|
The Smallpox Vaccination Plan: Challenges and Next
Steps
Bill Number: Oversight Hearing
Hearing Date: January 30, 2003
Witness:
Anthony S. Fauci, MD, Director
National Institute of Allergy & Infectious Diseases
Bethesda, MD
Testimony:
Mr. Chairman and Members of the Committee, thank
you for inviting me here today to discuss the implementation
of the President’s smallpox vaccination plan,
which is intended to protect the American people against
the threat of a smallpox attack. Because of the long-standing
expertise of the National Institute of Allergy and
Infectious Diseases (NIAID) of the National Institutes
of Health (NIH) in biomedical research on emerging
and reemerging infectious diseases, including smallpox
and other potential bioterror agents, the Institute
has been designated by President Bush to play a leading
role in the nation's fight against bioterrorism. As
Director of the NIAID, I am committed to bringing
all of our research expertise to bear on the full
implementation of this important effort.
SMALLPOX VACCINE IMPLEMENTION PLAN
On December 13, 2002, the President announced a plan
to prepare and protect the American people against
the threat of a possible smallpox attack by hostile
groups or governments. Under the plan, the Department
of Health and Human Services (DHHS), through the Centers
for Disease Control and Prevention (CDC), will work
with state and local governments to form volunteer
“Smallpox Response Teams” who can provide
critical services to their fellow Americans in the
event of a smallpox attack. To ensure that these teams
can mobilize and perform effectively in an emergency,
it is recommended that health care workers and other
critical personnel volunteer to receive the smallpox
vaccine. The President also announced that the Department
of Defense will vaccinate certain military and civilian
personnel who are or may be deployed in high threat
areas. Some U.S. personnel assigned to certain overseas
embassies also will be offered vaccination. It should
be noted that the Federal government is not recommending
vaccination for the general public at this time.
SMALLPOX – THE DISEASE
Smallpox is a serious, contagious, and sometimes
fatal disease. The symptoms of smallpox infection
appear approximately 12 to 14 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) all beginning
at the same time. These lesions become pus-filled
and begin to crust, forming scabs that 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, but are most infectious
during the first 7 to 10 days of rash. The mortality
of smallpox infection is approximately 30 percent,
although mortality is likely to be much higher in
those with compromised immunity, such as individuals
with HIV infection and those receiving cancer therapies
or drugs to prevent the rejection of transplanted
organs. Smallpox patients who recover frequently have
disfiguring scars over large areas of their body,
especially their face; some are left blind. There
is no licensed treatment for smallpox disease, and
the only known prevention is vaccination.
A massive vaccination program led by the World Health
Organization (WHO) eradicated all known smallpox disease
from the world in the late 1970’s, a resounding
success story for vaccination and public health. The
last case of smallpox in the U.S.A. was in 1949, and
use of the vaccine in this country was discontinued
in 1972. In 1980, WHO recommended that all countries
stop vaccinating for smallpox. At the present time,
small quantities of smallpox virus are stored in two
secure facilities in the United States and Russia
explicitly for research purposes, but it is believed
that unrecognized stores of smallpox virus exist elsewhere
in the world.
Prior to its eradication, smallpox was considered
one of the most devastating infectious diseases known
to mankind. Today, with the real possibility that
smallpox may be used as an agent of bioterrorism,
it may be once again poised to threaten public health
worldwide.
SMALLPOX – THE VACCINE
The “Smallpox Response Teams” and “first
responders” identified in the President’s
Smallpox Vaccination Plan will receive FDA-licensed
Dryvax smallpox vaccine in the undiluted form. This
vaccine was made by Wyeth Laboratories and approximately
15 million doses have been in storage since 1982,
when the company stopped making the vaccine. Historically,
Dryvax smallpox vaccine has proven to be 95% effective
in preventing smallpox infection. In unvaccinated
people exposed to smallpox, the vaccine can lessen
the severity of, or even prevent, illness if given
within 3 days after exposure.
The vaccine is freeze-dried, live vaccinia virus,
a poxvirus related to smallpox virus – it is
not a dead virus like many other vaccines. The vaccine
is delivered in an unusual way, using a technique
called scarification whereby the material is pricked
into the skin using a two-pronged needle. Successful
vaccination is measured by the development of a clear-cut
pustule 6-8 days after vaccination. This is known
as a “take.” The blister dries up and
a scab begins to form, and by the third week the scab
falls off, leaving a scar. The immunization site remains
contagious for vaccinia until the scab dries up completely
and falls off. For that reason, the vaccination site
must be cared for carefully to prevent the virus from
spreading. Approximately one week after vaccination,
many people experience fever, malaise, myalgia, soreness
at the vaccination site, and swelling of the lymph
nodes in the area of the vaccine, particularly under
the arms.
In order to determine whether the existing supply
of Dryvax vaccine (15 million doses) retained its
potency and could even be diluted to expand the stock,
a series of clinical trials were performed. In this
regard, NIAID conducted a study on adults who had
not been previously vaccinated to determine whether
Dryvax could be diluted effectively to make more doses
of this smallpox vaccine available. This clinical
trial showed that the existing U.S. supply of smallpox
vaccine was still very potent in its undiluted form
and could be diluted five-fold and retain its potency,
effectively expanding the number of doses of smallpox
vaccine in the United States to 75 million. A report
describing these findings appeared in the April 25,
2002, issue of The New England Journal of Medicine.
The Dryvax vaccine also is being studied by NIAID
in previously vaccinated populations to determine
whether any residual immunity exists from earlier
vaccinations.
In addition to Dryvax, NIAID is sponsoring clinical
trials of another vaccine against smallpox developed
by Aventis Pasteur. Eighty million doses of Aventis
Pasteur’s smallpox vaccine, a different formulation
of the vaccinia smallpox vaccine, have been in storage
for 40 years. NIAID-supported studies performed through
its Vaccine Treatment and Evaluation Units will determine
the safety and preliminary efficacy of various concentrations
of Aventis Pasteur's smallpox vaccine in adults. To
further ensure adequate supplies of smallpox vaccine,
DHHS has contracted with Acambis, Inc. to produce
a cell culture based smallpox vaccine for licensure.
SMALLPOX VACCINE RESEARCH – CHALLENGES AND
OPPORTUNITIES
While the Dryvax smallpox vaccine is currently the
most effective weapon against a possible smallpox
attack, it still poses risks, even in healthy populations.
Fortunately, most individuals experience only mild
symptoms. However, serious reactions to smallpox vaccination
are well documented in studies dating back to the
1960s when smallpox vaccination was routine in the
United States. Those data indicate that, for every
1 million people vaccinated, there are 14 to 52 life-threatening
adverse events such as post-vaccinial encephalitis
with 1 to 2 deaths. In addition, there are 49 to 935
serious, but not life-threatening events. Moreover,
because smallpox vaccination ceased in the U.S. more
than 25 years ago, there is limited experience with
this vaccine in the era of HIV infection, organ transplantation,
and immunosuppressive therapy.
The protection of all populations, including immunocompromised
individuals, pregnant women, and children is the next
critical important step in addressing the smallpox
threat. NIAID is carefully examining alternatives
to Dryvax including modified vaccinia Ankara (MVA),
which may be a viable “second generation”
smallpox vaccine for individuals at high risk of complications
from the current Dryvax smallpox vaccine.
Several of the complications of smallpox vaccination
can be treated with Vaccinia Immune Globulin (VIG),
which is derived from the plasma of volunteers who
previously have received a smallpox vaccination. DHHS
currently has more than enough VIG to cover the adverse
events that are projected to be associated with vaccinating
the smallpox response teams and first responders under
the President’s smallpox vaccination plan. Furthermore,
the CDC has contracted for additional supplies of
VIG to ensure an adequate stockpile of this product
by this summer to cover the severe adverse events
that might be expected for over 300 million vaccinees.
Assessments of MVA vaccine candidates in multiple
animal models, including immunosuppressed animals,
are providing important data on the safety and efficacy
of the vaccine. In addition, historical data from
people who received an MVA vaccine in Germany in the
1970’s adds to the body of scientific data.
Importantly, the clinical trials conducted in Germany
at the time included children, who are known to be
at risk for adverse events associated with the conventional
vaccinia-based vaccine. MVA vaccine also has been
tested recently as an experimental vaccine vector
for the delivery of other vaccine candidates, including
HIV and cancer vaccines. These studies suggest that
the vaccine may be safe in immunocompromised individuals.
In late 2002, the NIAID issued a Request for Proposals
(RFPs) intended to provide resources for the initial
development of MVA vaccine candidates. NIAID intends
to issue a second RFP during the summer of 2003, entitled
“Production and Acquisition of MVA Vaccine.”
The objective of the second RFP will be to manufacture,
formulate, fill and finish, and test, in accordance
with current Good Manufacturing Processes (cGMP) regulations,
up to 30 million doses of MVA vaccine to constitute
the U.S. government’s stockpile for emergency
use under Investigational New Drug (IND) status and
to provide a licensure plan to include the conduct
of expanded human safety studies required for licensure
and the conduct of pivotal animal protection studies.
A third contract solicitation for the acquisition
of a licensed product is being planned for 2005, under
the auspices of the CDC.
In addition, the NIAID Vaccine Research Center on
the NIH campus in Bethesda, MD, is conducting a clinical
trial to determine the safety of MVA and to compare
the immunogenicity of MVA and Dryvax. This study is
being conducted in healthy volunteers who have not
been previously immunized with vaccinia; a future
trial with vaccinia-experienced subjects is being
planned. NIAID also is looking ahead to develop “third”
generation smallpox vaccines, including recombinant
protein vaccines.
NIAID is also evaluating drugs for use against smallpox
virus. NIAID-supported scientists have developed a
form of the antiviral drug cidofovir that can be administered
orally. Injectable cidofovir already has been approved
by the Food and Drug Administration (FDA) for treating
CMV retinitis in individuals with HIV/AIDS and has
shown activity against smallpox and related viruses
in laboratory and animal studies. Preliminary data
from these experiments suggest that cidofovir may
be helpful in controlling the progression of serious
vaccinia-related complications. To illuminate this
issue, NIAID worked last year with colleagues at the
CDC, the FDA and the Department of Defense (DoD) to
develop an Investigational New Drug application to
evaluate cidofovir in the treatment of smallpox. NIAID
continues to explore the development of additional
therapeutic interventions against smallpox and other
potential bioterror agents.
BIODEFENSE RESEARCH
Smallpox is only one of a number of potential bioterror
threats to our nation. In 2002, NIAID convened two
Blue Ribbon Panels to provide objective scientific
advice on NIAID's biodefense research activities involving
smallpox as well as other potential agents of bioterror.
As a result of these deliberations, the Institute
has developed two research agendas: one focuses on
the CDC’s Category A agents, which include smallpox,
while the second focuses on NIAID’s Category
B and C Priority Pathogens. Guided by the recommendations
outlined in these agendas, NIAID developed a total
of 52 biodefense initiatives to stimulate research
in Fiscal Years 2002 and 2003; 36 are new initiatives
and 16 are significant expansions. During this same
time period, NIAID has seen a 30 percent increase
in the number of grant applications; the vast majority
of these are in response to our biodefense initiatives.
In Fiscal Year 2002, several NIAID initiatives encouraged
industry partnerships and focused on the development
of new diagnostics, vaccines and therapeutics for
CDC Category A agents. These types of research initiatives
have been well received. As a result, NIAID has expanded
and reissued many of these collaborative efforts in
Fiscal Year 2003, and plans to do the same in Fiscal
Year 2004. In addition, the new initiatives will be
broadened to address NIAID’s Category B and
C Priority Pathogens.
A number of significant advances in understanding,
treating and preventing potential agents of bioterror
have already been realized. For example, NIAID-supported
scientists determined how anthrax toxin gains entry
into a cell and demonstrated how the toxin can be
effectively blocked from entering the cell, suggesting
that the development of specific anthrax toxin-blocking
compounds could be a viable approach to treating anthrax
disease. Furthermore, intramural researchers at NIAID’s
Vaccine Research Center are working on the development
and pre-clinical testing of an Ebola vaccine, while
others have discovered a single gene mutation in the
plague bacterium, Yersinia pestis, which may have
been responsible for the emergence of the "Black
Death” in the 14th century.
NIAID also has expanded genomic sequencing of potential
agents of bioterrorism, including anthrax and plague,
and has recently awarded contracts to two companies
designed to spur development of a new anthrax vaccine.
Similarly, the Institute has new initiatives planned
to encourage development of vaccines against plague
and therapeutic strategies against Botulinum toxin.
In Fiscal Year 2003, NIAID will establish a nationwide
network of Regional Centers of Excellence for Biodefense
and Emerging Infectious Disease Research and pursue
an initiative to design, build, and renovate a system
of Regional and National Biocontainment Laboratories
to serve as national resources for biodefense research
and product development. These facilities will include
a small number of Biosafety Level-4 (BSL-4) laboratories,
the level of containment necessary to study highly
pathogenic organisms.
CONCLUSION
The threat of resurgent smallpox is real and its
potential is devastating; however, the President’s
Plan moves us in the right direction to address this
threat head-on. We will continue to work closely with
the Administration, including our colleagues within
HHS, to fully implement the President’s smallpox
vaccine action plan. In addition, NIAID will continue
to bolster our biodefense research efforts, which
span basic, clinical and product development research,
and infrastructure development. With a strong research
base and talented investigators throughout the country,
we fully expect that NIAID’s research programs
will provide the elements essential to enhance significantly
our nation’s defenses against the threat of
bioterrorism.
Thank you for the opportunity to testify. I will
be happy to answer any questions.
|
