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Lecture 33 Bioterrorism
• "Advantages" of biological weapons: relatively
inexpensive, easier to conceal than conventional
weapons, potentially easier to spread, have the
potential to cause widespread panic, have been
developed by military in a few countries (former
U.S.S.R, U.S.A) to high level of sophistication.
• Disadvantages of biological weapons: not easy
to obtain, easier to "backfire" on those using them,
unproven weaponry that may not work, easily
traceable to original source by genomic DNA
sequencing.
Possible viruses that bioterrorists
might use
• Variola (Smallpox)
• Haemorrhagic fever viruses (Ebola,
Marburg, etc)
• Influenza A
Select Agents: Criteria for inclusion
• Centers for Disease Control and Prevention where charged with
devising list of "Select Agents" that might be used. Critera:
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highly infectious or extremely toxic
have the potential for high mortality with ensuing infection or poisoning
have consequences following exposure that are difficult to manage medically
vaccines, antivirals, or chemoprophylactic drugs are not readily available for
most of these agents.
• Terrorists might acquire such agents in several ways:
– Produce agents themselves -- this requires microbiological expertise,
laboratories and equipment
– Obtain from "rogue states, that have developed biological and chemical
weapons, and maintain stockpiles. Fomer Soviet Union had major activity in
this area, not clear whether stockpiles exist.
– Steal existing agents from laboratories, hospitals, etc.
– "Select agent" regulations try to control access to the select agents,
terrorists may be prevented from obtaining and using these agents in an
attack.
Smallpox (Variola) Virus
• Infectious agent is Variola major virus.
Highly infectious -- only 10-100
particles can cause infection.
• Officially eradicated worldwide in 1980
• Variola is highly infectious as aerosol.
• Incubation period is 7-17 days, during
which virus multiplies in respiratory
tract, then spreads to blood and lymph.
• Causes characteristic inflammations
over surface of skin (pox).
Variola (Smallpox)
Smallpox in a child: Notice the progression and
distribution of the lesions from day 1 to day 7.
Smallpox: highly infectious
• The infectiousness of the virus was seen in
1970
• A German electrician returned from
Pakistan, having contracted the virus.
• He was hospitalized, and though he never
left his room, he infected 4 patients on the
floor he was staying, 8 on the floor above,
and 9 two floors above.
• One person infected was simply a visitor to
the hospital, and was never closer than 30
feet to the patients room
The only virus to have been
eradicated…or not?
• Virus has been officially eradicated as a result of
successful worldwide vaccination and quarantine
measures -- last known case occurred in 1970's,
except for an infected lab worker since.
• However, known stocks survive in Center for
Disease Control and Prevention (CDC) in Atlanta,
US, and in the Research Institute for Viral
Preparation in Moscow, Russia.
• It is possible that other stockpiles exist…the
French finally came clean in 2010.
Russian smallpox stocks: where are
they now?
• Soviet authorities in the 1970s had viewed the
acceptance of the Convention by virtually all countries
as presenting an unusual opportunity for the Soviet
Union to gain an important advantage in the Cold War.
• Accordingly, an extensive expansion of its bioweapons
research and production capacity began.
• In 1980 the Soviet leadership embarked on an aggressive
program to weaponize smallpox and to produce it on a
very large scale.
• By the late 1980s, production of high titer smallpox virus
in multi-ton quantities was achieved.
• It had been weaponized so as to be able to be transported
in intercontinental ballistic missiles and to be dispersed
effectively as an aerosol after reaching its target.
Russian bioweapons centers
• The massive bioweapons facility that undertook the research
and development program, is called VECTOR.
• Located in Koltsovo in Central Siberia.
Russian bioweapons centers
• VECTOR continues to function today as a research
enterprise, conducting studies of many exotic
viruses, including Ebola, Marburg, and Venezuelan
Equine Encephalitis, and smallpox.
• The WHO laboratory in Moscow that had
collaborated with the smallpox eradication effort
was closed, and its virus stocks transferred to
Koltsovo.
• The major production facility for the smallpox virus
is said to be at another location near Moscow,
operated by the Ministry of Defense.
• It has never been opened to inspection.
More scary Russian stuff
• Smallpox virus probably at least at two sites in
Russia.
• How secure the stocks may be is uncertain,
especially given the economic conditions in Russia
today, and the fact that salaries for scientists are
paid very late or not at all.
• Many have left their former institutions for other
countries.
• Reasonable evidence exists that at least ten nations
are now engaged in the development of
bioweapons and some are actively recruiting
scientists in Russia.
Smallpox as a weapon
• Vaccination ceased in this country in 1972.
• Today, very few persons have immunity,
either acquired because of past infection or
because of vaccination.
• Thus, effectively no one under the age of 25
has been vaccinated, and among those
older, few now have sufficient immunity to
protect against infection.
Smallpox as a weapon
• Smallpox in an aerosol form is very stable, and in a
cool, dry environment would be expected to survive
for at least 24 hours.
• Borne by wind currents, it would be wholly
undetectable.
• If one were to suppose that as few as 50 to 100
persons were exposed, they would begin
experiencing acute, severe illness some two weeks
later.
• Brought primarily to physicians who have never
before seen a smallpox case, the diagnosis would
not be made for several days to perhaps a week.
Smallpox as a weapon
• Meanwhile, each patient would have been in contact with
many others. A second wave of cases would occur two
weeks later with 10 or more new infections for every case in
the first wave or, in other words, 500 to 1000 cases in all.
• Complicating the problem would be the fact that perhaps as
many patients again would be experiencing unknown
illnesses with rash and fever, such as chickenpox or a drug
reaction, and would have to be treated as if they had
smallpox until the diagnosis was certain.
• Because of the risk of virus transmission in hospital,
patients would need to be housed in rooms under negative
pressure and the exhaust air filtered. In Maryland, there are
only 80 such beds.
Smallpox as a weapon
• 2010: France fesses up: they kept stocks of
smallpox…who else has it?
• Don’t even need bioweapons to pose a
threat: Iraq
Ebola and other hemorrhagic
fever viruses
Photo of Ebola virus particle
Viral Hemorrhagic Fevers (VHF) are
caused by 4 viral families
1. Filoviruses
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•
Ebola hemorrhagic fever
Marburg hemorrhagic fever
2. Bunyaviruses
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•
•
•
Crimean-Congo hemorrhagic fever
Rift Valley fever
Hantavirus Pulmonary Syndrome
Hemorrhagic Fever with Renal Syndrome (HFRS)
3. Flaviviruses
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Tick-borne encephalitis
Kyasanur Forest disease
Omsk hemorrhagic fever
VEEV, EEEV & WEEV
Viral Hemorrhagic Fevers (VHF) are
caused by 4 viral families
4. Arenaviruses
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•
•
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Argentine hemorrhagic fever
Bolivian hemorrhagic fever
Sabia-associated hemorrhagic fever
Lassa fever
Lymphocyctic choriomeningitis
• Venezuelan hemorrhagic fever
Viral hemorrhagic fevers share the
following characteristics
– They are all RNA viruses
– They are all zoonotic (natural reservoir is an
arthropod or other animal host)
– Disease is restricted to habitat of the host
– Humans become infected by contact with host
– Some viruses can be transmitted from human to
human
Transmission to humans (depends
upon specific virus)
– By contact with rodent urine, feces,
saliva, blood
– From mosquito or tick bites
– Contact with vector-infected
livestock
Pathophysiology
– The target organ is the vascular bed.
– Dominant clinical features are due to
microvascular damage and changes in
vascular permeability
– In most cases of viral hemorrhagic fever,
the coagulopathy is multifactorial,
including:
• hepatic damage
• disseminated intravascular coagulation
• primary marrow injury to megakaryocytes
Symptoms
– Fever, fatigue, dizziness, myalgias, and
prostration
– Signs of bleeding range from only conjunctival
hemorrhage, mild hypotension, flushing, and
petechiae to shock and generalized mucous
membrane hemorrhage and evidence of
pulmonary, hematopoietic, and neurologic
dysfunction
– Renal insufficiency is proportional to
cardiovascular compromise except in
Hemorrhagic Fever and Renal Syndrome in
which it is an integral part of the disease
Clinical syndromes
Epidemiologic information is usually the most helpful
clue to the diagnosis.
o Rift Valley, Congo-Crimean, Marburg, and Ebola
hemorrhagic fevers, and yellow fever: Jaundice and
hepatitis dominate the clinical presentation.
o Kyasanur Forest disease and Omsk hemorrhagic fever:
Biphasic illnesses with pulmonary symptoms followed
by central nervous system manifestations.
o Lassa fever: Severe peripheral edema without
significant hemorrhage.
o Congo-Crimean hemorrhagic fever: Severe hemorrhage
and nosocomial transmission.
o Hantavirus: Adult Respiratory Distress Syndrome.
Prevention
– Vaccination
• The only licensed vaccine available is for yellow
fever
• Experimental vaccine for Argentine hemorrhagic
fever is under investigation
– Control of rodent populations
– Control of insect and other arthropod
populations
Isolation and containment
– Viral hemorrhagic fever patients, with the
exception of hantavirus and dengue fever
infections, have significant infectious
virus in the blood and body secretions
– Strict adherence to standard precautions
• Keep patients in isolation
• Use of gowns, gloves, masks, eye protection
Ebola
• Symptoms of infection begin with fever,
headache, diarrhea, stomach pains -- symptoms
that could be due to many infections.
• Within a week, most victims also develop chest
pain. Some some go blind, bleed from the nose,
eyes, and other orifices.
• Bleeding results from the virus blocking blood
clotting as well as stimulating leakage of blood
vessels.
• Disease is very lethal: 70-90% of infected people
die
Ebola virus disease (EVD) outbreaks
Year
Virus
Geographic location
1976
1976
1977
1979
1988
1994
1994–1995
1995
1996
1996
1996–1997
SEBOV
EBOV
EBOV
SUDV
EBOV
TAFV
EBOV
EBOV
EBOV
EBOV
EBOV
2000–2001
2001–2002
SUDV
EBOV
2002
EBOV
2002–2003
EBOV
2003–2004
2004
2004
2005
2007
EBOV
EBOV
SUDV
EBOV
EBOV
2007–2008
2008–2009
BDBV
EBOV
2011
2012
2012
2012 (today)
SUDV
SUDV
BDBV
EBOV
Juba, Maridi, Nzara, and Tembura, Sudan
Yambuku, Zaire
Bonduni, Zaire
Nzara, Sudan
Porton Down, United Kingdom
Taï National Park, Côte d'Ivoire
Woleu-Ntem and Ogooué-Ivindo Provinces, Gabon
Kikwit, Zaire
Mayibout 2, Gabon
Sergiyev Posad, Russia
Ogooué-Ivindo Province, Gabon; Cuvette-Ouest
Department, Republic of the Congo
Gulu, Mbarara, and Masindi Districts, Uganda
Ogooué-Ivindo Province, Gabon; Cuvette-Ouest
Department, Republic of the Congo
Ogooué-Ivindo Province, Gabon; Cuvette-Ouest
Department, Republic of the Congo
Cuvette-Ouest Department, Republic of the
Congo; Ogooué-Ivindo Province, Gabon
Cuvette-Ouest Department, Republic of the Congo
Koltsovo, Russia
Yambio County, Sudan
Cuvette-Ouest Department, Republic of the Congo
Kasai Occidental Province, Democratic Republic of the
Congo
Bundibugyo District, Uganda
Kasai Occidental Province, Democratic Republic of the
Congo
Luweero District, Uganda
Kibaale District, Western Uganda
Orientale Province, Democratic Republic of the Congo
Luweero and Kampala districts of Uganda
Human cases/deaths (case-fatality
rate)
284/151 (53%)
318/280 (88%)
1/1 (100%)
34/22 (65%)
1/0 (0%) [laboratory accident]
1/0 (0%)
52/32 (62%)
317/245 (77%)
31/21 (68%)
1/1 (100%) [laboratory accident]
62/46 (74%)
425/224 (53%)
124/97 (78%)
11/10 (91%)
143/128 (90%)
35/29 (83%)
1/1 (100%) [laboratory accident]
17/7 (41%)
11/9 (82%)
264/186 (71%)
116/39 (34%)
32/15 (47%)
1/1 (100%)
24/17 (71%)
72/32 (44%)
6/4 (80%)
Ebola
• Even though this is a scary disease, it seems
highly unlikely it would be a potential
terrorist weapon.
• The virus is so lethal that it is classified as a
type IV agent, and requires maximum
protective features (sealed body suits,
totally contained laboratory environments)
to protect those studying it.
• Other agents are much easier to grow and
safer for those interacting with them.
AGENT
SYMPTOMS
INFECTION
VACCINE
Smallpox
About 12 days after
exposure, high fever,
fatigue, back aches begin,
followed in 2-3 days by a
rash and lesions on face,
arms and legs.
As many as 30% of
those infected may
die, usually during
the first two weeks of
illness.
Routine vaccinations
ceased in 1972, but about
15 million does are still
available and more are in
production.
Depending on the virus,
(Ebola, Marburg, etc.)
symptoms such as high
Viral
fever, muscle aches, chills
Hemorrhagic
and diarrhea begin within
Fever
a few days, followed by
severe chest pain, shock
and bleeding.
These diseases do not
always result in
death, but Ebola has
been up to 90% fatal
in some outbreaks,
with death occurring
a week after
infection.
No vaccines exist for
hemorrhagic fevers,
except for yellow fever
and Argentine
hemorrhagic fever.