Following was received from Thomas Holsinger. The layout is a bit odd, but that's my fault and that of some filters.
Cited below are many links to useful medical journal articles on smallpox, plus two whole articles from an issue of the New England Journal of Medicine. I found this with a simple Google search for the two words "Aralsk" and "smallpox".
Selected Reading
[Abstract]
Bicknell WJ. The case for voluntary smallpox vaccination. (Sounding Board) N Engl J Med 2002;346(17):1323-5
[Full text]
Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med 2002;346(17):1300-8
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CDC. Interim smallpox response plan and guidelines (Nov 11, 2001)
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CDC. Supplemental recommendations of the ACIP: use of smallpox (vaccinia) vaccine, June 2002
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CDC. Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR 2001;50(10):1-25
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Drazen JM. Smallpox and bioterrorism. (Perspective) N Engl J Med 2002;346(17):1262-3
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Fauci AS. Smallpox vaccination policy--the need for dialogue. (Editorial) N Engl J Med 2002;346(17):1319-20
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Feldman KA, Enscore RE, Lathrop SL, et al. The sequence of camelpox virus shows it is most closely related to variola virus, the cause of smallpox. J Gen Virol 2002 Apr;83(Pt 4):855-72
[Abstract]
Fenner F, Henderson DA, Arita I, et al. Smallpox and its eradication. Geneva, Switzerland: World Health Organization, 1988
[Full textbook]
Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med 2002;346(17):1265-74
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Frey SE, Newman FK, Cruz J, et al. Dose-related effects of smallpox vaccine. N Engl J Med 2002;346(17):1275-80
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G. J. Annas. Bioterrorism, public health, and civil liberties. N Engl J Med 2002;346(17):1337-42
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Gani R, Leach S. Transmission potential of smallpox in contemporary populations. Nature 2001;414(Dec 13):748-51
[Abstract –Requires free registration]
Haim M, Gdalevich M, Mimouni D, et al. Adverse reactions to smallpox vaccine: the Israel Defense Force experience, 1991 to 1996. A comparison with previous surveys. Mil Med 2000;165(4):287-9
[Abstract]
Henderson DA, Fenner F. Recent events and observations pertaining to smallpox virus destruction in 2002. Clin Infect Dis 2001;33:1057-8
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Henderson DA, Inglesby TV, Bartlett JG, et al, for the Working Group on Civilian Biodefense. Smallpox as a biological weapon: medical and public health management. JAMA 1999;281(22):2127-37
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Henderson DA. Smallpox: clinical and epidemiologic features. Emerg Infect Dis 1999;5(4):537-9
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LeDuc JW, Damon I, Meegan JM, et al. Smallpox research activities: US Interagency collaboration, 2001. Emerg Infect Dis 2002 Jul;8(7)
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Meltzer MI, Damon I, LeDuc J, et al. Modeling potential responses to smallpox as a bioterrorist weapon. Clin Infect Dis 2001;7(6)
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Tucker JB, Zilinskas RA. CNS Occasional Paper No 9: The 1971 smallpox epidemic in Aralsk, Kazakhstan, and the Soviet biological warfare program. June 2002
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Smallpox and Bioterrorism
This issue of the Journal contains more information about smallpox than I hope you will ever need. Smallpox was eradicated as a naturally occurring disease over 20 years ago. Thus, any new case of smallpox would have to be the result of human misadventure, either planned or unplanned, involving the laboratory stocks of the virus that were retained in the United States and the former Soviet Union when the disease was contained. Is smallpox a threat to our health? At the present time, there is no way to know. If smallpox virus (see figure) is in the hands of bioterrorists, then it could be a threat. If all the infective virus is securely held by responsible authorities, then it is not a threat. Since virus stocks cannot be tracked with accuracy, it is impossible to know the answer to this important question. This issue of the Journal brings you a considerable amount of information about a killer disease that we can no longer ignore. The goal is to educate and inform.
Two Original Articles in this issue demonstrate that our current stocks of smallpox vaccine can be diluted 5-to-10-fold without substantial loss of efficacy. Immunity comes at a cost. Even in these well-controlled trials involving healthy young adult volunteers there was considerable morbidity, including both systemic effects and substantial local reactions. A Review Article about smallpox provides additional information to help medical professionals recognize and treat this condition when and if it occurs. Unfortunately, even if we all become well acquainted with the clinical presentation of smallpox, by the time the disease is recognizable, it will probably be too late to prevent hundreds or thousands of deaths. Thus, the most pressing question is whether we need a preemptive vaccination campaign against smallpox. The decision on such a plan depends on the likelihood that terrorists will use smallpox as a weapon. A year ago it seemed unthinkable. Recent events, however, have raised the possibility that such an attack could conceivably occur. In an editorial in this issue, Fauci frames the critical issues about smallpox vaccination and calls for an open and thorough debate on this subject. I strongly agree.
To open the debate, Bicknell, in a Sounding Board article, outlines the case for mass vaccination. He provides realistic estimates of the incidence of deleterious side effects and the number of deaths that might occur if we immunize the entire population. One such hazard, disseminated vaccinia, is illustrated in the Image in Clinical Medicine. The risk of this complication is especially great in persons with undiagnosed immunodeficiency syndromes. Bicknell also outlines what might ensue if we do not immunize the population and a coordinated smallpox attack occurs. A letter to the editor from Dworetzky provides a firsthand account of managing a reasonably contained smallpox epidemic. It is clear from his description that as a U.S. Army physician during World War II, he felt personally threatened in dealing with smallpox even though it was a disease to which he was immune.
The final decision on the best course of action for the country should be made after all the potential risks and benefits have been carefully weighed. We need to hear from those with the greatest knowledge of the subject, and we need to consider what operational plans might be workable. If we do proceed with large-scale vaccination, we need to consider who should be immunized, when they should be immunized, and how to reduce unintended sequelae. Although medical facts frame the decision-making process, the choice in the end will be in the hands of our government officials.
In my opinion the people of the United States have made it clear since September 11 that they are willing to make sacrifices for the common good. The debate on preemptive vaccination cannot go on indefinitely; we need to make a decision. I believe that if the decision calls for widespread vaccination, despite its attendant risks, we will accept those risks bravely, with our sleeves rolled up, ready for action.
Jeffrey M. Drazen, M.D.
The Case for Voluntary Smallpox Vaccination
The former Soviet Union developed variola virus, which causes smallpox, for use as a biologic weapon, and supplies may have fallen into other hands. As Lev Sandakhchiyev, the director of Russia's Vektor Institute, has warned, "All you need is a sick fanatic to get to a populated place."1 U.S. experts agree.2,3 The benefits of preemptive, voluntary vaccination are great. One immediate outcome is deterrence. Vaccination before exposure dramatically reduces the value of smallpox as a weapon; in the case of an attack, the number of unimmunized persons will be greatly reduced, and the outbreak will be much easier to manage. The United States is the most likely target of bioterrorism, and preexposure vaccination in this country reduces the risk of secondary exposure elsewhere in the world. A survey has shown that 61 percent of Americans would want to be vaccinated if smallpox vaccine were available, and the public thus appears to be ready for this approach.4
The risk of an attack involving variola virus is impossible to quantify, but the vulnerability of the U.S. population is evident. The 119 million U.S. residents born after the program of mass vaccination was terminated in 1972 lack immunity. Moreover, the immunity of the 157 million U.S. residents who were born earlier is waning and therefore uncertain. The federal government recognizes the risk and has ordered the production of sufficient supplies of vaccine to immunize the entire U.S. population.5
The responsibility for deciding how to administer vaccine rests with the Centers for Disease Control and Prevention (CDC). The CDC currently recommends postexposure "ring vaccination," an approach that requires rapid identification and quarantine of exposed persons, with immunization of their contacts and the contacts' contacts.6 Ring vaccination is an effective strategy for the eradication of small, localized outbreaks in a population with widespread immunity. In a largely nonimmune and highly mobile population, however, epidemic control after multiple simultaneous exposures is a vastly different challenge. The CDC's strategy of postexposure ring vaccination is predicated on certain assumptions that merit scrutiny. One assumption is that smallpox makes patients so visibly sick that infected persons can be identified and quarantined within the four-day period after exposure during which vaccination may be effective.2,3 Smallpox is "most contagious during the preeruptive period by aerosol droplets from oropharyngeal lesions."7 A person may be infective for several days before smallpox is clinically obvious.8 Infected terrorists could expose people in several cities (and on public transportation between cities) before becoming visibly ill. Identifying such cases of exposure within the four-day period is logistically impossible. Furthermore, aerosolized dispersion of the virus could make the situation much worse.
The CDC strategy also appears to be based on the assumption that each infected person will infect only two or three others: "Our data suggest that the lowest rate (2 persons infected per infectious person) is the most accurate representation of previous transmission rates."9 But in the Yugoslav and German smallpox outbreaks in the 1970s, for each case of infection, the number of infected contacts ranged from 11 to 38.8 A single case of smallpox in the Yugoslav outbreak required the administration of 18 million doses of vaccine to arrest the spread of disease in a population with substantial immunity.10 Moreover, the deliberate exposure of a population to smallpox introduces multiplicative factors with effects that are unforeseeable.
Finally, the logistic complexity of administering millions of vaccine doses in a crisis is daunting. An epidemic is highly likely to outrun the vaccinators. Effective enforcement of quarantine is also difficult.11 Official reassurances followed by further uncontrolled outbreaks could provoke panic, flouting of authority, and even the breakdown of medical and public health services. In June 2001, the Johns Hopkins Center for Civilian Biodefense Studies sponsored a simulation exercise, called Dark Winter, in which experienced officials used a containment-after-exposure strategy in response to a smallpox attack.12 There was logistic havoc. It was attributed to the unclear and conflicting authority of competing jurisdictions, a shortage of vaccine, weak information-sharing mechanisms, and inadequate crisis capacity in the health care system.
Preexposure vaccination does not pose the logistic difficulties of vaccination during an outbreak and is less expensive. It also reduces the risk of infection among immunocompromised persons.10 The primary objection to voluntary preexposure vaccination is the risk of serious complications, but exposure of immunocompromised persons to vaccinia is much easier to control in a noncrisis setting than during an outbreak.3,10 An increased level of immunity in the population would reduce the overall risk of infection among immunocompromised persons in the event of an attack.
In 1968, the last year for which we have data on mass vaccination, 14.2 million persons in the United States were vaccinated. Nine deaths resulted — six primary vaccinees and three revaccinees — for a death rate of less than one per million. Complications included postvaccinal encephalitis (16 cases, 4 of which were fatal), progressive vaccinia (11 cases, 4 fatal), eczema vaccinatum (126 cases, 1 fatal), and generalized vaccinia (143 cases, none fatal). Vaccinia immune globulin is effective for the treatment of eczema vaccinatum and certain cases of progressive vaccinia, and it is also recommended for severe generalized vaccinia but not for all complications.2,10
Applying the 1968 data to today's population suggests that there would be 180 deaths from vaccination nationwide, which is approximately the number of deaths from traffic accidents every 1.5 days.13 Since there are many more immunocompromised persons today than there were in 1968, complication rates may be higher, but vigilance, voluntary testing for human immunodeficiency virus before vaccination, wide availability of vaccinia immune globulin, and good medical care should help keep the rates of death and serious complications close to those in 1968.3 These rates, which the American public accepted before 1972, must be weighed against the possibility of a much higher rate of death from a well-coordinated terrorist attack.
Consider the hypothetical case of an attack on numerous cities that put 50 percent of the U.S. population at risk. If we applied the lowest historical case fatality rates (3 percent among persons with partial immunity and 5 percent among nonimmune persons) and also assumed (optimistically) that an intensive postexposure vaccination program and good medical care would further reduce the rates of transmission and death by 90 to 95 percent, there could still be 100,000 to 1 million deaths.8,14 In comparison, the influenza pandemic of 1918–1919 caused about 500,000 deaths in the United States.15
Voluntary smallpox vaccination requires precise planning. As soon as sufficient supplies of vaccine are available, first responders and other key public-safety and public health personnel should be offered voluntary immunization. (The CDC has already vaccinated its own smallpox-response teams.) Vaccinia immune globulin should be stockpiled rapidly by initially immunizing first responders who have a history of smallpox vaccination and then obtaining blood from them for the production of vaccinia immune globulin. Immunized personnel should be monitored for adverse reactions before a program of widespread voluntary vaccination is initiated. This approach will also facilitate the evaluation of any new vaccine derived from tissue culture.10
An aggressive educational campaign will be needed to inform the public about the risks and benefits of smallpox vaccination. Guidelines for the protection of immunocompromised persons and infants should be formulated and publicized. When there are sufficient supplies of vaccinia immune globulin, the vaccine should be made available to the entire population on a voluntary basis through ambulatory care providers and public health departments. The CDC guidelines indicate that federal support to the states in the form of staffing will be limited. The CDC director will maintain control of the distribution of vaccine, but the states should insist that vaccine purchased with tax dollars be made available to them promptly, without restrictions on its use for preexposure vaccination.
Postexposure containment of a terrorist-induced smallpox outbreak is unlikely to be successful. Widespread, voluntary vaccination before exposure will greatly reduce the number of victims, if an attack occurs, and it will be much easier to protect unimmunized persons through additional ring vaccination. With a reduced risk of infection in the United States, secondary epidemics in other countries will be less likely. Speaking as a former commissioner of the Massachusetts Department of Public Health, I would underscore that the assessment of risk entails a value judgment that belongs in the public forum. It is time for a full and open debate about the best protection against the possible reappearance of smallpox.
William J. Bicknell, M.D., M.P.H.
Boston University School of Public Health
Boston, MA 02118-2526
I am indebted to Ken Bloem, Susan Foster, Jane Hale, Ann Goodsell, Lucy Honig, David Ozonoff, and James Plorde for their very helpful comments. This article was published at www.nejm.org on March 28, 2002. References
- Picard A. Experts raise smallpox alert: global vaccination campaign urged by scientists fearing bioterror threat. Globe and Mail. November 6, 2001:1.
- Henderson DA, Inglesby TV, Bartlett JG, et al. Smallpox as a biological weapon: medical and public health management. JAMA 1999;281:2127-2137.[ISI][Medline]
- Millar JD. Paradox in prevention: managing the threat of smallpox bioterrorism. Health policy focus. Washington, D.C.: Public Health Policy Advisory Board, 2000. (Accessed March 12, 2002, at http://www.phpab.org/Editorials/ReprintOfParadoxIn.htm.)
- Study no. Q946. Media, Pa.: International Communications Research, November 2001.
- Petersen M. Shares of tiny smallpox vaccine maker soar. New York Times. November 30, 2001:C2.
- Interim smallpox response plan & guidelines: draft 2.0. Atlanta: Centers for Disease Control and Prevention, November 21, 2001. (Accessed April 5, 2002, at http://www.bt.cdc.gov/DocumentsApp/Smallpox/RPG/index.asp.)
- Chin J, ed. Control of communicable diseases manual. 17th ed. Washington, D.C.: American Public Health, 2000:457.
- Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization, 1988:1-68, 121-208. (Accessed April 5, 2002, at http://www.who.int/emc/diseases/smallpox/Smallpoxeradication.html.)
- Meltzer MI, Damon I, LeDuc JW, Millar JD. Modeling potential responses to smallpox as a bioterrorist weapon. Emerg Infect Dis 2001;7:959-969.[ISI][Medline]
- Rosenthal SR, Merchlinsky M, Kleppinger C, Goldenthal KL. Developing new smallpox vaccines. Emerg Infect Dis 2001;7:920-926.[ISI][Medline]
- Barbera J, Macintyre A, Gostin L, et al. Large-scale quarantine following biological terrorism in the United States: scientific examination, logistic and legal limits, and possible consequences. JAMA 2001;286:2711-2717.[ISI][Medline]
- O'Toole T, Inglesby T. Shining light on Dark Winter. Baltimore: Johns Hopkins Center for Civilian Biodefense Strategies, 2001. (Accessed April 5, 2002, at http://www.hopkins-biodefense.org/lessons.html.)
- National Transportation Safety Board. Report on injuries in America, 2001. (Accessed March 12, 2002, at http://www.nsc.org/library/rept2000.htm.)
- Cohen J. Bioterrorism: smallpox vaccinations: how much protection remains? Science 2001;294:985-985.[Full Text]
- National Vaccine Program Office. Pandemic influenza: pandemics and pandemic scares in the 20th century. Atlanta: Centers for Disease Control and Prevention, 2001. (Accessed April 5, 2002, at http://www.cdc.gov/od/nvpo/pandemics/flu3.htm#8.)
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This article has been cited by other articles:
- (2002). Smallpox in Theory and Practice: Controversies Abound. Journal Watch General Medicine 2002: 1-1
[Full Text] - Annas, G. J. (2002). Bioterrorism, Public Health, and Civil Liberties. N Engl J Med 346: 1337-1342
[Full Text] - Fauci, A. S. (2002). Smallpox Vaccination Policy -- The Need for Dialogue. N Engl J Med 346: 1319-1320
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