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: – 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.

• 2010: France fesses up: they kept stocks of smallpox…who else has it?

• Don’t even need bioweapons to pose a threat: Iraq

Smallpox as a weapon

Ebola and other hemorrhagic fever viruses

Photo of Ebola virus particle

1. Filoviruses • Ebola hemorrhagic fever • Marburg hemorrhagic fever

2. Bunyaviruses • Crimean-Congo hemorrhagic fever • Rift Valley fever • Hantavirus Pulmonary Syndrome • Hemorrhagic Fever with Renal Syndrome (HFRS)

3. Flaviviruses • Tick-borne encephalitis • Kyasanur Forest disease • Omsk hemorrhagic fever • VEEV, EEEV & WEEV

Viral Hemorrhagic Fevers (VHF) are caused by 4 viral families

Viral Hemorrhagic Fevers (VHF) are caused by 4 viral families

4. Arenaviruses • 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.oRift Valley, Congo-Crimean, Marburg, and Ebola hemorrhagic fevers, and yellow fever: Jaundice and hepatitis dominate the clinical presentation.oKyasanur Forest disease and Omsk hemorrhagic fever: Biphasic illnesses with pulmonary symptoms followed by central nervous system manifestations.oLassa fever: Severe peripheral edema without significant hemorrhage.oCongo-Crimean hemorrhagic fever: Severe hemorrhage and nosocomial transmission.oHantavirus: 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

Year Virus Geographic locationHuman cases/deaths (case-fatality rate)

1976 SEBOV Juba, Maridi, Nzara, and Tembura, Sudan 284/151 (53%)1976 EBOV Yambuku, Zaire 318/280 (88%)1977 EBOV Bonduni, Zaire 1/1 (100%)1979 SUDV Nzara, Sudan 34/22 (65%)1988 EBOV Porton Down, United Kingdom 1/0 (0%) [laboratory accident]1994 TAFV Taï National Park, Côte d'Ivoire 1/0 (0%)1994–1995 EBOV Woleu-Ntem and Ogooué-Ivindo Provinces, Gabon 52/32 (62%)

1995 EBOV Kikwit, Zaire 317/245 (77%)1996 EBOV Mayibout 2, Gabon 31/21 (68%)1996 EBOV Sergiyev Posad, Russia 1/1 (100%) [laboratory accident]1996–1997 EBOV Ogooué-Ivindo Province, Gabon; Cuvette-Ouest

Department, Republic of the Congo62/46 (74%)

2000–2001 SUDV Gulu, Mbarara, and Masindi Districts, Uganda 425/224 (53%)2001–2002 EBOV Ogooué-Ivindo Province, Gabon; Cuvette-Ouest

Department, Republic of the Congo124/97 (78%)

2002 EBOV Ogooué-Ivindo Province, Gabon; Cuvette-Ouest Department, Republic of the Congo

11/10 (91%)

2002–2003 EBOV Cuvette-Ouest Department, Republic of the Congo; Ogooué-Ivindo Province, Gabon

143/128 (90%)

2003–2004 EBOV Cuvette-Ouest Department, Republic of the Congo 35/29 (83%)2004 EBOV Koltsovo, Russia 1/1 (100%) [laboratory accident]2004 SUDV Yambio County, Sudan 17/7 (41%)2005 EBOV Cuvette-Ouest Department, Republic of the Congo 11/9 (82%)2007 EBOV Kasai Occidental Province, Democratic Republic of the

Congo264/186 (71%)

2007–2008 BDBV Bundibugyo District, Uganda 116/39 (34%)2008–2009 EBOV Kasai Occidental Province, Democratic Republic of the

Congo32/15 (47%)

2011 SUDV Luweero District, Uganda 1/1 (100%)2012 SUDV Kibaale District, Western Uganda 24/17 (71%)2012 BDBV Orientale Province, Democratic Republic of the Congo 72/32 (44%)

2012 (today) EBOV Luweero and Kampala districts of Uganda 6/4 (80%)

Ebola virus disease (EVD) outbreaks

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.

ViralHemorrhagicFever

Depending on the virus, (Ebola, Marburg, etc.) symptoms such as high fever, muscle aches, chills and diarrhea begin within 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.