The Johns Hopkins University, Center for Civilian Biodefense Strategies

Risk of a Deliberate Release of Smallpox Virus;
Its Impact on Virus Destruction

D.A. Henderson, M.D., M.P.H.
Working paper - WHO ad hoc Committee on Orthopoxvirus Infections
January 1999

Introduction

Smallpox poses the most serious bioterrorist threat to the civilian population and so deserves special consideration. None of the other potential agents combine the attributes of a high case-fatality rate (30%+) and an ability to spread from person to person throughout the population in any part of the world. Moreover, there is no therapeutic agent for the treatment of smallpox and only limited supplies of vaccine available for epidemic control. Although smallpox has long been feared universally as the most devastating of all the infectious diseases, its destructive potential today is far greater than at any time in history. Because routine vaccination ceased throughout the world nearly 20 years ago, there is now a highly susceptible population that travels more widely and frequently than ever before, thus facilitating rapid dissemination of disease.

Smallpox as a Biological Weapon

Smallpox was probably first used as a biological weapon during the French and Indian Wars (1754-67) by British forces in North America (1). They distributed blankets that had been used by smallpox patients with the intent of initiating outbreaks among American Indians. Catastrophic epidemics occurred with case-fatality rates of 50% and higher. However, the potential threat of smallpox as a bioweapon greatly diminished after Jenner's discovery of vaccination in 1796 and its increasing availability. In fact, the possible use of smallpox as a biological weapon received almost no attention until the last few years.

After the global eradication of smallpox had been confirmed in 1980, a WHO Expert Committee recommended that all laboratories destroy their stocks of variola virus or transfer them to one of two WHO Reference Laboratories, one at the Centers for Disease Control in Atlanta and the other at the Institute for Virus Preparations in Moscow (2). This proposal was endorsed by the World Health Assembly. The Moscow strains were later transferred to the Russian State Research Center of Virology and Biotechnology in Koltsovo, Novosibirsk Region. By 1984, all countries reported being in compliance with the WHO resolution. The Expert Committee later recommended unanimously that all virus stocks be destroyed and proposed that this be accomplished on 30 June, 1996 (3). After debate in the 1996 WHO Executive Board and the World Health Assembly, the date of 30 June, 1999 was decided (4). A few countries, however, later objected to setting any date for virus destruction and are now seeking to reverse the Assembly decision.

Meanwhile, a number of events, some of which have only recently come to light, have heightened concern that the stocks of smallpox might not be limited to only two laboratories and that they may not be so secure as had been hoped. The Soviet Union, despite the provisions of the 1972 Biological Weapons Convention, maintained a large scale bioweapons program into the 1990s, a fact confirmed in 1992 by President Yeltsin (5). Under the aegis of an organization called Biopreparat, there are reported to have been 18 scientific institutes and 5 production facilities employing 25 000 scientists and technicians in research and development (6). Reports published in 1998 quote the former deputy director of this bioweapons program as saying that early in the 1980s, the government embarked on an ambitious program to grow smallpox virus in large quantities and to adapt it for use in bombs and intercontinental ballistic missiles (7). He reported this effort to have been successful. He also reported that the Soviet Union had developed an industrial capacity which was capable of producing annually many tons of smallpox virus and a research program, still active today, that seeks to produce more virulent and contagious recombinant strains. Because of the fact that many laboratories in Russia, including the one in Koltsovo, are now fiscally constrained and decreasing in size, there are growing concerns that existing bioweapons expertise and equipment might move or perhaps may have already moved to other countries. At least 10 other countries are now engaged in bioweapons development programs (8).

Who Might Release the Virus

The number of potential groups which might acquire smallpox virus and use it is as a bioweapon is constrained by the fact that the virus is less readily available than many other agents, such as anthrax or plague, which are endemic infections and whose strains are present in many laboratories. Moreover, special skills are required to grow smallpox virus in large quantities and to process it to make it suitable for dispersion as an aerosol. Thus, smallpox would be an unlikely weapon for such as small, technically unsophisticated dissident or fanatical groups. For a nation-state to openly engage in the use of a biological weapon would also seem unlikely given the fact that such an act would invite unacceptably severe retaliatory measures. Thus, it is the well-organized and financed groups such as the Aum Shinrikyo and state-sponsored terrorist organizations which would appear to pose the most serious threat.

Likely Population Exposed and Infected After an Aerosol Release

Although a number of models have been constructed to forecast the probable extent of spread and the proportion of the population affected when aerosolized organisms have been released, none, so far as is known, have been constructed for smallpox. However, it is known that vaccinia virus (as a smallpox surrogate) is extremely stable in an aerosolized form under conditions of cool temperatures and low humidity (table 1) and if shielded from ultra-violet light (9). Thus, significant quantities of virus could readily survive for 24 hours or more. What virus concentrations would be infective is unknown because of the lack of a suitable animal host in which to measure an ID-50 dose. However, from the experience in a 1970 hospital outbreak in Germany (10), it is clear that the infectious dose of aerosolized variola can be very small indeed. Given this information, it is probable that the numbers of persons potentially infected, were smallpox to be released, would approach the numbers predicted in anthrax release models (11).

Other releases of smallpox virus, such as into closed air circulation systems, would probably induce infection in most of the occupants. Following any type of aerosol release, secondary human-to-human transmission would significantly increase the total number of smallpox cases.

Secondary Transmission

The potential for secondary spread of the disease markedly heightens the potential impact of smallpox as a bioweapon. After an incubation period of 12 to 14 days, infected individuals would begin to experience the prodromal fever and aching pains of smallpox followed, after 2 to 4 days by the characteristic rash. With the development of the rash, patients would become infectious to others. Recognition of the possible existence of an epidemic of smallpox and its confirmation would not be likely until 3 to 4 days after the onset of rash, i.e. when the rash became sufficiently distinctive to be diagnosed. The implementation of effective containment measures would require at least a further 2 to 3 days. Thus, under most circumstances, some 19 to 25 days would probably elapse between release of the aerosol and the initiation of effective containment measures. By then, a large number of persons would have been in close contact with the first generation of patients and this during the first 7 to 10 days of rash when the disease is most contagious. Although vaccination of exposed persons within a few days after exposure can often prevent the development of smallpox or at least a fatal outcome, it is unlikely that many of those exposed to the first generation of cases would be reached in time.

It is difficult to estimate what number of second generation cases might occur. There is no contemporary experience in which smallpox has been introduced into populous areas that had so little protective immunity as is present now. Very few persons in any community have sufficient immunity to escape disease if exposed. The few who have previously experienced clinical smallpox are protected because second attacks of smallpox are rare. In addition, limited data suggest that some of those who have been successfully vaccinated and revaccinated in the past may possess sufficient immunity to resist infection (12). However, all persons up to age 18 (and in some areas, beyond this age) are wholly unprotected and, among those that are older, vaccination immunity will have waned significantly. Protection following primary vaccination alone diminishes substantially after 10 years (13). Thus, it is probable that in most communities, at least 90% of the population will be fully susceptible to smallpox with perhaps 20% of adults having some protective immunity and none of the children.

Some indication of what might be expected today following a release of smallpox virus can be derived from past experiences when smallpox was imported into non-endemic areas. Europe is of special interest because over the past 45 years, it experienced more importations of smallpox than other areas and reasonably complete documentation is available for most outbreaks. Throughout this period, vaccination immunity was reasonably good because, until 1980, routine vaccination was customary throughout Europe. Although it is probable that comparatively few were revaccinated, routine childhood immunization would have sustained overall levels of population immunity and these would have been significantly higher than today. Thus, further transmission from an imported case would have been substantially less likely than now.

Since 1953, there have been 34 importations of smallpox into Europe, the last occurring in 1973 (14). Ten of these occurred in the June to November period when transmission is at a seasonal low and, indeed, in none of the 10 were there more than 3 secondary cases. The 24 introductions during the December to May period divide sharply into two quite different groups (14). For 8 importations, there were no secondary cases; for another 9, there were 4 cases or fewer (table 2). In general, these were cases which were quickly diagnosed and which had limited contact with others during the acute phase of illness. However, 7 outbreaks documented 10 or more second generation cases. The number ranged from 10 to 19 cases with an average of 13 cases per outbreak. In the 1972 Yugoslav outbreak, the initial case went undiagnosed; he infected 11 others who likewise were undiagnosed (14). The 11 cases infected 140 others, a ratio of approximately 13:1.

Today, in a more highly susceptible population, it would seem reasonable to expect transmission rates of not less than 10:1 to 15:1 between one generation of cases and the next if control measures have not been instituted. However, as earlier noted, it is unlikely that effective control measures could be mounted following a terrorist attack in time to prevent disease spread from the first generation of aerosolized victims to their contacts. Thus, even if a release of smallpox virus infected only 200 to 300 persons, the next generation of cases would number perhaps 2000 to 4500. How many cases would occur in succeeding generations would depend on the availability of vaccine and the speed and efficiency of the public health services.

Vaccination

An immediate, large-scale vaccination program would be needed to counter the outbreak. A targeted campaign directed specifically at those who had been in face-to-face contact with patients could, in theory, stem the spread. However, timely vaccination is of the essence and when there are hundreds of suspect cases, time constraints would preclude an effort to determine precisely who was at risk and who was not. Moreover, even if there were, for example, only 200 to 300 true cases, probably 50 to 100 other persons would be experiencing some sort of illness with fever and rash sufficiently suggestive of smallpox to require that they be dealt with as possible cases. There would also be a number of travelers in other cities and countries who would have been somewhere near the site of release. Some might be infected; some would pose diagnostic puzzles; but most would demand that vaccine be made liberally available. In brief, even a small outbreak would inevitably involve a far larger geographic area and the demands for vaccine predictably would be insistent and widespread. Yugoslavia, in 1972, faced with some 140 cases at the time smallpox was first diagnosed, saw no option but to undertake a nationwide program in which 20 million persons were vaccinated.

What to do about vaccination would pose a further dilemma. Globally, reserve stocks of vaccine are very low. There are probably less than 50 million doses of vaccine of acceptable potency. No country has a sufficient vaccine supply to deal with a major outbreak and it would seem doubtful that any health authority would willingly deplete its own stocks of vaccine to help others when there was a spreading epidemic and implicit threats of further bioterrorism.

Vaccine production ceased in the early 1980s and most producers destroyed their production equipment. New production facilities could be constructed but these would take time, probably not less than two to three years, to achieve significant levels of production.

Meanwhile, such stocks of vaccine as are available would have to be carefully conserved, perhaps diluted to extend them further. Some might wish to revert to old arm-to-arm vaccination methods and one might anticipate that an unsupervised, uncontrolled "cottage industry" of vaccine production might spring up. Under such circumstances, the likelihood of an intensive, effective and coordinated public health vaccination program would be impossible.

Medical Care

Because of the capacity of smallpox to spread as an aerosol from an infected person throughout a hospital, as it did in Germany in 1970 (10), special measures would be needed to care for smallpox patients. Those admitted to hospital would require rooms under negative pressure with air exhausted through HEPA filters. Hospitals have few beds of this type. Alternatively, buildings or ward with separate air handling facilities might be used. However, if patients numbered in the hundreds, the most feasible solution might be home care for most, given the fact that little but supportive therapy can be offered the afflicted patient. Implementing such a program would be complicated.

Other Issues

It is beyond imagination to sketch a full scenario of the likely problems and challenges of epidemic smallpox involving hundreds, perhaps thousands of patients, in an epidemic which threatens to spread across a national and an international landscape.

Isolation of contacts to prevent further dissemination of infection poses special problems. Hundreds of patients would translate into thousands of contacts. For epidemic control purposes, they should be kept under surveillance and promptly isolated if they experience febrile illness. The logistics of tracking such large numbers and enforcing isolation are formidable. Indeed, if the numbers of cases were very large, it is possible that the quarantine of entire towns or geographic areas might be necessary but could this be done?

Would medical care staff remain on duty in the face of one of the most loathsome and feared epidemic diseases known? They have not always done so. Could civil and health authorities sustain confidence in government and in the health system during an evolving epidemic of a feared disease which almost certainly would continue to spread for upwards of two months or more before control was achieved? No historical experience of this century approaches the potential catastrophe of a contemporary epidemic of smallpox. The 1918 influenza pandemic, serious as it was, pales in comparison to the potential of epidemic, let alone pandemic smallpox.

Arguments for Retention of the Virus

The hypothetical argument that destruction of the virus could result in the loss of genetic information of potential but presently unrecognized value is a valid one. However, through the efforts of WHO and the Committee on Orthopoxvirus Infections, major strides have been made in conserving much of the genetic information -- through sequencing virus strains and the preparation of libraries of cloned DNA fragments. Moreover, the pathogenesis of monkeypox so closely mimics that of variola that it can continue to be studied. Destruction of the virus would not result in the interruption of major on-going studies. The fact is that outside of Russia, the only laboratory research during the past 20 years which has involved use of the intact variola virus has been conducted in the BSL4 high containment laboratories at the Center for Disease Control in Atlanta, the only laboratory in the USA where such studies can be conducted. At CDC during this period, smallpox virus was propagated to obtain material for sequencing and cloning and two studies were performed. In one study, a panel of possible antiviral agents was screened against variola virus and other orthopoxviruses in tissue culture. Two antiviral agents were identified for further work. A second study sought to validate PCR diagnostic probes against scab specimens from patients. These studies have also been completed. Meanwhile, over the past 20 years, no investigators have at any time applied to undertake studies at the CDC laboratories that required use of the variola virus. Clearly, research studies involving use of the intact variola virus do not command a high priority. In significant measure, this is because the virus grows well only in man; there is no satisfactory laboratory animal model. Thus, basic research in the poxvirus field has traditionally been performed using orthopoxviruses other than smallpox.

At various times, a variety of different arguments have been advanced with respect to the need for retaining variola virus:

  1. That smallpox virus would be needed for vaccine development if the smallpox virus reemerged from nature or if a recombinant strain, resistant to vaccine-induced immunity, were to be released. Not so. The smallpox virus is a wholly different organism and has never been employed in vaccine development. The vaccinia virus provides a broad immunity that is effective against all known strains of smallpox as well as against other orthopoxviruses, including monkeypox. In the unlikely event that a smallpox strain emerged which evaded immunity provided by the current vaccine, the solution to a new vaccine would rest in studies involving the new strain.

  2. By retaining the collection of smallpox strains, scientists might be able to pinpoint where a new strain had come from. Not so. The collection of strains now extant in Russia and the USA was never collected with the intent of creating a world library of strains such as is being done with polio, measles and anthrax. Most strains are from the later years of the program and no specimens are available from major geographic areas and from a number of major epidemics.

  3. Some argue that through basic research utilizing the smallpox virus, we could decipher the human immune system, that it represents potentially a sort of Rosetta stone to understanding immunity. Some have gone so far as to suggest that its study might lead to a cure for AIDS, for cancer and for rheumatoid arthritis, among other conditions. Few scientists reflect this view. Most are skeptical that such studies would do anything of the sort and find it difficult, inter alia, to reconcile this argument with the fact that basic research utilizing the intact variola virus has not been pursued outside of Russia for more than 20 years.

  4. That the smallpox virus is needed for the development of possible antiviral drugs. Not so. Candidate drugs are normally screened in vitro to determine their possible action against a given organism. However, this is only a screen. Many agents which are effective in vitro prove not to be effective when screened in vivo and, conversely, some agents which are not effective in vitro prove to be effective in vivo. In brief, tissue culture screening of anti-viral drugs is but one screen in a series and is not essential to drug development.

  5. That unless it can be absolutely guaranteed that all stocks of virus are destroyed, no action internationally could or should be taken. Underlying this argument are the concerns of many who have struggled over the years with the issues of nuclear disarmament and the implicit fear that disarmament by one side might engender an action by the other and so threaten national security. For nuclear weapons, the argument may have a rationale. However, does a decision, for example, to destroy all known stocks of smallpox virus in the USA without assurance that Russia would do the same have comparable implications? Does this suggest that if one country were to use smallpox as a bioweapon that it would be the intent of the USA to retaliate in kind? It seems unlikely.

Conclusion

The deliberate reintroduction of smallpox into the population would be an international crime of unprecedented proportions. A spreading, highly lethal epidemic in an essentially unprotected population, with limited supplies of vaccine, no therapeutic drugs, and with shortages of hospital beds suitable for patient isolation is an ominous specter. Thus, it would seem only prudent to take all possible steps to mitigate against the likelihood of such an occurrence. The World Health Assembly in 1996 called for all countries on 30 June 1999 to destroy all "remaining stocks of variola virus, including all whitepox viruses, viral genomic DNA, clinical specimens and other material containing infectious variola virus." It would seem only prudent to reaffirm this resolution and to seek the support of all concerned governments in carrying it out.

References

  1. Stearn, E.W. & Stearn, A.E. The Effect of Smallpox on the Destiny of the Amerindian. Boston, Bruce Humphries, 1945. return
  2. World Health Organization. The global eradication of smallpox. Final report of the Global Commission for the Certification of Smallpox Eradication. Geneva, WHO, 1980. return
  3. World Health Organization Ad Hoc Committee on Orthopoxvirus Infections. Communicable disease prevention and control:Smallpox eradication-destruction of variola virus stocks. Geneva, World Health Organization, 1995. return
  4. World Health Assembly (49th). Smallpox eradication - destruction of variola virus stocks. In: World Health Assembly, Geneva, 1996. return
  5. Leitenberg, M. The biological weapons program of the former Soviet Union. Biologicals. 21: 187-191 (1993). return
  6. Leitenberg, M. Biological weapons arms control. College Park, Maryland, Center for International and Security Studies, 1996, pp. 87. return
  7. Preston, R. The Cobra Event. New York, Random House, 1997. return
  8. Moodie, M. Arms control programs and biological weapons. In: Roberts, B., ed. Biological Weapons. Washington, Center for Strategic and International Studies, 1993, pp. 47-57. return
  9. Harper, G.J. Airborne micro-organisms: survival test with four viruses. Journal of Hygiene. 59: 479-486 (1961). return
  10. Wehrle, P.F. et al. An airborne outbreak of smallpox in a German hospital and its significance with respect to other recent outbreaks in Europe. Bulletin of the World Health Organization. 43: 669-679 (1970). return    2nd instance
  11. WHO Group of Consultants. Health Aspects of Chemical and Biological Weapons. Geneva, World Health Organization, 1970. return
  12. El-Ad, B. et al. The persistence of neutralizing antibodies after revaccination against smallpox. Journal of Infectious Diseases. 161: 446-448 (1990). return
  13. Downie, A.W. & McCarthy, K. The antibody response in man following infection with viruses of the pox group. III. Antibody response in smallpox. Journal of Hygiene. 56: 479-487 (1958). return
  14. Fenner, F. et al. Smallpox and Its Eradication. Geneva, World Health Organization, 1988.

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