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Smallpox: From Eradicated Disease to Bioterrorist Threat

A discussion of the new book
Scourge: The Once and Future Threat of Smallpox
(New York: Atlantic Monthly Press, 2001).

Jonathan B. Tucker, Ph.D.
Director, Chemical & Biological Weapons Nonproliferation Program
Center for Nonproliferation Studies
Monterey Institute of International Studies, Washington, DC Office

September 26, 2001

1. Overview of Presentation
   • Description of smallpox and its control.
   • Global eradication of the disease.
   • Consolidation of laboratory stocks of smallpox virus.
   • Biological warfare/terrorism threat from smallpox.
   • Reassessing the threat after the events of September 11.
   • Responding to the threat.
   • Broader lessons.

2. Characteristics of Smallpox
   • Two-week incubation followed by fever, pustular skin rash.
   • Virus probably originated in a rodent virus that jumped to humans.
   • A uniquely human disease for at least 10,000 years.
   • Killed hundreds of millions of people over human history.
     • Far more than the plague (Black Death), which was more episodic.
   • Two major forms of smallpox, variola major and variola minor.
     • Variola major killed about 10 to 30 percent of its victims, variola minor only about 1 percent.
   • Survivors disfigured, sometimes blinded; disease also caused miscarriage.

3. Treatment and Prevention of Smallpox
   • No effective treatment, only prevention.
     • Isolation and quarantine in "pest houses," ships in harbors.
   • Variolation – deliberate inoculation of smallpox to induce permanent immunity.
     • First developed around 1,000 B.C. in India, spread widely.
     • Various methods of variolation, such as sucking powdered scabs into nose, inoculation of pus into skin.
     • One out of 100 people variolated developed a fatal case of smallpox, but most survived and became immune for life.
     • Where people faced a high probability of contracting natural smallpox, many took the risk of variolation.
     • Variolation was first introduced to England in the 1720s by Lady Mary Wortley Montagu, the wife of the British ambassador in Turkey.
   • Smallpox vaccine discovered by Jenner in 1796.
     • Jenner found that inoculation with cowpox virus—a relative of variola virus—produced a benign infection that protected against smallpox.
     • Vaccination was much safer than variolation, but it did not provide permanent immunity.
       • Had to be repeated every 5 to 10 years to maintain protection.
   • Cowpox vaccine later replaced by vaccinia virus, whose origin was unknown.
   • Vaccination was not entirely harmless and involved a small but significant risk of complications, which had to be weighed against the risk of contracting smallpox.

4. Global Eradication Campaign
   • In 1958, Soviet Union proposed a global campaign to eradicate smallpox.
     • Campaign funded at a low level by the World Health Organization (WHO).
     • Made little progress because of inadequate funding and lack of U.S. support.
   • In 1966, the WHO was finally persuaded to launch a ten-year intensified campaign to eradicate smallpox.
   • Eradication strategy was based on vaccination with a heat-stable, freeze-dried vaccine, delivered into superficial layers of the skin with a bifurcated needle.
   • Mass vaccination was gradually replaced by more targeted strategy of "surveillance-containment."
     • Search for outbreaks, isolate infected individuals, and vaccinate around them to halt the transmission of the virus, similar to building "firebreak" to stop a forest fire.
   • Biggest challenges were in South Asia, especially India and Bangladesh, because of the density and mobility of the population and the high virulence of the disease.
   • Last case of endemic variola major found in Bangladesh in 1975.
   • Last case of endemic variola minor in Somalia in 1977.
   • In 1978, a laboratory accident in a smallpox research lab at the University of Birmingham, England, caused one death and led to the suicide of the laboratory director.
   • In May 1980, after two years of intensive surveillance in each formerly endemic country, WHO officially declared smallpox eradicated.
   • WHO also called for halting routine vaccination, both to save money and to avoid the risks of complications of vaccine.

5. Consolidation of the Variola Virus Stocks
   • In 1976, WHO urged 75 labs in several countries that retained stocks of variola virus to destroy or transfer them to official WHO repositories in U.S. and Soviet Union.
   • South Africa was last country to destroy its virus stocks in December 1983.
   • Henceforth, the variola virus stocks were limited to WHO collaborating centers in Atlanta and Moscow.
   • In 1994, Russia unilaterally moved its virus stocks from Moscow to Vector, a former BW research center in Koltsovo, near Novosibirsk.

6. Possible Scenarios for a Return of Smallpox
   • Accidental release from an official WHO repository; unlikely due to high security.
   • Global warming thaws smallpox corpses buried in the permafrost
     • Any resulting outbreak would probably be small and easily contained by vaccination
   • Mutation of a related poxvirus such as monkeypox, which occasionally infects humans to fill the ecological niche vacated by smallpox by becoming more virulent and contagious.
     • To date, no evidence that monkeypox is evolving in this way.
   • Deliberate use of smallpox as military/terrorist weapon
     • Most likely source of a recurrence.

7. History of Smallpox as a Biological Warfare Agent
   • British used smallpox as a biowarfare agent during the 18th century
     • In the aftermath of French and Indian War, British gave smallpox-contaminated blankets to rebellious Indian tribes.
     • In the American Revolutionary War, British deliberately spread smallpox during the sieges of Boston and Quebec.
   • U.S., UK, Canada and Japan did military research on smallpox during World War II.
   • But the secret Soviet effort to mass-produce and weaponize smallpox outstripped all other efforts.

8. Soviet Weaponization of Smallpox
   • Kanatjan Alibekov (a.k.a. Ken Alibek), the first deputy director of Biopreparat, defected to the U.S. in 1992 and revealed the Soviet weaponization of smallpox.
   • Initial development of smallpox as a weapon occurred at Center of Virology in Zagorsk (today Sergiev Posad).
   • Mass production of variola virus in eggs reportedly began in late 1940s.
   • Viral suspension was stored in multi-ton quantities at Zagorsk.
   • Planned delivery by intercontinental strategic bomber and ballistic missiles against U.S. cities (and after 1968, Chinese cities as well).
   • Possible military doctrine: eliminate the survivors of a nuclear exchange.
   • Development of "improved" smallpox weapons at the Vector laboratory in Koltsovo during the late 1980s.
     • Development of large-scale production method in bioreactors.
     • Genetic engineering of chimeric strains, including transfer of toxin genes and virulence factors from other viruses.
     • Experiments initially done in vaccinia virus, with the intent of repeating them in variola.

9. Undeclared Stocks of Smallpox Virus
   • Between 3 and 8 countries have been implicated as possessing undeclared stocks of variola virus.
     • Strongest evidence implicates Russia, North Korea, Iraq.
   • Circumstantial evidence, but no "smoking gun":
     • Vaccination of troops in North Korea, Iraq.
     • 1993 Russian Federal Security Service report on North Korea's biowarfare program mentioned work on smallpox.
     • Outbreak of natural smallpox in the Middle East in 1970-72: clinical specimens could have been preserved in freezers.
     • Iraqi BW research on camelpox virus, a close relative of variola that could have served as a surrogate for studies of production and weaponization.
   • No indications of large-scale production of variola virus in suspect countries.
   • No apparent preparations for use as a weapon.

10. Smallpox as a Bioterrorist Threat
    • Smallpox virus is robust and can be disseminated through the air as an aerosol.
    • Unlike anthrax bacteria, the smallpox virus can spread from person to person.
    • Terrorists might spread the smallpox virus covertly, resulting in delayed outbreak after an incubation period of 12-14 days.
    • Civilian populations are highly susceptible to infection.
      • Mandatory vaccination of U.S. children at school entry halted in 1972.
      • Rationale for halting routine vaccination: risk of complications from vaccine assessed to be higher than risk of contracting natural smallpox.
    • Vaccine can protect against smallpox if given even 3-4 days after infection but before the appearance of symptoms. However, initial cases of smallpox resulting from the terrorist release of virus would probably be diagnosed too late for the vaccine to be effective.
    • Because of a lack of "herd immunity" in the population, a smallpox outbreak could have a transmission ratio of 1:10 or even 1:15.
    • Successive waves of infection would be separated by two-week incubation periods.
    • Urgent need to contain the spread of the epidemic through isolation of infected individuals and vaccination of all known or potential contacts.

11. Reassessing the Threat Since the Events of September 11, 2001
    • Terrorists would have to overcome a series of technical hurdles:
      • Acquisition of virulent seed cultures;
      • Cultivating the virus in eggs or cell culture;
      • Testing for effectiveness (no good animal model of disease);
      • Dispersing agent as a fine-particle aerosol over a large area.
      • Smallpox is not a "targetable" weapon – if not contained by vaccination, it could spread worldwide and threaten the very Muslim populations on whose behalf the terrorists ostensibly carried out their attack.
    • Still, the sophisticated planning that went into the September 11 attack, including long-term preparation and training of operatives, suggests that this terrorist network might be capable of carrying out a bioterrorist attack with smallpox if they devoted a major, long-term effort to acquiring samples of the virus and the technology and know-how needed to produce and disseminate it.
    • Assistance from a state-sponsor or former Soviet bioweapons weapons scientists could shortcut the acquisition process. So far, however, no clear evidence exists that a state has provided such assistance or that terrorists have recruited former Soviet bioweapons scientists.
    • The threat of terrorist use of smallpox remains low, but because the consequences are potentially catastrophic, the U.S. must take measures to reduce its current vulnerability to attack.

12. U.S. Policy on Destruction of Variola Virus Stocks
    • May 1990: Health and Human Services (HHS) Secretary Louis Sullivan called on the Soviet Union to jointly determine the DNA sequences of selected strains of variola virus, followed by destruction of the virus stocks in Atlanta and Moscow. Sullivan argued that this program would build confidence against possible use of virus as a biological weapon.
      • Original plan was to destroy virus stocks in December 1993.
      • Slow pace of research caused planned date of destruction to be delayed until June 1995.
      • Scientific opposition to destruction caused a further delay until June 1999.
      • In 1998-99, an intense debate over virus destruction took place within the U.S. government.
    • Arguments for destruction of the variola virus stocks:
      • Smallpox vaccine derived from different virus than variola virus, so live virus stocks not needed for protection.
      • DNA sequences of representative strains already determined.
      • Opportunity costs of using maximum-containment labs, an extremely limited resource that could better be devoted to study of current disease agents.
      • Continued work with live variola virus would entail a small but real risk of accidental release.
      • Alternatives for poxvirus research exist, such as animal poxviruses.
      • Lack of a realistic animal model for smallpox limits the relevance of smallpox research for understanding the human immune system.
      • Normative benefits of virus destruction: applying moral suasion on would-be proliferators and terrorists to desist from using smallpox as a weapon.
      • Opportunity for the U.S. to demonstrate moral leadership.
    • Arguments for retention of the variola virus stocks:
      • Live virus needed to develop defensive drugs and vaccines.
      • Other poxviruses are not identical to variola and hence not ideal surrogates.
      • Testing with live virus is needed for FDA licensure of new, safer vaccine and antiviral drugs.
      • Study of viral pathogenesis could provide useful scientific knowledge, possibly new drugs.
      • Potential therapeutic benefits of variola proteins in modulating human immune responses.
      • Rogue states are not influenced by ethical or legal norms.
      • Effective medical defenses offer best deterrent against terrorist use.
    • March 15, 1999: Institute of Medicine (IOM) of the National Academy of Sciences released a study on "future scientific needs for live variola virus"
      • IOM study concluded that live variola virus would be needed for the testing of antiviral drugs, possible development of a next-generation vaccine, and basic research on disease mechanisms.
    • April 22, 1999: Clinton administration announced its intention to retain the variola virus stocks stored at the CDC.
    • May 21, 1999: World Health Assembly (WHA), the annual meeting of the World Health Organization, passed a resolution to retain the variola virus stocks stored at the CDC and Vector for three more years for purposes of biodefense research.

13. Smallpox Research Agenda
    • All research projects with live variola virus to be conducted in maximum-containment labs at CDC and Vector, with close oversight by a WHO expert group, the WHO Committee for Variola Virus Research.
    • Approved projects:
      • DNA sequencing of additional strains of variola virus;
      • Development of new diagnostic tests;
      • Screening of antiviral drugs in cell culture and animal models (mice with cowpox, monkeys with monkeypox, monkeys with smallpox);
      • Development of non-human primate model of smallpox (infecting monkeys with variola virus);
      • Producing monoclonal antibodies (as a possible VIG substitute);
      • Developing a next-generation vaccine safer for use in at-risk populations (e.g., HIV-positive).

14. Fate of the Smallpox Virus Stocks
    • Policy options
      1. Destroy stocks as planned on 21 December 2002
      2. Delay destruction for a specified period of months or years to complete current research
      3. Retain stocks indefinitely for ongoing or future research
      4. Transfer stocks to an international lab under WHO auspices
    • Next decision point: World Health Assembly in May 2002 will probably decide whether to extend the research program with live variola virus or to destroy the official stocks at the end of 2002.

15. Smallpox Vaccine Stockpile
    • Current U.S. stockpile of freeze-dried smallpox vaccine was produced in 1970s. It contains only about 7.5 million doses and is deteriorating slowly.
      • New smallpox vaccine to be produced in cell culture rather than scarified calf skin, for quality-control reasons.
      • Two separate contracts have been issued to obtain vaccine for military and civilian use:
        • Military stockpile: Dept. of Defense contract with DynPort Corp. for 300,000 doses.
        • Civilian stockpile: CDC contract with OraVax (renamed Acambis) for 40 million doses, with delivery expected by mid-2004. As the vaccine stocks age, additional vaccine will be produced periodically until the year 2020.
      • U.S. will maintain a "warm" production line for up to 60 million additional doses, and will continue to store expired lots as a back-up.
      • Vaccine will be kept on the shelf, for use only in the event cases of smallpox are diagnosed and confirmed.
      • If the threat of bioterrorist use of smallpox is assessed as high, the U.S. government may seek to accelerate the acquisition of new vaccine. Options include:
        • Cut corners on FDA approval process for new cell-culture vaccine
        • Release new vaccine as an Investigational New Drug
        • Dilute existing stocks of Dryvax vaccine up to ten-fold
        • As a last resort, production of more vaccine by the old method (in calf skin rather than cell culture).

16. Recommendations for Reducing U.S. Vulnerability to Smallpox
    • Improve security of variola virus stocks in the U.S. and Russia.
    • Increase supply of vaccine available in the U.S. and worldwide.
    • Depending on the assessed threat, accelerate FDA approval and production of the new cell-culture smallpox vaccine.
    • Train emergency physicians and GPs to recognize symptoms of smallpox at an early stage, and distribute diagnostic tools and protocols.
    • Improve disease surveillance and communication between primary physicians and city and state public health departments.
    • Assist hospitals to develop emergency response plans, such as increasing the number of hospital isolation rooms and making contingency plans for satellite facilities in the event of a large outbreak (e.g., commandeering gymnasiums, armories, hotels for use as isolation centers).
    • Clarify the relevant legal issues: quarantine authority, posse comitatus, etc.

17. Broader Lessons Learned
    • The irony of eradication.
      • Smallpox eradication vanquished a horrible disease in one of the greatest achievements of 20th century medicine. Yet, in a bitter irony, eradication created a new vulnerability to the deliberate use of the virus as a means of biowarfare and terrorism.
      • Measles is potential target for global eradication, but it is also a potential biowarfare agent.
      • Highly contagious virus, transmitted through the air.
      • Measles can cause significant morbidity and mortality, particularly in adults of military age.
      • WHO may need to plan for post-eradication of other disease agents to reduce vulnerability to bioterrorism, including stockpiling vaccine and therapeutic drugs, and improving biodetection and diagnostic capabilities.
      • Costs of addressing these issues may reduce the "eradication dividend."
    • Public health as a national security issue.
      • Bioterrorism and emerging infections (such as West Nile) are two sides of the same coin. Improving public health systems can respond to both threats.
    • Need to reinforce ethical and legal norms.
      • Vital to strengthen international law, social norms, and professional code of scientific ethics as a bulwark against the proliferation of biological weapons to rogue states and terrorists.
      • An oversight system will be required to monitor scientific and technological advances in the life sciences and prevent the misuse of this powerful knowledge for nefarious purposes.

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