A DIFFERENT VIEW OF SMALLPOX AND VACCINATION



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03 Feb 2003

Source: New England Journal of Medicine 348 (5), 460-463, January 30, 2003

SOUNDING BOARD

A Different View of Smallpox and Vaccination

Thomas Mack, M.D., M.P.H.

According to federal,[1] academic,[2] and lay [3] observers, smallpox might be used as a weapon of terrorism. Variola virus is presumed to be available,[4] and a terrorist could introduce it, leading to secondary spread and deaths. Current policy is to promote vaccination, initially to 1/2 million hospital-selected health care providers [5] and subsequently to as many as 10 million others.[6] This policy should be compared with alternatives in the light of the likely outcome of an introduction of variola virus into this country. Three decades ago, I was among those who investigated the dynamics of smallpox transmission by direct observation in Pakistan.

Risk of Smallpox

Smallpox was eradicated because its chain of transmission is inherently vulnerable. The clinical characteristics of an infectious patient restrict spread, because most virus shedding [7] and almost all transmission [8] occur during the first week of florid rash, and this period coincides with rapidly evolving symptoms severe enough to keep infectious patients in bed. Although the virus can be isolated from pharyngeal washings at the onset of rash and from month-old scabs,[9] neither of these seems to be important in practice.[8] Moreover, the physical appearance of an unvaccinated person with variola major is alarming and quite unlike anything else, including the appearance of persons with varicella. Once they are infectious, 98 percent of previously unvaccinated patients have disease severe enough [10] to be recognized by any professional or layperson familiar with the characteristic appearance (Figure 1). Whether clustered densely or sparsely, the lesions, uniform in stage and set deeply in the dermis of the face and extremities, [11] are unmistakable.

Transmission would not be expected to occur over more than very short distances. Although virus can be grown from pharyngeal washings and the face and bedding of infectious patients, [12] attempts to grow it from exhaled air or from unbroken vesicles have been unsuccessful, [12,13] suggesting that virus is usually discharged not in droplet nuclei but in saliva droplets too large to be wafted long distances. Moreover, the viability of artificially airborne virus is measured in minutes.14

Smallpox is not as infectious as its reputation would suggest. Whether in Punjab, [15] Bengal,[16] or Europe,[17] variola major was almost always transmitted at the bedside of the source, not at an external location. The source of infection was reported for about 96 percent of the cases that resulted from 51 introductions into highly susceptible European populations after World War II.[17,18,19] Among the 18 cases, on average, per introduction, 3.8 occurred among household contacts and only 1.1 appeared among the multitude of community residents with no acknowledged exposure. None of the 945 cases involved disease contracted on an airplane, train, or bus. Any spread into the community from an introduction would thus be limited. Past experience is likely to be a more accurate predictor of future events than models based on arbitrary assumptions.[20]

Enhancing the vulnerability of the smallpox chain is the interval of one to three weeks [8,17] between exposure and infectiousness. This interval provides the time to intervene and limit secondary spread. Close contacts of each case patient can be listed, located, given postexposure prophylaxis, placed under surveillance for symptoms, and isolated, if symptoms occur (and infectiousness is anticipated). If a case is identified only after contacts would have become symptomatic, attention can turn to the contacts of these contacts.

A generation ago, such control efforts were effective. Of the case patients known to be responsible for European outbreaks, [17,18,19] 84 percent had consulted physicians. Even without a terrorist threat or an alert public, 78 percent of those patients, many with vaccine-modified disease, were correctly diagnosed and isolated. Twenty-five percent of the introductions into those susceptible European populations resulted in no transmission at all, 60 percent were controlled before a third indigenous generation of cases,[17] and smallpox always disappeared within a few months.

Disappearance was facilitated, not impeded, by economic development. Long before the World Health Organization's Smallpox Eradication Program began, and despite low herd immunity, unsophisticated public health facilities, and repeated introductions, smallpox disappeared from many countries as they developed economically, among them Thailand, Egypt, Mexico, Bolivia, Sri Lanka, Turkey, and Iraq.[9] The largest and longest outbreak in postwar Europe occurred in Kosovo, in the least developed corner of the continent.[19]

In the United States, secondary spread would probably be greatly limited by our high level of literacy, efficient means of personal and public communication, and organized public health services. Graphic photographs would saturate the media, and subsequent infectious patients would be recognized, avoided, and reported. Contacts would seek, not avoid, medical assistance and could be efficiently kept under surveillance wherever they were. Few new diagnoses would be expected more than a month or so after an introduction.

Although virus might be weaponized for mass delivery or even altered genetically to enhance virulence or resistance to vaccine-induced immunity, such changes would not impair our ability to limit secondary spread. Even if multiple cases were produced by the same introduction,[4,21] there is no reason to expect disease to persist longer, although more teams would be required to establish control. Smallpox as a terrorist weapon corresponds more closely to a grenade than to a catastrophic "dirty" bomb or even a dissemination of anthrax spores.

Our greatest concern should be about transmission within hospitals. In postwar Europe, 4.4 cases per introduction occurred among caregivers and related professionals, and 6.7 cases occurred among hospital patients and visitors numbers that together represent over 60 percent of the total. Only in hospitals has substantial transmission occurred at some distance from the beds of the source patients. Contact with infected linens has been responsible,[22] as has, in one case, air recycled from a coughing patient to other rooms.[18] Hospital spread also has been responsible for protracted outbreaks in Kuwait [23] and Brazil,[23] and it was responsible for the majority of cases in each of the last three outbreaks in the United States in Seattle,[24] New York City,[25] and the Rio Grande valley.[26]

Vaccination Policy

Prophylactic vaccination of contacts is an important containment strategy, although the actual effectiveness depends on the timing [17,27] of the vaccination in relation to exposure. Nearly twice as effective as vaccine alone, however, is vaccination followed by the administration of vaccinia immune globulin.[28,29,30]

Vaccination before importation offers the only possible protection to households directly targeted by an introduction (assuming that genetic engineering has not rendered the strain of virus resistant [31]). However, we cannot identify those households in advance, and vaccinia is a dangerous live vaccine. It causes substantial morbidity among both healthy vaccinees and their pregnant or eczematous contacts.[32] Despite recommendations for screening and treatment with vaccinia immune globulin, deaths from complications occurred at a rate of 1 to 2 per million primary vaccinees.[33] Today, immunosuppressed patients with chronic disease or transplanted organs and carriers of the human immunodeficiency virus with or without AIDS, especially those with skin lesions, constitute additional vulnerable groups.[34] Complications today will surely be several times as common as previously. Even with a rate of 3 deaths per million, primary vaccination of 250,000 persons would be more likely than not to cause death. Moreover, liability for complications is unclear, marketing prophylaxis to adults is generally unsuccessful, and herd immunity will be difficult to achieve. Vaccine complications will be quickly, widely, and graphically reported in the media. Americans are better informed and less trusting than in the past, and noncompliance will be common.

Caregivers, at high risk of secondary transmission, deserve preferential protection. However, we cannot predict which hospitals will be affected, and undertaking staff vaccination through programs at all hospitals poses serious problems. There is substantial turnover among emergency room personnel, and some caregivers will refuse to be vaccinated. It will be difficult to protect highly vulnerable inpatients and outpatients from the spread of vaccinia. Moreover, the existence of hospital-based vaccination programs may lead to the knowing admission of patients with smallpox, putting those who are not protected at very high risk.

Costs and Benefits

Extrapolating from the European experience, we can predict that an initial smallpox introduction is likely to result in substantially fewer than 20 cases [17] and 10 deaths [11,17]; experience would lessen the impact of subsequent introductions. Many well-informed members of the general public will refuse vaccination. Every million primary vaccinations will cause at least 3 deaths from vaccinia, and the chance of preventing deaths from smallpox would be less than 0.4 percent (1 in 275 million). To prevent all potential deaths from smallpox would require universal compliance with vaccination, with as many as 800 deaths from complications. Even after an introduction, mass vaccination would do more harm than good.

About 2 1/2 million health care professionals and technicians work in U.S. hospitals [35] and are at some excess risk of caring for a patient with smallpox. Vaccination of the entire 2 1/2 million, assuming 100 percent compliance, would prevent all deaths of caregivers from smallpox, but at a cost of at least 7 to 8 deaths from vaccinia. Risk to other members of the antiterrorist infrastructure is likely to be similar to that of the general public.

Better Options

A terrorist introduction of smallpox could produce a short outbreak of cases and deaths, but the current vaccination policy will provide little protection, and the cost in deaths from vaccine complications will outweigh any benefit. Only if evidence suggests that a massive attack or sustained biologic warfare is probable can such a vaccination policy be justified. Safer options would be more effective. I recommend the following.

Every effort should be made to facilitate rapid diagnosis. Posters with dramatic photographs of florid smallpox cases should be distributed widely. No suspicious patient should be admitted to or even knowingly examined at a general hospital, even one with isolation facilities and an already vaccinated staff. Alternative dedicated facilities, even National Guard field hospitals, should be identified and activated at first diagnosis. Limited numbers of preselected (preferably older, previously vaccinated) field investigators, diagnostic laboratory personnel, caregivers, and paramedics and some law-enforcement personnel should be recruited, vaccinated, and committed to serve wherever necessary in the event of an introduction. No more than 15,000 persons would be required. Reserves of vaccinia immune globulin should be large enough to meet the anticipated need for both treatment of complications and postexposure smallpox prophylaxis. Experts should be convened to develop protocols for postexposure prophylaxis and treatment. Finally, the authorities and the media should provide more detail about the dangers of vaccination and more accurate, less inflammatory information about the potential for the spread of smallpox.

Source Information

From the Keck School of Medicine, University of Southern California, Los Angeles.

This article was published at www.nejm.org on December 19, 2002.

References

1. Broad WJ. U.S. to vaccinate 500,000 workers against smallpox. New York Times. July 7, 2002(section 1):1.

2. Bicknell W. The case for voluntary smallpox vaccination policy. N Engl J Med 2002;346:1323-1325.[Full Text]

3. de Rugy V, PeZa CV. Responding to the threat of smallpox bioterrorism: an ounce of prevention is best approach. Cato policy analysis. No. 434. Washington, D.C.: Cato Institute, April 18, 2002:1-16.

4. Alibek K. Biohazard: the chilling true story of the largest covert biological weapons program in the world, told from the inside by the man who ran it. New York: Random House, 1999.

5. Advisory Committee on Immunization Practices. Summary of October 2002 ACIP Smallpox Vaccination Recommendations. Atlanta: Centers for Disease Control and Prevention, 2002. (Also available at http://www.bt.cdc.gov/agent/smallpox/vaccination/acip-recs-oct2002.asp.)

6. Cowley G. The plan to fight smallpox. Newsweek. October 14, 2002.

7. Downie AW, St Vincent L, Meiklejohn G, et al. Studies on the virus content of mouth washings in the acute phase of smallpox. Bull World Health Organ 1961;25:49-53.

8. Mack TM, Thomas DB, Muzaffar Khan M. Epidemiology of smallpox in West Pakistan. II. Determinants of intravillage spread other than acquired immunity. Am J Epidemiol 1972;95:169-177.

9. Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization, 1988.

10. Rao AR. Smallpox. Bombay, India: Kothari Book Depot, 1972.

11. Mack TM, Thomas DB, Khan MM. Variola major in West Pakistan. J Infect Dis 1970;122:479-488.

12. Downie A, Meiklejohn G, St Vincent L, Rao AR, Sundara Babu BV, Kempe CH. The recovery of smallpox virus from patients and their environment in a smallpox hospital. Bull World Health Organ 1965;33:615-622.

13. Meiklejohn G, Kempe CH, Downie AW, Berge TO, St Vincent L, Rao AR. Air sampling to recover variola virus in the environment of a smallpox hospital. Bull World Health Organ 1961;25:63-67.

14. Mayhew C, Hahon N. Assessment of aerosol mixtures of different viruses. Appl Microbiol 1970;20:313-316.

15. Thomas DB, Mack TM, Ali A, Muzaffar Khan M. Epidemiology of smallpox in West Pakistan. 3. Outbreak detection and interlocality transmission. Am J Epidemiol 1972;95:178-189.

16. Thomas DB, McCormack WM, Arita I, Khan MM, Islam S, Mack TM. Endemic smallpox in rural East Pakistan. I. Methodology, clinical and epidemiologic characteristics of cases, and intervillage transmission. Am J Epidemiol 1971;93:361-372.

17. Mack T. Smallpox in Europe, 1950-1971. J Infect Dis 1972;125:161-169.

18. Gelfand H, Posch J. The recent outbreak of smallpox in Meschede, West Germany. Am J Epidemiol 1971;93:234-237.

19. Lane J. Smallpox in Yugoslavia: September 22, 1972. CDC Epidemiology Program Report. Atlanta: Center for Disease Control and Prevention, 1972.

20. Meltzer MI, Damon I, LeDuc JW, Millar JD. Modeling potential responses to smallpox as a bioterrorist weapon. Emerg Infect Dis 2001;7:959-969.

21. Dark Winter: bioterrorism exercise. Washington, D.C.: Andrews Air Force Base, 2001.

22. Dixon CW. Smallpox. London: J. & A. Churchill, 1962.

23. Arita I, Shafa E, Kader A. Role of hospital in smallpox outbreak in Kuwait. Am J Public Health 1970;60:1960-1966.

24. Palmquist EE. The 1946 smallpox experience in Seattle. Can J Public Health 1947;38:213-218.

25. Weinstein I. An outbreak of smallpox in New York City. Am J Public Health 1947;37:1376-1384.

26. Irons JV, Sullivan TD, Cook EBM, Cox GW, Hale RA. Outbreak of smallpox in the lower Rio Grande valley of Texas in 1949. Am J Public Health 1953;43:25-29.

27. Heiner GG, Fatima N, Russell PK, et al. Field trials of methisazone as a prophylactic agent against smallpox. Am J Epidemiol 1971;94:435-449.

28. Kempe CH. Studies on smallpox and complications of smallpox vaccination: E. Mead Johnson Award address. Pediatrics 1960;26:176-189.

29. Marennikova SS. The use of hyperimmune antivaccinia gamma-globulin for the prevention and treatment of smallpox. Bull World Health Organ 1962;27:325-330.

30. Kempe CH, Bowles C, Meiklejohn G, et al. The use of vaccinia hyperimmune gamma-globulin in the prophylaxis of smallpox. Bull World Health Organ 1961;25:41-48.

31. Jackson RJ, Ramsay AJ, Christensen CD, Beaton S, Hall DF, Ramshaw IA. Expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox. J Virol 2001;75:1205-1210.

32. Neff JM, Lane JM, Fulginiti VA, Henderson DA. Contact vaccinia -- transmission of vaccinia from smallpox vaccination. JAMA 2002;288:1901-1905.

33. Lane JM, Ruben FL, Abrutyn E, Millar JD. Deaths attributable to smallpox vaccination, 1959 to 1966, and 1968. JAMA 1970;212:441-444.[Medline]

34. Redfield RR, Wright DC, James WD, Jones TS, Brown C, Burke DS. Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease. N Engl J Med 1987;316:673-676.

35. 2000 National industry-specific occupational employment and wage estimates: SIC 806 hospitals. Washington, D.C.: Bureau of Labor Statistics, Department of Labor, 2002. (Also available at http://www.bls.gov/oes/2000/oesi3_806.htm.)