Sounding Board
Poxvirus Dilemmas — Monkeypox, Smallpox, and Biologic Terrorism
N Engl J Med 1998; 339:556-559August 20, 1998
- Article
More than 20 years have passed since the last case of smallpox was confirmed and 18 years since the International Commission for the Certification of Smallpox Eradication of the World Health Organization (WHO) concluded that the global eradication of smallpox had been achieved.1,2 Now, new dilemmas confront the world. Could recent outbreaks of human monkeypox in the Democratic Republic of the Congo (known as Zaire from 1971 to 1997)3-5 represent the return of another form of smallpox?6 Could variola (smallpox) virus be used as a weapon of biologic terrorism? And what are the implications of the decision of the WHO to advise the destruction of all isolates of the smallpox virus in June 1999?7
Monkeypox in Humans
Recent reports of large outbreaks of possible cases of monkeypox in the Democratic Republic of the Congo have raised questions as to whether monkeypox could sustain itself as an infection transmitted from human to human, in the same way as smallpox.3-5 Smallpox vaccine protects against monkeypox, but no one is being immunized against smallpox anymore. Might monkeypox soon take over the ecologic niche left vacant by smallpox?6 The available data do not support this possibility.
The first case of human monkeypox was identified in 1970, and through 1979, 55 cases of monkeypox were confirmed by the WHO in forested areas of western and central Africa, of which 44 cases (80 percent) occurred in the Democratic Republic of the Congo.8-10 The clinical picture of monkeypox (Figure 1Figure 1
Human Monkeypox in a Six-Year-Old Girl in Zaire, Now the Democratic Republic of the Congo.) resembles that of smallpox in Central Africa.9 The intensified WHO-sponsored field studies between 1980 and 1986 detected an additional 349 cases; virtually all were laboratory-confirmed. The case fatality rate among patients not vaccinated against smallpox was 11 percent (15 percent for children under five years of age).10 Of patients from the Democratic Republic of the Congo, 72 percent represented primary cases and were presumably infected from an animal source; the others represented spread to a second, third, fourth, and fifth generation of patients.10,11 Among 431 unvaccinated household contacts, the secondary attack rate was only 9 percent, far lower than the rates of 25 to 40 percent seen with smallpox.12,13
Computer simulations were carried out to determine the likelihood that human-to-human transmission of monkeypox would continue, assuming that vaccination-induced immunity to smallpox fell to zero and secondary attack rates were at the upper 95 percent confidence limits of the observed attack rates — 14 percent for household contacts and 5 percent for nonhousehold contacts.10,14,15 The model forecast that individual outbreaks might last as long as 14 generations of human-to-human transmission before dying out, but that continuing transmission was highly unlikely.
Only 13 cases of monkeypox were reported from 1987 through 1992, and none from 1993 through 1995.16 Beginning in February 1996, monkeypox outbreaks in the Democratic Republic of the Congo were reported, but investigations were limited because of civil disorder.3,4 A joint team from the WHO and the Democratic Republic of the Congo visited the province of Kasai Oriental and concluded that 511 cases of suspected monkeypox had occurred between February 1996 and October 1997.5,16 Laboratory studies have since revealed that a substantial proportion of the suspected cases were actually cases of varicella; hence, the observed high incidence of possible household transmission (42 percent) was not surprising. Moreover, the disease was relatively mild, and overall case fatality rates were about 1 percent. On the basis of the available data, one cannot conclude that monkeypox has changed genetically or in its pathogenesis, severity, or propensity for human-to-human spread. Careful field studies, to provide more definitive answers, are planned by the WHO.
Smallpox as a Biologic Weapon
There is increasing concern that biologic weapons might be deployed in warfare or for terrorist purposes. Terrorism has become more dramatic and destructive in recent years.17-22 State sponsorship of terrorism has risen, and there is worldwide diffusion of technology both through the Internet and because experts have left laboratories in Eastern Europe. Until recently, smallpox was considered an unlikely agent of bioterrorism because of the high level of population immunity to the disease, the availability of a vaccine, and the knowledge that vaccination of patients' immediate contacts could rapidly control outbreaks.
Circumstances have changed. All vaccination against smallpox ceased after eradication of the disease was affirmed.1,23 All countries realized substantial savings, both in the costs of vaccine administration and in vaccination-caused illnesses and deaths that were averted.24 Virtually all children and many adults are now fully susceptible to smallpox. Only limited supplies of vaccine (vaccinia virus) are available. The WHO retains about 500,000 doses of vaccinia, and 60 million to 70 million doses are retained elsewhere, not all of which are properly stored or monitored regularly for potency. The U.S. stocks might be adequate to vaccinate 5 million to 10 million persons. Facilities for manufacturing smallpox vaccine have been converted to other uses or destroyed. The production of vaccine in cell culture is under study in the United States, but large-scale manufacture is years away. Genetically engineered vaccinia strains are being investigated, mainly as vectors for other antigens.25,26
Where might smallpox virus be obtained? In 1980, the WHO's international commission recommended that “all institutions maintaining stocks of variola virus destroy or transfer these stocks to WHO collaborating centers equipped with adequate security” and that such laboratories be visited at least every two years to evaluate security and adherence to WHO safety directives.23 Of 76 laboratories identified as having variola virus by 1980, 74 destroyed their stocks or transferred them to a WHO collaborating laboratory.2 Currently only two laboratories are known to retain variola virus: the Centers for Disease Control and Prevention (CDC) in Atlanta, and the Russian State Research Center of Virology and Biotechnology in Koltsovo, Novosibirsk Region, Russian Federation. Both are WHO collaborating centers and have biosafety-level 4 facilities.
Some speculate that there are additional variola-virus isolates, either long-held unreported stocks or those obtained from a WHO reference center through a lapse in security.27,28 It has also been hypothesized that smallpox virus has been recombined with other dangerous pathogens for use as a biologic weapon, but the accuracy of these scenarios is unknown.
Were smallpox virus released as an act of terrorism, the results could be catastrophic. A large proportion of the population has no immunity. There is little available vaccine and no effective treatment. The expected case fatality rate would be higher than 25 percent. Although there are no simple measures to detect or prevent biologic terrorism with smallpox (or other agents),29 four specific actions could diminish this risk.
First, the WHO should call on all countries to destroy immediately all stocks of variola virus. This would be a clear signal to any group or nation contemplating the use of the virus that such action would be the most reprehensible of crimes.
Second, efforts should be intensified to secure international agreements enforcing inspection of all suspect facilities anywhere in the world. This would include strengthening the Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction.30
Third, the capacity for large-scale manufacture of additional smallpox vaccine should be developed. Production, with use of WHO-approved vaccinia strains and cell culture, should begin at selected sites and should include the planning of an emergency vaccine-distribution system.
Fourth, a plan to cope with an attack with smallpox virus should be developed as part of a national plan to confront the release of biologic agents. Such an initiative was announced recently by President Bill Clinton.31 Vaccination should be considered for persons who would be responsible for the investigation and control of suspected outbreaks of smallpox and for patient care.
Although smallpox virus represents an extremely serious threat, the same cannot be said for monkeypox. The effect of an aerosol of monkeypox released among humans is difficult to predict, but case fatality rates would probably be below 15 percent, substantially lower than the rate expected among unvaccinated smallpox victims.1 Moreover, monkeypox virus is difficult for humans to acquire naturally and has a limited capacity for spread.
Destruction of Variola Virus
At meetings in 1986 and 1990, a WHO expert committee on orthopoxvirus infections affirmed the desirability of destroying stocks of Variola major and V. minor, but recommended additional mapping, cloning, and sequencing studies. By 1994, this work was virtually completed, and the committee recommended the destruction of all stocks of variola virus. This decision was supported in 1993 by the Council of the American Society of Microbiology, the executive board of the International Union of Microbiological Societies, the board of scientific counselors of the National Center for Infectious Diseases of the CDC, the board of directors of the American Type Culture Collection, and the Russian Academy of Medical Sciences.
There are cogent arguments for both the destruction and the retention of smallpox virus. Opponents of destruction argue that the unique host specificity of variola virus is justification for its preservation32-34 and that the virulence segment of the variola-virus genome has not been identified. Studies of variola-virus–encoded proteins that might alter host immune and regulatory functions have been proposed, in the belief that such studies might improve our understanding of human defense mechanisms and help society cope with new poxviruses and other emerging infections.
Proponents of destruction argue that the genomes of reference strains have been cloned and sequenced,35-37 through cooperative efforts of American and Russian scientists.38-42 Moreover, monkeypox virus has proved a valuable surrogate for variola: its genomic DNA has more than 90 percent homology with that of variola virus. Monkeypox illness in humans and in macaques closely resembles smallpox in humans, and the disease can be prevented in animals by vaccination. In contrast, there is no satisfactory animal model of smallpox. Work with variola virus must be performed in a biosafety-level 4 laboratory, whereas studies with monkeypox require less stringent precautions. The views of developing countries where smallpox was formerly endemic must also be weighed, since they contributed the most money and human resources to the eradication of smallpox. These countries have advocated the destruction of variola-virus stocks.7
During 1995, scientists from the Department of Defense and the Department of Health and Human Services undertook to determine what, if any, studies involving the use of intact variola virus would be critical to public health and national security. It was decided that if a model of monkeypox infection in macaques proved unsatisfactory, studies would be warranted to find a technique to grow variola virus in a genetically or chemically altered mammalian host. The macaque monkeypox model indicated that studies of pathogenesis, the protective efficacy of vaccines, and the therapeutic potential of antiviral compounds could be conducted successfully (Jahrling P, U.S. Army Medical Research Institute for Infectious Diseases: personal communication).
Furthermore, 23 antiviral compounds were evaluated in tissue culture, with comparison of their action against variola, monkeypox, vaccinia, camelpox, and cowpox viruses. Three compounds had significant antiviral activity against variola virus but only moderate inhibitory activity against the other orthopoxviruses. Cidofovir, its cyclic derivative, and ribavirin are in advanced clinical testing or are approved for other viral infections. Further studies of these compounds have begun, with use of a mouse model of cowpox and the macaque monkeypox model (Jahrling P: personal communication). A hypothetical case can be made for the retention of intact variola virus for as yet incompletely defined research that cannot be conducted with monkeypox virus, cloned variola fragments, or sequence data. This possible use must be balanced against the benefits of a global decision to destroy all stocks of the virus.
Conclusions
Reports suggesting that monkeypox might replace smallpox as a serious epidemic threat are unsubstantiated, but the threat posed by the possible use of smallpox as a terrorist weapon is genuine. Because of the gravity of this threat, all known stocks of variola virus should be destroyed as soon as possible. The deliberate deployment of this virus must be discouraged by whatever means possible.
Joel G. Breman, M.D., D.T.P.H.
National Institutes of Health, Bethesda, MD 20892-2220D.A. Henderson, M.D., M.P.H.
Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD 21205-2179The views expressed in this article are those of the authors and do not necessarily reflect the views of the institutions with which they are associated.
We are indebted to Joseph J. Esposito, Karin Esteves, Frank Fenner, David L. Heymann, John W. Huggins, Peter B. Jahrling, Catherine Laughlin, Brian W.J. Mahy, Bernard Moss, and Mark Szczeniowski for their thoughtful comments on the manuscript.
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- Letters
