Invited submission to the
Committee on Government Reform for its November 14, 2001 Hearing: Comprehensive
Medical Care for Bioterrorism Exposure
Preparing a Medical Response to Bioterrorism
-- A broad view of the problem
-- Seeking affordable protection
-- Identifying research needs
-- How much protection is
obtainable?
Preparing
a Medical Response to Bioterrorism
Written Testimony of Meryl Nass,
MD
House Committee on Government
Reform
November 21, 2001
Overview
of biowarfare agents
When
planning responses to bioterrorism, there are a wide range of existing
pathogens and toxins to consider, and untold genetically engineered organisms
that might be encountered. Anthrax and
smallpox have long been considered the most likely microorganisms that will be
used, based on their innate ability to be easily disseminated, their high mortality
rates and relative ease of preparation.
Many nations, and potentially some terrorist groups, have the scientific
and technical ability to weaponize these two diseases. It is thought that a
smaller number of nations or groups can produce more technically demanding, or
genetically engineered organisms.
It
makes sense, certainly in the short term, to be prepared for anthrax and
smallpox; but in the longer term, we should anticipate a much greater range of
possible pathogens. For example, NOVA
(1) and three NY Times reporters (2) have shown that the Soviet Union developed
horrifying, genetically engineered germs for which there is currently no
adequate response. A modified
Legionella bacterium that produces multiple sclerosis after an episode of pneumonia
is one such microorganism. Scientists with the know-how to create such germs
have left the Soviet Union, and could be anywhere on earth. Therefore, although important, simply
preparing for anthrax and smallpox is insufficient for the challenges faced
now.
There
are 3 levels of complexity for biological weapons
a)
Low technology organisms:
smallpox, anthrax, plague, brucella, tularemia, cholera, typhoid, shigella. These were weaponized circa 1940 by various
nations and require no advanced technology to produce in quantity. They may be disseminated using widely
available means.
Countermeasures (antibiotics,
antivirals and vaccines) are generally known and effective.
b) Higher
tech weapons developed in the US, USSR, Iraq and other nations more recently. These organisms require sophistication to
produce and disseminate, but the know-how to produce them (or the weapons
themselves) may have been transferred to any nation or group. Examples are the Legionnaire’s
Disease-Multiple Sclerosis bacterium, or vaccine-resistant viruses or
bacteria.
Countermeasures are not generally
known, but may have been created by the weapons’ developers.
c)
Ever more complex and
difficult-to-respond-to microorganisms, which could be developed now or in the
foreseeable future.
These might, for example, apply advances in knowledge of the human
genome, and genetic variability among different populations, to create
organisms specifically tailored to certain groups or military needs. Examples might be a bacterium that secretes
cytokines causing autoimmune diseases, but would only affect those of
Scandinavian descent, or a gastrointestinal infection that produces
sterility. In each case, autoimmune
destruction of tissue would be irreversible.
There are unlikely to be effective
countermeasures available for these pathogens.
·
No attempt was made to use anthrax for mass casualties,
such as dissemination in a subway tunnel or ventilation system
·
The letters were taped shut, in an apparent attempt to
prevent spores from escaping en route
·
Although the letters contained weaponized anthrax, they
informed recipients of their contents, so that effective antibiotics could be
started. The perpetrator desired to
frighten, not to kill
·
The media targets were probably chosen to ensure the
attacks were publicized
·
Members of Congress might have been targeted because
Congress controls programs for bioterrorism.
·
Anthrax-tainted letters may have preceded the September
11 attacks. CDC has advised those who spent more than an hour in the American
Media News building since August 1, 2001 to take prophylactic antibiotics
(3).
Our responses to these
anthrax attacks have been relatively successful. But congratulations are not in order: the anthrax attacks we
experienced, terrible as they were, were actually a “best case” scenario. The attacks can almost be viewed as a drill,
designed to assess our readiness for a truly malicious biowarfare attack. Possibly this is what the perpetrator was
after: to test us, and send a wake-up call.
Had an enemy put
undetectable but deadly quantities of anthrax into envelopes without a warning
letter, many more casualties could have ensued. Antibiotics would only be started after people became ill. How would we know which facilities to test
for spores? If an antibiotic-resistant
anthrax had been used, most of those inhaling an infectious dose would
die. If anthrax were released in a
subway tunnel, instead of an envelope, thousands of deaths could be
anticipated.
Although the attacks
appear to have been done for effect, the ramifications have been
significant. Mail remains in storage,
undelivered for weeks. Millions of
dollars are being spent for electron beam machines to sterilize the mail. Congressional offices remain closed, until
removal of anthrax spores can be assured.
Could we respond
effectively to a truly serious anthrax attack? Or an attack using more sophisticated pathogens? Anthrax may be the least frightening of the
bioterrorism scenarios we could face in the future.
Yes, we can
respond. How effectively we can respond
is a challenge I will come back to later.
The following list is a general overview of what could
identify and treat illnesses resulting from bioterrorism. Both generic (useful for a range of
pathogens) and pathogen-specific measures should be developed, with an emphasis
on developing responses that could be used for a variety of pathogens. Measures to boost immunity after an exposure
should be studied; although this is a relatively new area of medical research,
it could yield substantial dividends in addition to those for bioterrorism.
1) Strengthening
our public health infrastructure is essential: sharing of knowledge
regarding bioterrorism threats and appropriate responses, ability to provide
appropriate laboratory assays and medical care at the local level, and improved
communications between public health facilities are needed (4).
2) Stockpiling
antibiotics is appropriate.
There should be a range of antibiotics, including those for which adding
resistance is more difficult. Researching storage methods to maximize effective
shelf life would be useful. Possibly
one or more novel antibiotics should not be licensed for mass use, but held in
reserve for a bioterrorism response. It
would be difficult for a perpetrator to engineer resistance to novel (unknown)
antibiotics. Researching methods that
encourage early anthrax spore germination in the exposed patient, and
establishing an optimal duration of antibiotic use would be helpful, since we
do not know whether 60 days of antibiotics will be sufficient for all those
exposed to anthrax.
3) Vaccinations
are useful, but the infinite variety of potential pathogens, the time needed to
develop new vaccines, and the time lag for developing immunity following
vaccination, conspire to make it unlikely they will be a robust form of defense. Vaccines are often ineffective against selected
strains of microorganisms, and it is known that vaccine-resistant pathogens
were sought out for biological weapons (5).
Issues requiring urgent investigation include whether and how vaccines
may lead to chronic illness. How would
a genetically diverse population tolerate 50 or 500 vaccinations? Dr. Ken Alibek blames his severe allergies
on multiple vaccinations (5), but there is no reliable research that addresses
the issue.
4) Identifying
the virulence factors present in all known pathogenic microorganisms, and their
molecular targets, will allow us to develop generic responses to them. This will probably lead to use of fewer,
more specific vaccine antigens.
Decoding the genome of pathogens will yield the molecular composition of
spores and toxins, permit analysis of their tertiary structures, and allow
targeted countermeasures to be developed more easily. (The federal government is supporting this initiative.) Computer modeling of these structures might
permit rapid drug design outside the laboratory, and creation of new drugs with
novel mechanisms of action (6-7). We
can anticipate that most genetically engineered pathogens make use of known
virulence factors, so this approach can conceivably yield treatments for
pathogens we have never seen before, in advance of an attack.
5) Many
pathogenic microorganisms exert at least some of their effects though
toxins. It is relatively simple (and
inexpensive) to create libraries of antitoxins, or monoclonal antibodies that
could inactivate toxins. This would
almost certainly yield treatments that are more effective than antibiotics
alone, and might work in the late stages of disease. These treatments would be harder to thwart than vaccines.
6) Such
products can also be employed in early diagnostic tests; for example,
monoclonal antibodies could help distinguish anthrax from influenza while the
patient is still in the emergency room.
Additional rapid diagnostic tests must be developed for smallpox,
anthrax, and other expected pathogens (8).
The federal government should provide specialized training, diagnostic
kits and equipment, such as polymerase chain reaction (PCR) machines, to state
and local laboratories, so that a) important results are made available to
treating physicians in a timely manner, b) local communities are better able to
respond to an attack, c) hoaxes can be quickly distinguished from real attacks,
and d) the federal system will not be overwhelmed by the volume of samples to
be tested. Cultures may yield useful
information more rapidly than expected; anthrax colonies grow in 12-18
hours. Working with cultures on a
compressed schedule, for instance, subculturing every 12 instead of 24 hours,
may be useful and should be considered for unknown organisms. Identifying antibiotic resistance could be
expedited by detecting known molecules that confer resistance, such as
penicillinases, or their genes using PCR techniques.
7) Antivirals
may be effective against some viral pathogens, including smallpox(9). Efficacy testing of libraries of licensed and
unlicensed antiviral drugs needs to be performed for serious viral pathogens.
8) Certain
areas are particularly vulnerable to attack.
These include municipal water supplies, ventilation systems of
buildings, and tunnels. Ships and planes
could be used, wittingly or unwittingly, as delivery systems for microorganisms
or toxins. Biosensors or other
detection methods should be available to monitor such areas. Although none yet have perfect sensitivity
and accuracy, a variety of systems do exist to perform such tasks (8, 10-13).
Simple HEPA filters installed in ventilation systems could trap anthrax spores,
though they would not keep out all viruses and toxins. The material trapped by
filters could be routinely tested for microbes. For those places most at risk (for example, the New York City
subways), sensors should be made available now, and replaced when better
devices become available.
Development of these devices has been under military control for more
than a decade; in order to rapidly encourage the best approaches, and speed
production, a streamlined system for evaluation and procurement should be
considered.
9) Vaccine,
drug and device development needs to be expedited, but safety testing cannot
become a casualty of a streamlined review. Safety testing in animals can be made more
rigorous; for example, more extensive toxicity testing and drug interaction
studies can be performed for all new drugs and vaccines in animal models, and
extensive testing in the pregnant animal model can be done. Human safety testing can be done in parallel
with animal efficacy testing, for those drugs and vaccines that appear most
promising. Additional effort could go
into finding or developing animal models for human diseases that lack such
models. It should be emphasized,
however, that animal safety testing of new products is never sufficient to
identify and rule out all problems that may occur in humans; human safety
testing, using adequate numbers of subjects who are followed for adequate
periods of time, is the only way to identify all but the rarest adverse
reactions, prior to mass use.
10) The
FDA should release its final rule on licensing of new biowarfare drugs and
vaccines, so that its expectations for industry are clear (14).
11) Testing
of new drugs and vaccines may require Biosafety Level 3 or 4 facilities, and
access has been a bottleneck for development and licensure of new products for
use against bioterrorism, although a large number of these facilities exist. These
labs must be made available for testing the most promising drugs and vaccines,
possibly through new procedures involving the Office of Homeland Defense, or
the Secretary of HHS.
12) The
Joint Vaccine Acquisition Program (JVAP) has been called “a terrible operation”
by Dr. DA Henderson, the head of the new Office of Public Health Preparedness,
and “a disaster” by Major General (Dr.) Phillip Russell, a former head of both
Walter Reed Army Institute of Research and USAMRIID, who has recently been
asked to supervise development of an improved anthrax vaccine (15). As bioterrorism expert Stephen Block pointed out, “We don’t have a general way of
making a general vaccine that gets an artbitrary pathogen that lasts for any
length of time… The fact of the matter is that making a vaccine is still very
much a black art (16).” Vaccine development is difficult and time-consuming,
and success cannot be predicted. The
JVAP should be replaced. Top
civilian vaccinologists who understand both the art and science of vaccine
creation should be recruited to develop safe and effective vaccines, designed
to work for a range of pathogens.
13) Research
on spore decontamination is urgently needed. In general, either the DNA or the spore coat
must be disrupted. Oxidizing agents and
radiation are effective, but safer methods are needed. Improving mechanical removal of spores
should be explored. If one could get
all the air moving in buildings, using vacuum cleaners or fans, and filter the
air as it moved, most spores could be collected.
Anthrax and Smallpox: Treatments and Vaccines
For anthrax, the number
one priority is early detection of
a) spores
in the environment, and
b) disease
in the individual.
Early detection allows
pre-emptive antibiotic treatment after an exposure, and as soon as patients
present to a medical facility, for maximal survival rates provided the bacteria
are sensitive to antibiotics.
Antitoxins, either in the form of antisera or human monoclonal antibodies, would probably be an effective treatment for cases diagnosed late, or unresponsive to antibiotics. Novel treatments, such as the mutant PA developed by John Collier at Harvard, are very promising but require additional animal and human trials before use (7).
A safe and effective,
rapidly immunizing vaccine that would cover all anthrax strains and instill
long-lasting immunity is highly desirable.
It is not clear which high risk groups should receive the vaccine. According to the current vaccine’s package
insert, “If a person has not previously been immunized against anthrax, injection
of this product following exposure to anthrax bacilli will not protect against
infection (17).” Although the
suggestion was made that persons exposed to anthrax who are allergic to
antibiotics should instead be vaccinated, this is not an approved use of the
vaccine. Because vaccine-induced
immunity requires more than one vaccine dose, and anthrax kills quickly,
post-exposure vaccination without antibiotics is ineffective at preventing or
treating disease.
This is not the case
for smallpox. There is a long
incubation period for smallpox, and vaccination after exposure is known to
prevent the disease or lessen its severity (18). Although smallpox is contagious from person to person, unlike
anthrax, the disease only spreads after a rash develops. Thus, it is obvious that one is infectious,
so measures such as quarantining cases, and vaccinating those who are exposed
can be taken.
Detailed discussions
regarding the adverse effect profile of the US’ stored smallpox vaccine, and
possible mandatory smallpox vaccinations, have taken place in a variety of
public forums and in the media (19-22).
Surprisingly, no discussion regarding the risks of anthrax vaccine
has taken place, although the US population was attacked with anthrax, not
smallpox. During the past four
years, 520,000 military personnel were vaccinated for anthrax. This large cohort ought to provide
comprehensive data on the vaccine’s safety and efficacy.
The federal government
is negotiating to purchase enough new smallpox vaccine to immunize every
American, at an estimated cost of 2 billion dollars. The efficacy and adverse event profile for this novel smallpox
vaccine have not been publicly discussed, and may not be known (15).
The cost to develop a commercial
vaccine and bring it to market is estimated at $400 to $500 million. With streamlined trials and FDA review, the
cost might decrease substantially.
Parallel development of many vaccines using shared technologies might
drop costs further. Using yeasts or
other microorganisms for vaccine production, instead of eggs and calves’
bellies, will result in lower costs.
The discussion of
smallpox vaccine risks provides a framework with which to evaluate the risks
and benefits of all vaccines. Smallpox
vaccine is a particularly impure product, and historically has been made by
harvesting the pustules of calves infected with cowpox. The vaccine is
scratched on the skin, rather than injected, but still killed or severely
injured between one and four people per million recipients. If it were given to all Americans, there
would be an increased rate of serious reactions, because so many people are
immunocompromised by disease or medical treatments. Careful risk/benefit analysis is therefore critical to making the
best decision regarding who should be vaccinated, and when.
Science
magazine reported last month that officials “are considering…mak[ing smallpox
vaccine] available within a few months as an unlicensed ‘investigational new
drug (8).’ How streamlined would the
review process would be for such a product?
Although the earliest vaccine recipients might receive vaccine under an
experimental protocol, they should be enrolled in safety and efficacy trials,
so that adequate data is collected and analyzed prior to vaccinating
millions of Americans, who deserve a fully tested vaccine.
Pharmaceutical
manufacturers have asked for indemnification from the federal government for
potential liability related to production of bioterrorism vaccines. This could invite manufacturers to
de-emphasize safety issues, and eventually increase the government’s cost for
these vaccines considerably. Would
receiving vaccine under an IND prevent recipients from seeking compensation if
they had a severe reaction?
The US stockpiled 15
million doses of freeze-dried smallpox vaccine about thirty years ago, “but
because the rubber seals are deteriorating, about a quarter are suspect
(23).” Recent, small scale tests of
vaccine in humans suggest that a 1:5 dilution will still induce immunity in 70%
of recipients. How much residual
immunity exists for those who were vaccinated decades ago is controversial
(18). It is possible they may still be
protected.
Smallpox is a virus, not a
bacterium, and therefore will not respond to antibiotics. But it will probably respond to antivirals
(9). And anthrax selected for
bioterrorism might not respond to antibiotics.
Their differences do not explain why the immediate procurement of 300
million doses of smallpox vaccine has assumed such importance, while obtaining
anthrax vaccine for civilians has been entirely ignored. Nor do they explain why anthrax vaccine
manufacture remains in the hands of a small start-up company, when the
Secretary of HHS insisted smallpox vaccine be obtained only from large,
reputable manufacturers (24). Since
purchasing the anthrax vaccine facility over three years ago, the manufacturer
has collected over $100 million from the federal government, but not a single
lot of new vaccine has been approved for use.
The public should be informed how these apparently contradictory
decisions with respect to anthrax and smallpox vaccines have been made.
At least forty known human pathogens could be used for biological
warfare. (Many more could be used
against crops or livestock.) Effective
vaccines have been created for only a few.
None have been stockpiled for use by the American people. What would it cost to develop vaccines for
these pathogens and stockpile them for all Americans? Based on estimates for producing the new smallpox vaccine, whose
development costs have already been paid, the total could easily exceed 100
billion dollars. And we might still be
attacked with microorganisms or toxins for which we had no vaccine. Furthermore, the human cost (in adverse
reactions) of administering that many vaccines is unknown.
Rather than choosing to
develop individual vaccines, the use of attenuated strains or vectors carrying
multiple virulence factors could produce immunity to many pathogens with one
vaccination. Methods for developing
animal models, and expediting safety testing, could be applied to development
of many vaccines.
One suggestion is to
avoid stockpiling most vaccines en masse (25); long-term storage invites
deterioration and a host of uncertainties.
Instead, vaccines should be developed and tested in animals and humans,
but manufactured in small quantities at regular intervals. A federal surge capacity for vaccine
manufacture should be created, and maintained.
Then, depending on what vaccine was needed, it could be produced over a
period of weeks in the desired quantity.
Although testing would be needed to assure quality, test methods and
release protocols are being designed to facilitate rapid manufacture and
use. Traditionally, spore-forming
organisms have required dedicated manufacturing facilities, because of
persistent spore contamination. New
research into decontamination methods will likely result in effective cleanup
methods, possibly eliminating the need for individual vaccine production
facilities for spore formers.
Many new vaccine
technologies are in development: DNA plasmid vaccines and novel adjuvants are
just two of these. It’s time for FDA to
look very closely at these technologies and decide whether or not they are
safe. If not, discard them and stop
wasting the industry’s time. If they
can be used, move them forward. This
evaluation should be very deliberate and scientific. Critical regulatory decisions must be uninfluenced by political
considerations, and Congressional oversight is needed to assure this.
A number of suggestions
have been made for optimizing US preparation and responses for biological
attack. I believe these approaches to
be comprehensive and prudent. Methods were chosen with affordability in mind.
However, the cost of what was outlined may be more than our nation can afford. On this, Maj Gen John Parker, commanding general of Fort Detrick, and I agree (26). Furthermore, even if all the above measures were taken, there would continue to be weaknesses in our defenses that our enemies could exploit. Regrettably, our defenses can never catch up to the speed at which new pathogens and toxins can be created. It is doubtful that effective treatments will be available for many high-tech biological weapons developed with current, not to mention future, techniques. Our technologies have already outstripped our ability to control them.
It has been said that the
arms race bankrupted the Soviet Union.
One can conceive of biological terrorism preparations and responses
bankrupting the United States.
Rethinking the nature of the
threat
The
White House has suggested that recent anthrax attacks used an anthrax strain
and an additive developed by the US biowarfare program. If true, this is a bitter pill: not only
must we fear the former Soviet Union and Iraq’s bioweapons, but the fruits of
our own government’s biological warfare program.
Questions
could profitably be asked about the origin of the anthrax recently used:
·
Who had access to the American
bioweapons stockpile? Who had the
knowledge to prepare weaponized anthrax?
·
What other microorganisms and
toxins did the US program develop and produce, which could potentially also be
used against us?
·
The US biological weapons
stockpile was supposedly destroyed before the Biological and Toxin Weapons
Convention came into force. Who handled
the destruction? Was destruction of
all materials verified?
·
A 1977 Senate hearing (the “Church
Committee”) found that not all the weapons had been destroyed, but that some,
including a supply of 100 grams of anthrax, were stored for the CIA by a
contractor, Becton-Dickinson (27). Were
the materials destroyed following these revelations?
·
Was the anthrax stored at
Becton-Dickinson identical to that found in Senator Daschle’s letter?
·
Do foreign letters allegedly
containing anthrax contain the same preparation as the US anthrax letters? Were they postmarked from the US?
Developing
Solutions
Our
allies may understandably fear that they, too, could face a biological attack
with weapons developed by the US program, as well as what the Soviets, Iraqis
and others may have created. Here is
one approach to the problem.
Two
weeks ago, the US met with a number of our allies in Ottawa to develop
networking approaches to bioterrorism.
We should be networking to develop vaccines together, to order drugs
together and to improve communications regarding epidemics, as well as creating
mutual assistance plans, rapid response teams, and sharing of biotechnology.
But
more than this, in the environment we now find ourselves, it could be in our
best interest to “come clean” with our allies (and possibly, in the right
circumstances, our enemies) about what was created in our laboratories, and
share all available countermeasures, as long as they share full knowledge with
us of the bioweapons and countermeasures developed in their programs. This would make the diaspora of former
biological warfare scientists much less threatening. Their knowledge would no longer be so valuable, once it had been
shared with all biological defense establishments. This would reassure other nations that if US-made weapons were
used on them, our best countermeasures would be available to respond. Similarly, we could be reassured that the
best Soviet countermeasures were available to us. It would mean that scientists from many nations could be jointly
engaged in finding solutions and countermeasures to some of the most horrific
threats we face, and it would reduce the cost to any one nation of defensive
measures.
Our species could be
obliterated from the face of the earth using technologies widely available
today. Our friends as well as our enemies know this; and they share this
predicament with us. Thus it behooves
us to create new forms and ideas if we are to effectively contain this threat.
When all is said and
done, the words of Nobel laureate Joshua Lederberg sum up the situation. “There
is no technical solution to the problem of biological weapons. It needs an ethical, human and moral
solution if it’s going to happen at all.
There is no other solution.”
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November 14, 2001. Additional
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www.pbs.org/cgi-bin/wgbh/printable.pl
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New York, NY.
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U.S. advises anthrax drug for visitors to a publisher. New York Times, November
16, 2001.
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19. Zwillich T. Expert: Federal law
needed on smallpox vaccination. Reuters Health (Washington), November 5, 2001.
20. Bioterror: Coping with a new
reality. Shown on PBS, November 14, 2001.
21.Rosenthal SR et al. Developing new smallpox
vaccines. Emerging Infectious Diseases 2001:7 (6).
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say their vaccines are cheaper. New York Times. November 8, 2001.
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warfare agents. Undated. Declassified September 15, 1975.