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Smallpox and Bioterrorism
by Toyin Ajayi

Smallpox is the ultimate weapon of mass destruction. It has killed more people throughout history than any other infectious disease, including the bubonic plague. The U.S. population grows more vulnerable to the potential ravages of its effects as time goes by. Yet our most crucial defense against bioterrorism - the public health systemæ has been systematically eroded by decades of under-funding and poor management. In light of the events of September 11, we can be certain that thousands of lives depend on the speed and efficiency with which we address these shortcomings.

Smallpox in History

Smallpox is the most vicious infectious disease to have ever afflicted mankind. For at least three millennia, smallpox infection ravaged human populations, sparing few countries. The mummy of Ramses V (1160 B.C.) exhibits a rash suggestive of smallpox, and Hindu texts from as early as 1000 B.C. describe ointments for its treatment.1 As populations grew and migrated, the disease spread across the globe, killing millions of people and shaping the course of history. In Europe, smallpox killed five reigning monarchs in the eighteenth century alone, and was responsible for the deaths of 200,000 to 600,000 people each year.2

The infection was named Small Pox by an English physician in the late sixteenth century to distinguish it from the Great Poxæ syphilisæ which had reached epidemic proportions in Europe.3 Pox refers to the eruption of pus-filled rashes that characterize smallpox. Symptoms begin with high fever, fatigue, head and back aches, followed in two to three days by the rash. Lesions develop on the face, abdomen, arms and legs, evolving at the same rate all over the body. They become pus-filled, and begin to crust early in the second week of the rash. Scabs eventually develop, leaving permanent scars (pock-marks) on patients who survive.4

Smallpox is caused by the variola virus, which belongs to a genus of viruses known as orthopoxvirus. The word variola originates from the Latin varus, or pimple.5 The severity of variola is related to the virulence of the infecting strains. Variola major and variola minor are the two predominant clinical forms, caused by distinct strains of the virus. The case fatality is about 1% for the minor form and between 15 and 45% for the major.6 The two less common clinical forms are the hemorrhagic and flat-type. Death from smallpox is usually the result of severe toxemia, septic shock or disseminated intravascular coagulation.

In 1796, Edward Jenner, a country doctor in southwestern England administered the first vaccination against smallpox. Common lore held that people who had been exposed to cowpox were immune to smallpox. Based on this observation, Jenner conducted an experiment to test the use of cowpox as a vaccine against smallpox. His first patient was an eight-year-old boy, whom he inoculated with pus from a cowpox lesion on the hand of a dairymaid. Jenner subsequently inoculated the boy with variolous matter taken from the pustule of a person suffering from smallpox. Aside from local inflammation around the site of the inoculation, the boy showed no signs of infection or illness. Jenner published his findings later that year, and by 1801, more than 100,000 people had been vaccinated in England.

The Campaign to Eradicate Smallpox

Despite improvements in the preparation of the vaccine and its rapid widespread use in Europe, smallpox still persisted in many parts of the world a century and a half later. In 1966, the Nineteenth World Health Assembly adopted a resolution proposed by the Soviet Union, and launched an intensive global smallpox eradication program. Its aim was to ensure that 80% of the worlds population was vaccinated within a period of two or three years. Progress was slow in some regions of the world, particularly Africa and Southeast Asia. Finally, in 1977, Somalia became the last country to declare itself smallpox-free.7

In December 1979, the Global Commission for the Certification of Smallpox Eradication verified that smallpox had indeed been globally eradicated. In their report, the Commission recommended the discontinuation of smallpox vaccination, the retention of only two variola stocks worldwide, the maintenance of an international reserve of freeze-dried vaccine under WHO control, and the commitment to thorough investigation of reports of suspected smallpox.8

The remaining stocks of viable variola virus were eventually transferred to reference laboratories in the Centers for Disease Control and Prevention (CDC) in Atlanta, and the Research Institute for Viral Preparations in Moscow. Following the collapse of the former Soviet Union and without prior knowledge of the WHO, the Russian collection was transferred to Novosibirsk in central Siberia.9

In its final comments, the Commission addressed the possibility of a deliberate release of smallpox virus into the world, concluding that the possibility of variola virus being deliberately released by an individual group as an act of sabotage or terrorism cannot be excluded. The potential harm of such an act would increase as the immunity of the population waned; in addition to illness and death there would be psychological and possibly socioeconomic damage.10 The Commission therefore stressed the importance of maintaining strong, integrated public health services to respond to such a possibility. It also called for the two smallpox stocks to be destroyed after an undefined sufficient time period, during which research into the genome and virulence of the virus was to be conducted.

Smallpox as a Bioweapon

In accordance with recommendations put forth by the Commission, the United States ceased routine vaccination of most of its population in 1972.11 Today, almost thirty years later, the level of immunity retained by those who were vaccinated is unknown. Dr. D.A. Henderson, Director of the Johns Hopkins Center for Civilian Biodefense Studies, estimates that no more than 10 to 15% of the U.S. population today retains immunity to smallpox. Henderson directed the WHOs global smallpox eradication campaign, and was one of the first public health specialists to alert the public to its increasing vulnerability to smallpox and other bioweapons agents.

The CDC recently added its voice to the ongoing debate about the capacity of Americas public health infrastructure to respond to deliberately-introduced biological agents in the civilian population. At a meeting of experts convened by the CDC in June 1999, of all the potential biological weapons identified, smallpox was unanimously determined to pose the greatest threat to the United States.12 This fear stems from recognition of difficulties inherent in diagnosing and rapidly containing a disease that most physicians have never seen. Two natural outbreaks of smallpox that occurred in the 1970s illustrate some of the clinical and epidemiological features of smallpox infection that would make variola virus such an effective bioweapon.

Case 1

In Germany in 1970, smallpox was transmitted in a well-vaccinated population with such speed and efficiency as to raise concern about the possibilities for the dissemination of aerosolized variola.13 The outbreak began with a German electrician returning from Pakistan, who became sick with high fever and diarrhea and was admitted to Meschede Hospital on January 11th, 1970. Suspecting typhoid fever, the doctors put him in isolation in a separate room on the ground floor. The patient had contact with only two nurses over the next three days.

On January 14th, he developed a rash, and on January 16th, doctors confirmed a diagnosis of smallpox. He was immediately rushed to one of Germanys isolation hospitals, and about 100,000 people who were judged to be at risk were vaccinated. Hospital staff and patients were quarantined for four weeks and vaccinated immediately.

Unfortunately, the patient had developed a cough, a symptom rarely seen with smallpox. His coughing produced a large-volume, small-particle smallpox aerosol similar to what might occur in a terrorist attack. Aerosolized smallpox produces a fine suspension of high-density liquid droplets that are easily inhaled and highly infective. In this instance, 19 cases resulted from exposure in the hospital: four in other rooms on the ground floor, eight on the floor above, and nine on the third floor. Of these, two involved direct contact with the initial patient. The remainder could only have been a result of inhalation of the aerosolized virus. One of the subsequent infections was in a visitor who had spent about 15 minutes in the hospital, and had briefly opened a corridor door thirty feet from the patients room, to ask directions. Three of the patients were nurses, one of whom died.

Case 2

The second case was an outbreak in Yugoslavia involving the rare and difficult to identify hemorrhagic-type variola, again among a well-vaccinated population.14 Given that this disease is caused by a distinct strain of the virus which has been isolated and cloned by both American and Russian scientists, the possibilities in terms of a deliberate release of this specific type of variola in a terrorist attack are frightening. Hemorrhagic-type variola eruption occurs in 3% of patients, and is characterized by extensive mucosal hemorrhage and toxemia. This type of smallpox is almost always fatal; patients essentially bleed to death. In most cases, they do not even develop the typical smallpox lesions. This different clinical picture makes hemorrhagic variola very difficult to diagnose in a non-epidemic situation.

Prior to this outbreak, the last smallpox case in Yugoslavia had occurred in 1927. Nevertheless, the country had continued nationwide vaccination to protect against imported cases. In February 1972, a previously vaccinated pilgrim returning from Mecca became ill with an undiagnosed febrile disease. Two weeks later, 11 of his friends and relatives (who had visited with the patient) became ill with high fever and rash. They were unaware of each others illness, and their doctors (few of whom had ever seen a case of smallpox) could not reach a correct diagnosis.

One of the 11 patients, a teacher, quickly became critically ill with the rare hemorrhagic form. He was first given penicillin at a local hospital, but as he became increasingly sick, he was transferred to a dermatology ward in a city hospital, and finally to a critical care unit because he was bleeding profusely and in shock. He died before a definitive diagnosis was made and was buried two days before the initial case of smallpox was recognized.

The first cases were diagnosed four weeks after the first patient became ill. By then, 150 people were already infected; of these, 38 were infected by the teacher. The cases occurred in separate areas of the country, and it was unknown how many undetected cases remained. Health authorities launched a nationwide vaccination campaign. Mass vaccination clinics were held, and checkpoints along roads were established to examine vaccination certificates. All twenty million people in Yugoslavia were re-vaccinated. Ten thousand contacts of cases were quarantined, and neighboring countries closed their borders. The outbreak was finally contained, nine weeks after the first patient became sick. A total of 175 patients contracted smallpox, 35 of whom died.

Our First Defense

As both of these examples suggest, the first public health measure following the diagnosis of a smallpox case will most likely in volve vaccination of several thousand individuals deemed at risk. The vaccine is believed to be effective in preventing smallpox in people who have been exposed to the virus, if administered within 72 hours of exposure.15 Yet, even assuming adequate vaccine coverage of populations, the potential for mass mortality stemming from only one case of smallpox is vast.

In the event of a smallpox outbreak, the size and integrity of the CDCs available vaccine stocks is unclear. The CDC claims that it has approximately 15 million doses available for immediate use.16 Experts like D.A. Henderson believe that, due to damage, poor storage conditions and the passage of time, the amount of useful smallpox vaccine is actually closer to 6 or 7 million doses.17 Moreover, as these stocks have been frozen for twenty years, it is unclear how effectual they remain. In September last year, the CDC negotiated a contract with the British vaccine company OraVax to produce a new smallpox vaccine. Forty million doses were scheduled to be available by 2004, and by 2020, it was planned that sufficient stocks would have been amassed to address an emergency situation.18

Recent events in the United States have had a dramatic impact on plans to combat a potential bioterrorist attack using smallpox. Since September 11th, the threat of bioterrorism has become a painful reality in this country. As of the 21st of November, 2001, ten people in the United States have been diagnosed with bioterrorism-related inhalational anthrax. Of these, four have died.19 These outbreaks of anthrax are clearly the work of a terrorist group. The bacterial spores have been sent in concentrated, highly refined powder form through the regular mail system.20 Fortunately, however, the public health infrastructure has thus far been able to adequately respond to the anthrax release. Anthrax, unlike smallpox, is not contagious. It cannot be transmitted from one person to another.

As a precautionary measure, public health experts have begun to prepare for the release of a more virulent bioweapon, smallpox being the most critical possibility. Tommy G. Thompson, Secretary of Health and Human Services, has announced that the government has begun negotiations with seven pharmaceutical companies to manufacture additional supplies of the smallpox vaccine. His goal is to acquire 300 million doses of vaccine so that every American can be assured that there is a dose with his or her name on it. At the very soonest, these stocks will be available in February or March, 2002.21

Yet, as the outbreaks of smallpox in Yugoslavia and Germany illustrated, access to vaccines plays only a small part in any endeavor to successfully contain this disease. Effective diagnostic, communication and administrative systems were central to the eventual control of both outbreaks. Yugoslavia took immediate steps to close its borders and to identify and isolate exposed individuals. In Germany, once a diagnosis of smallpox had been made, the patient was quickly quarantined, a risk assessment conducted, and 100,000 people vaccinated. Many experts today, however, seriously doubt the ability of our current public health system to respond to a bioterrorist attack involving smallpox, even with sufficient vaccine stocks at its disposal. Simply attaining sufficient vaccine will not solve the problem. For example, the vaccine cannot be administered to immunocom-promised individuals. Therefore, pregnant women, HIV positive individuals and people with autoimmune diseases will not benefit from mass vaccination campaigns. Furthermore, the lag time between initial exposure to the smallpox virus and the onset of symptoms can be up to several days, during which time thousands of people run the risk of being secondarily exposed. In addition, terrorist attacks might employ several biological agents in concert with each other, precluding easy identification, and thus defying most public health measures.

Dr. Scott Lillibridge of the CDC expressed his concern over the capability of the U.S. public health system to withstand bioterrorist attacks, stating that these events will exploit vulnerabilities in our public health system. The lack of capacity at the local level means isolates may not be confirmed in a timely manner. Preparedness must include the public health community as a full partner.22 At present, the capacity of the public health system to effectively diagnose, quarantine, and identify smallpox infection is limited, due in large part to an underestimation of the actual threat of bioterrorism.

Until the first envelope containing anthrax was opened, many analysts still doubted the seriousness of the possibility of a bioterrorist attack. Biological warfare was long considered too technically difficult to pose a significant threat to the population of the United States.

Historical Precedents

Indeed, a historical account of bioweaponry did appear to support this view. Of the 415 documented terrorist attempts to use chemical, biological, radiological or nuclear materials in the 20th century, only 33 involved use of biological agents. Of these, none actually succeeded in causing fatalities.23 In 1999, Dr. Jonathan Tucker, director of the Chemical and Biological Weapons Nonproliferation Project at the Monterey Institute of International Studies argued that, despite the hype, few terrorist groups possess the scientific-technical resources required for the successful large-scale release of a biological agent.24 However, it is much less clear today whether any technological or scientific barriers to the development of bioweapons still persist.

Terrorist groups worldwide have begun in recent years to obtain alarming levels of technological sophistication and financial capability. Now, it is extremely likely that there are groups with the resources to build and staff large-scale high-tech laboratories and research facilities to further their terrorist aims. The level of refinement of the anthrax used in the recent attacks certainly attests to the technological capacity of terrorists seeking to weaponize biological agents.

The virtual disappearance of thousands of state-employed scientists from the former Soviet Union raises fears about the level of scientific expertise available to terrorist groups with sufficient funding.25 Information emerging from the former Soviet Union certainly raises doubts about the sanctity of the smallpox stocks held in Russia. In addition, defectors to the United States have told of an extensive Soviet biowarfare program that included twenty tons of militarized smallpox, as well as weaponry to aerosolize the virus.26 The former USSR was considered by many to possess more men and women with the intellectual knowledge of how to turn microbes into weapons than any other nation.27

Conclusion: The Dual-Use Model

The events of September 11, 2001 were a painful indication of how truly proximate the possibility of terrorism on American soil remains. Since then, the likelihood of further acts of terrorism has increased. Explicit threats have been made, and few will ever doubt again the seriousness with which terrorists regard their mandate. The recent developments bring to the forefront concerns of national security analysts on the heightening possibility that bioweapons will be further employed in this country.28

As politicians and the press have become increasingly aware of the threat of a terrorist attack using biological agents, so federal spending on the issue of biodefense has increased. The Department of Defense is currently at the center of initiatives to enhance federal capabilities to respond to biological terrorist threats, and to build state and local response capacities.29 However, many public health specialists feel that such an emphasis is both unwarranted and unwise. In light of the anthrax cases, it is now an indisputable fact that the primary responders in the event of bioterrorist attacks will be civilian physicians and healthcare workers. Therefore, funds must be allocated to strengthen the health infrastructures capacity to respond to a deliberate outbreak.

To this end, in the early 1950s, the CDC created the Epidemic Intelligence Service (EIS) with the specific possibility of biological warfare in mind. EIS officers investigate unusual disease out breaks across the country, keeping in mind the possibility of intentional release of biological agents. Although it has yet to uncover an unnatural outbreak, the EIS has proven itself to be a valuable and cost-effective part of the nations public health infrastructure.30 The application of public health measures to both serve as contingency measures in the event of bioterrorist attacks and also to provide practical responses to natural outbreaks has been termed the dual-use model.

This dual-use model has been promoted heavily as the most effective response to a potential terrorist attack. The approach is based on the belief that money spent on improving public health capacities will never be wasted. Committing resources to maintaining effective disease surveillance mechanisms and improving epidemiologic and laboratory capacities nationwide will serve the public health infrastructure well, even in the absence of a bioterrorist attack. In particular, the coordination and communication links between primary health workers and nationwide structures need to be strengthened to minimize response times in the event of an outbreak.

At a time in which natural outbreaks of infectious diseases like West Nile encephalitis, Ebola, BSE and Rift Valley Fever pose very tangible threats to U.S. populations, the capacity of the public health community to respond to such challenges has been systematically eroded.31 Therefore, any efforts to improve the capabilities of the system will be of untold value. Former U.S. President Bill Clinton, speaking at the National Academy of Sciences in 1999, echoed these sentiments, observing that these cutting edge efforts will address not only the threat of weapons of mass destruction, but also the equally serious danger of emerging infectious diseases. So we will benefit even if we are successful in avoiding these attacks.32

Polemicists in the public health field go further to argue that the furor generated by fears of bioterrorism has created a valuable opportunity to secure funding for notoriously underfunded public health systems. The very feature that makes the concept of bio-terrorism so frighteningæ its direct impact on civilian organizations and individualsæ will also potentially have profound impacts on the capabilities of the U.S. public health infrastructure. In this way, the threat of bioterrorism may be harnessed to create historic opportunities for the diversion of federal spending away from military defenses towards strengthening broad-based public health capabilities.33

As a potential biological agent, the specter of smallpox looms heavy on the horizon. However, as a tool for the improvement of critical health systems, the memory of smallpox will likely prove immensely effective. Hopefully, smallpox will never again afflict human populations. Yet in its absence, other threats to the health of global populations will invariably persist, challenging the capabilities of public health systems, and demanding swift, effective responses.

Endnotes

1 World Health Organization. The Eradication of Smallpox: Final Report of the Global Commission for the Certification of Smallpox Eradication, Geneva, December 1979. Geneva: World Health Organisation. 1980. p. 16.

2 Harris, D. Fraser. Edward Jenner and Vaccination, in Scientific Monthly. October 1915; Vol. 1, Issue 1. p. 66-85.

3 Harris, p. 66.

4 Behbehani, A.M. The Smallpox Story: Life and Death of an Old Disease, in Microbiology Review. 1983; Vol. 47. p. 455-509.

5 Harris, p. 68.

6 Massung, R.F. et al. Potential Virulence Determinants in Terminal Regions of Variola Smallpox Virus Genome, in Nature. 1993; 336. p. 748-751.

7 WHO, p. 57.

8 WHO, p. 11.

9 Garrett, Laurie. Betrayal of Trust: The Collapse of Global Public Health. New York: Hyperion. 2000. p. 488.

10 WHO, p. 62.

11 Centers for Disease Control and Prevention. Smallpox and Bioterrorism. Atlanta: CDC. June, 2001.

12 McCrary, S. Van. Smallpox and Bioterrorism: A Growing Threat, in Health Law and Policy Perspectives; University of Houston Health Law and Policy Institute http://www.law.uh.edu/healthlawperspectives/. posted 3rd August, 1999.

13 Wehrle, P.F., Posch, J., Richter, K.H., Henderson, D.A. An Airborne Outbreak of Smallpox in a German Hospital and its Significance with Respect to Other Recent Outbreaks in Europe, in Bulletin of the World Health Organisation. 1970; Issue 4. p. 669-79.

14 Henderson, D.A. Bioterrorism as a Public Health Threat, in Emerging Infectious Diseases. July-Sept. 1998; Vol. 4, No. 3.

15 Salpeter, Shelley. Bioterrorism: Physician Preparedness. Unpublished, October 2001.

16 CDC, p. 2.

17 Henderson, D.A. Smallpox: Clinical and Epidemiologic Features, in Emerging Infectious Diseases July-Aug. 1999; Vol. 5, No. 4. p. 538.

18 Grauerholz, John. A New Defense for an Old Enemy, in Insight on the News. Nov, 2000; Vol. 16, No. 2. p. 25.

19 Program for Monitoring Emerging Diseases (ProMed-mail). Anthrax, humanæ USA. http://www.promedmail.org/pls/promed/promed.searchhtml. showmail?p_filename=20011111.2785& p_year=&p_month=&topic_search=YES. posted 11th November, 2001.

20 Rosenbaum, David E. and Purdum, Todd S. Another Postal Worker Contracts Inhaled Anthrax. The New York Times. October 26, 2001.

21 Bradsher, Keith and Petersen, Melody. Drug Makers Plan Vaccines for Smallpox. The New York Times. October 25, 2001.

22 Lillibridge, Scott. Quoted in Betrayal of Trust. p. 489.

23 Tucker, Jonathan B. Historical Trends Related to Bioterrorism: An Empirical Analysis, in Emerging Infectious Diseases July-Aug. 1999; Vol. 5, No. 4. p. 498-504.

24 Tucker, p. 503.

25 Garrett, p. 514.

26 Alibek, K. and Handelman, S. Biohazard. New York: Random House. 1999. p. 107-122.

27 Garrett, p. 507.

28 Carus, W. Seth. The Threat of Bioterrorism. National Defense University Strategic Forum, Institute for National Strategic Studies September 1997; Number 127.

29 Carus, p. 2.

30 Carus, W. Seth. Biohazard, in The New Republic. Vol 221, Issue 5. p. 14-16.

31 Garrett, p. 481-544.

32 Clinton, W.J. Remarks by the President on keeping America secure for the 21st Century. National Academy of Sciences, Washington, D.C., 22nd January, 1999.

33 Guidotti, Tee L. Bioterrorism and the Public Health Response, in American Journal of Preventative Medicine. 2000; Vol. 18, Issue 2.