selected pathogens.
As concern grows
about the use of biological agents in acts of terrorism
or war, federal health agencies are evaluating and accelerating
measures to protect the public from the health consequences
of such an attack. The National Institute of Allergy and
Infectious Diseases (NIAID), a component of the NIH, supports
research on the diagnosis, prevention and treatment of
infections caused by a wide variety of pathogens, including
those with potential for use as biological weapons.
Our ability to
detect and counter bioterrorism depends to a large degree
on the state of biomedical science. Basic and applied
research supported by NIH complements the efforts of other
agencies by developing the essential tools -- diagnostic
tests, therapies and vaccines -- needed by physicians,
nurses, epidemiologists and other public health workers
to prevent and control a disease outbreak.
Smallpox: The
Disease
Smallpox, caused
by a virus known as Variola major, is considered one of
the most dangerous potential biological weapons because
it is easily transmitted from person to person, and because
few people carry full immunity to the virus. Although
a worldwide immunization program eradicated smallpox disease
in 1977, small quantities of smallpox virus still exist
in two secure facilities in the United States and Russia.
However, it is possible that unrecognized stores of smallpox
virus exist elsewhere in the world.
The symptoms of
smallpox infection appear approximately 12 days (range:
7 to 17 days) following exposure. Initial symptoms include
high fever, fatigue, and head and back aches. A characteristic
rash, most prominent on the face, arms, and legs, follows
in 2-3 days. The rash starts with flat red lesions (a
"maculopapular" rash); the lesions evolve at the same
rate. Lesions become pus-filled and begin to crust early
in the second week. Scabs develop and then separate and
fall off after about 3-4 weeks. Individuals are generally
infectious to others from the time period immediately
prior to the eruption of the maculopapular rash until
the time of the shedding of scabs. The mortality of smallpox
infection is approximately 30 percent; those patients
who recover frequently have disfiguring scars. Smallpox
spreads directly from person to person, primarily by aerosolized
saliva droplets expelled from an infected person. Contaminated
clothing or bed linens also can spread the virus.
Smallpox vaccine
has proven to be highly effective in preventing infection.
In unvaccinated people exposed to smallpox, the vaccine
can lessen the severity of, or even prevent, illness if
given within 4 days after exposure. Vaccine against smallpox
does not contain the smallpox virus, but rather a laboratory
strain of a related virus called vaccinia.
Vaccinations to
prevent smallpox have not been required in the United
States since 1972. People vaccinated prior to 1972 very
likely have diminished immunity to smallpox; people born
in the United States after 1972 are not routinely vaccinated.
Currently, smallpox vaccination is recommended and available
only for individuals who are at risk of imminent exposure,
such as laboratory personnel who work with orthopox viruses
related to smallpox virus, including vaccinia. No new
smallpox vaccine has been manufactured in almost 20 years.
Smallpox Research:
Vaccines
The NIAID strategy
for smallpox vaccine research is a three-part program
that addresses immediate, intermediate, and long-term
needs. In the near-term, a bioterrorist attack involving
smallpox would require the utilization of stores of the
existing smallpox vaccine. Approximately 15 million doses
of the FDA-approved "Dryvax" vaccine have been stored
since production stopped in 1983. This clearly would not
be enough to respond to a national smallpox epidemic.
As a response, NIAID last year initiated a study to determine
the feasibility of expanding the use of the existing stores
of the Dryvax vaccine by dilution. In this study, investigators
examined the skin and immune system responses of normal
unimmunized adult volunteers who were given a 1:10 dilution
(10 percent) or a 1:100 dilution (1 percent) of off-the-shelf
Dryvax vaccine They compared responses to those from other
volunteers who had received the full-strength vaccine.
The results showed that the full-strength vaccine had
maintained its potency, and that 70 percent of people
who received a single dose of the 10-percent vaccine developed
a sore followed by a scab at the injection site and antibodies
in their blood, indicating protection. Even though the
10-percent vaccine was capable of stimulating an immune
response in most people in the study, it is unlikely that
it would protect enough people in a large population to
sufficiently stop the spread of smallpox. Based on these
findings, a new study was designed to determine if a diluted
vaccine combined with an alternative vaccination schedule
could protect a greater number of people than did the
standard dose and regimen.
This study, which
will enroll up to 684 people, is evaluating three different
doses of Dryvax. Researchers will study the ability of
the various vaccine formulations to stimulate a scab,
or "take," at the vaccination site and to produce antibodies
in the blood. If participants have not developed a scab
in seven to nine days after vaccination, they will be
revaccinated with the same vaccine they received the first
time. By that strategy, researchers hope to learn which
vaccine dose given in a single injection elicits the best
response among the largest number of people and whether
"boosters" can fortify the immune response in those who
did not react to the first vaccination. This study is
being conducted at several NIH Vaccine and Treatment Evaluation
Units around the United States, including Saint Louis
University, Baylor College of Medicine, the University
of Maryland, and the University of Rochester. Recruitment
of study participants began on Oct. 26, 2001.
NIAID-intermediate-term
plans include development of a new smallpox vaccine: a
safe, sterile product grown in cell cultures using modern
technology. This vaccine will be rapidly tested in human
clinical trials; 250 million doses will be produced and
delivered to the federal government by the end of 2002.
In the long-term, basic research promises to provide a
third generation of smallpox vaccines that could be used
in all segments of the population, including pregnant
women and people with weakened immune systems. As the
research evolves, NIAID continues to be actively involved
in the development and testing of new vaccines, including
the initiation of clinical trials to determine vaccine
safety and efficacy, particularly in special populations.
Therapeutics
Research
NIH therapeutics
research focuses on the development of new antimicrobials
and antitoxins, as well as the screening of existing antimicrobial
agents to determine whether they have activity against
organisms that might be employed by bioterrorists. For
example, in collaboration with DOD, NIH has rigorously
screened a large number of antiviral drugs against smallpox
and related viruses. One of these agents is an antiviral
called cidofovir, which is approved by the Food and Drug
Administration (FDA) for treating certain AIDS-related
viral infections. Cidofovir has shown potent activity
against smallpox and related viruses in test tube studies
and in animal models. NIH has taken the lead in developing
a protocol that would allow cidofovir to be used in emergency
situations for the treatment of smallpox.
Concurrently, other
anti-smallpox agents are being investigated. NIAID and
the U.S. Army Medical Research Institute of Infectious
Diseases (USAMRIID) funded initial screening of approximately
500 compounds for potential antiviral activity against
smallpox. Compounds were selected for antiviral testing
from the following categories: FDA approved drugs effective
against other viruses; antiviral compounds in clinical
development for other viruses; known experimental antiviral
compounds; and new chemical entities. Several drugs tested
in these screening studies, including several cidofovir
derivatives, have been shown to be active against both
vaccinia and cowpox by in vitro evaluation. Promising
leads will be further tested with additional in vitro
studies, animal model testing, or combination therapy
studies. In addition, the design of medications active
against known drug-resistant variants of microbes and
the development of broad-spectrum agents are important
NIH research priorities.
Together with
our many research partners, NIH has made substantial progress
in the research effort that is critical to our Nation's
fight against terrorism. Much remains to be accomplished,
however, and the challenges posed by bioterrorism will
require a protracted and sustained commitment. With a
strong research base, talented investigators throughout
the country, and the availability of powerful new research
tools, we fully expect that our basic and applied research
programs will provide the essential elements that will
help enhance our defenses against those who attempt to
harm us with bioterrorism.
This concludes
my testimony. I would be happy to answer any questions
which you or members of the Subcommittee may have.