AMERICAN ACADEMY OF

POLICY STATEMENT Organizational Principles to Guide and Define the Child Health Care System and/or Improve the Health of All Children

Committee on Infectious

Smallpox

ABSTRACT. After an extensive worldwide eradication period of 7 to 17 days (mean: 12 days), the period of program, the last nonlaboratory case of oc- infectivity begins as an enanthema and a rash char- curred in 1977 in Somalia. In 1972, routine smallpox acterized by maculae progressing to papules, vesi- was discontinued in the United States, cles, and pustules all in the same stage, developing and since 1983, vaccine production has been halted. first on the face and extremities. Patients remain Stockpiled vaccine has been used only for laboratory contagious until the scabs have been shed. Most researchers working on . In recent years, there has been concern that smallpox virus stocks may be patients are sick enough during the prodromal pe- in the hands of bioterrorists, and this concern has been riod to be confined to bed by the time the rash heightened by the terrorist attack on the World Trade develops. For this reason, household contacts, hospi- Center and the Pentagon on September 11, 2001. Because tal workers, and other health care professionals are most of the population is considered to be nonimmune, the most likely individuals to develop secondary there is debate as to whether smallpox immunization cases. should be resumed. This statement reviews the current status of , the adverse effects that were associated with smallpox vaccine in the past, and the OUTCOME, TREATMENT, AND PROTECTION major proposals for vaccine use. The statement provides Case fatality rates of 30% or higher were observed the rationale for a policy based on the so-called ring during epidemics of smallpox. Death, when it oc- strategy recommended by the Centers for curred, was usually a result of viral toxemia associ- Control and Prevention, in which cases of small- pox are rapidly identified, infected individuals are iso- ated with circulating immune complexes. The more lated, and contacts of the infected individuals as well as discrete and sparse the lesions, the better the prog- their contacts are immunized immediately. nosis. Four forms of smallpox are recognized. In addition to typical smallpox (more than 90% of cases), there ABBREVIATIONS. HIV, human immunodeficiency virus; CDC, are 2 forms of variola major, hemorrhagic (character- Centers for Disease Control and Prevention; VIG, im- mune globulin; AAP, American Academy of Pediatrics. ized by hemorrhage into skin lesions and dissemi- nated intravascular coagulation) and malignant or SMALLPOX: THE DISEASE flat type (in which skin lesions do not progress to the mallpox is a highly contagious caused pustular stage but remain flat and soft). Each variant by the DNA virus variola, a member of the occurred in 5% of cases and was associated with a genus . As recently as 1967, mil- 90% to 100% mortality rate. Variola minor, or S alastrim, is associated with a longer incubation pe- lions of smallpox cases per year were reported in Asia and Africa. The last known nonlaboratory case riod, a milder prodromal period, fewer skin lesions, of smallpox occurred in 1977 in Somalia and signaled and a lower mortality rate than variola major or 1 the end of a successful worldwide, decade-long erad- typical smallpox. ication effort. The United States discontinued routine In the absence of preexisting , a favor- childhood immunization against smallpox in 1972 able prognosis is less likely for , the elderly, and routine immunization of health care profession- and pregnant women. Immunodeficiency, whether als in 1976. In 1980, the World Health Organization from immunosuppressive therapy or from human declared that smallpox had been eradicated - immunodeficiency virus (HIV) infection, is likely to fully worldwide. have a negative impact on prognosis. Smallpox is spread most efficiently in droplets or Secondary bacterial of the skin, eyes, aerosols from the oropharynx of infected individu- and respiratory tract can develop and lead to septi- als. Smallpox also can be spread by direct contact cemia and disseminated bacterial disease. Laryngeal with infected lesions or with clothing or bed linens lesions can lead to edema and airway obstruction. contaminated with the virus. After an incubation also may complicate smallpox. Protection from infection was provided in the past by immunizing all children beginning at 1 year of PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad- age. An individual’s concentration of neutralizing emy of Pediatrics. declines significantly over a 5- to 10-year

Downloaded from www.aappublications.org/news by guestPEDIATRICS on September Vol. 26, 1102021 No. 4 October 2002 841 period, and people who were immunized as infants virus stimulates an immune response that cross-re- or children before 1972 are unlikely to remain fully acts with variola and protects the vaccine recipient. protected against disease, but protection against Smallpox vaccine was last used in the general pop- death afforded by antibodies and -mediated im- ulation in the United States in 1971. At that time, the munity may persist for 30 years. risk of serious adverse effects from immunization There is no known effective antiviral agent to treat was judged to be greater than the risk of exposure to smallpox, although there is speculation that cidofo- smallpox, the last nonlaboratory US case of which vir may offer some benefit. Infected patients should occurred in 1949.6 In 1983, distribution of the vaccine receive supportive care, including hydration and to civilian populations was discontinued, and vac- treatment of secondary bacterial infections, when ap- cine production was stopped. Since 1990, when im- propriate. Contacts of infected persons should be munization of military personnel ended, smallpox immunized against smallpox within 3 to 4 days after immunization has been recommended only for lab- exposure. This postexposure immunization provides oratory workers at risk of exposure to orthopoxvi- substantial protection against disease and especially ruses and for researchers using vaccinia virus. Re- against a fatal outcome. sponse teams from the Centers for Disease Control and Prevention (CDC) with special expertise in CURRENT CONCERN ABOUT SMALLPOX smallpox management were immunized in 2001.7 Stocks of smallpox virus were retained in govern- The vaccine also has been given to adult volunteers ment-run laboratories in the United States and the specifically for the purpose of determining whether former Soviet Union. There are reports that, before stored vaccine and diluted vaccine retain immuno- the dissolution of the Soviet Union, smallpox was genicity.8,9 being developed as a weapon of biological war- fare.2,3 In addition, decreasing financial support for EFFECTS AND RISKS OF IMMUNIZATION TO Russian government laboratories in recent years led PREVENT SMALLPOX to concern that the virus and the expertise to prop- Immunization causes a local infection that is pru- agate a large amount of smallpox virus may have ritic and uncomfortable. Fever, malaise, and regional fallen into non-Russian hands. The rapidity with lymphadenitis often occur about a week after immu- which smallpox could spread in the US population nization. The site of immunization develops a papule has led to concern that this agent would present a that matures into a pustule and then a scab that particularly potent threat if it were used as an agent separates by about the third week after immuniza- of .4,5 At this time, there are no validated tion. Reimmunization typically causes a milder le- estimates of the chance of smallpox being introduced sion that develops more quickly. Occasionally, satel- into the US population, but many bioterrorism ex- lite or distant pustules develop when a vaccine perts consider it to be quite unlikely. recipient scratches the pustule and autoinoculates the virus at another site. SMALLPOX VACCINE A major reason not to initiate universal immuni- Smallpox vaccine is associated with the early his- zation in the absence of actual cases of smallpox, tory of immunization. In 1798, re- besides the limited availability of vaccine, is the risk ported that with virus protected of serious complications of immunization. Severe people from smallpox. The only smallpox vaccine complications of immunization include death, post- currently available in the United States is a live-virus vaccinal encephalitis, progressive vaccinia, eczema preparation. The vaccine does not contain variola but vaccinatum, generalized rash, and accidental inocu- contains a related virus, vaccinia, which is distinct lation to the face, eye, or other sites (see Table 1). from the cowpox virus used by Jenner for immuni- Smallpox vaccine has been known for decades to zation. The current vaccine is inoculated into the produce significant adverse effects, especially in im- deltoid area or lateral area of the lower leg using a munocompromised persons. In patients with chronic bifurcated needle with a series of jabs that force a skin conditions, smallpox vaccine can cause a severe, drop of the material beneath the epidermis. Success- sometimes fatal dermatologic involvement termed ful immunization is evident by development of a “.” The list of conditions that pustular lesion at the site. Infection with vaccinia place patients at risk of eczema vaccinatum is long

TABLE 1. Risks of Death and Complications From Smallpox Immunization (per Million Vaccine Recipients)* Complication Age (Years) at Immunization 11–45–19 20ϩ Death (from all complications) 5 0.5 0.5 Unknown Progessive vaccinia (vaccinia gangrenosa) 1 0.5 1 7 Encephalitis 6 2 2.5 4 Eczema vaccinatum 14 44 35 30 Accidental inoculation 507 577 371 606 Generalized rash including hypersensitivity 394 233 140 212 reactions * Sources: J. M. Neff, MD (personal communication, April 2002), and Lane and Millar.12

842 SMALLPOX VACCINEDownloaded from www.aappublications.org/news by guest on September 26, 2021 and includes most disorders that disrupt epidermal sure immunization is recommended for persons who integrity. Atopic dermatitis is the most common dis- have had face-to-face, household contact with or order associated with severe eczema vaccinatum, have been in proximity to a person who has active and people with this disorder may be susceptible smallpox skin lesions, persons who have been in- even if the skin disorder is in remission. Even unim- volved in the care of such an individual, and persons munized susceptible individuals can have such reac- exposed in any way to laboratory specimens or bed- tions if the virus spreads to them from those who ding from an infected patient. Such a plan (referred have been immunized. to as a “ring vaccination” program) would allow the Studies from the 1960s indicate an overall rate of most effective use of available stocks of vaccine while complications of 1254 per million primary immu- exposing a minimal number of individuals to the nized individuals.6,10–12 In the past, vaccinia immune risks of immunization. globulin (VIG) was used to treat and decrease the Variola virus as an agent of bioterrorism has been severity of many of these complications, but only discussed widely, but the difficulty of introducing about 600 doses of VIG currently are available. Using the virus into the population and the limited effects 1968 US data, at least 40 individuals per million of doing so have persuaded most au- immunized developed significant and potentially thorities that the chances of a smallpox outbreak are life-threatening complications for which VIG would very small. Because of the known adverse effects of be used. With the increase in the number of people smallpox immunization (see preceding section and who are immunosuppressed in 2002, the current VIG Table 1), the large number of immunocompromised supply is inadequate. people in the population, and the currently limited Smallpox vaccine is not recommended for people supplies of vaccine and VIG, all stockpiled vaccine is with eczema or other exfoliative skin disorders, for considered an investigational agent and is available pregnant women, or for people with immunodefi- for use by public health authorities only. ciencies, whether primary or secondary. Atopic der- matitis, a genetically based immune abnormality, oc- PROPOSED STRATEGIES FOR IMMUNIZATION curs within the first 5 years of life and affects 15% of The major proposed strategies for smallpox immu- the population.13 nization in the face of a bioterrorism threat include Before its discontinuation, universal smallpox im- mass immunization, voluntary immunization, and munization was recommended in the United States ring vaccination or “surveillance and containment.” for children 1 to 2 years of age. Reimmunization was The proponents of mass immunization claim it to be recommended every 5 years and annually for people the strategy that would most effectively prevent working in endemic areas. The current recommen- spread of disease. They also postulate that a bioter- dation for those individuals at high risk because of rorist would be unlikely to introduce variola into a occupational exposure is immunization every 3 well-immunized population. Those who favor vol- years. People with multiple during untary immunization feel that each individual childhood probably have longer-lasting immunity, should be allowed to weigh the pros and cons of but the degree of protection for those immunized immunization and act according to his or her own before 1972 is unknown. analysis.16 Unfortunately, much of the population is not familiar with the problems and complications of VACCINE: CURRENT STATUS vaccinia immunization. The ring vaccination strategy Currently, smallpox vaccine is stocked in a lyoph- is discussed below, along with reasons why the ilized (freeze-dried) state by the CDC.14 Approxi- American Academy of Pediatrics (AAP) considers mately 15 million doses are available in the United this the best approach at present. States for immunizing military personnel and for controlling a possible outbreak, but this amount is RECOMMENDED STRATEGY: RING VACCINATION not sufficient for the entire US population. Studies (SURVEILLANCE AND CONTAINMENT) conducted in 2001 suggest that the vaccine may be The AAP supports the current CDC recommenda- diluted at least 1:5 to 1:10 and still provide a satis- tion of the strategy known as ring vaccination, also factory response.7,8 Additionally, a previously unac- referred to as surveillance and containment. Using counted-for stock of approximately 85 million doses this approach, if smallpox were introduced in an act of concentrated smallpox vaccine put aside by Aven- of terrorism, infected patients would be isolated. tis Pasteur (Swiftwater, PA) is still biologically ac- Contacts of infected individuals as well as their con- tive.15 In addition, the US government has contracted tacts would then be identified and immunized by for delivery of approximately 200 million doses of specially trained teams of health care professionals. tissue culture-derived vaccinia vaccine, which is cur- This strategy can control a localized outbreak with rently in production but has not gone through the minimal exposure of vulnerable populations to the evaluation steps for approval by the US Food and complications of immunization. The ring strategy is Drug Administration. based on the knowledge that vaccination can prevent In the event of a known bioterrorist release of or ameliorate disease severity if given within 3 to 4 smallpox virus, vaccine would be administered to days of initial exposure and can decrease symptoms exposed individuals. If vaccine is given within 3 to 4 if given within the first week of exposure. days of exposure, immunity can develop before the Immunizing and monitoring a ring of people disease occurs, and this would be expected to pre- around each infected individual and his or her con- vent or ameliorate the severity of disease. Postexpo- tacts would help protect those at the greatest risk of

Downloaded from www.aappublications.org/news by AMERICANguest on September ACADEMY 26, 2021 OF PEDIATRICS 843 contracting the disease and form a buffer of immune is desirable to have patients with smallpox cared for individuals to prevent the spread of disease. This by persons who have been immunized. Thus, na- strategy would be more desirable than a preevent tional, state-based, and local teams of health care mass immunization campaign for the following rea- professionals who already have been immunized sons17: will be trained in all aspects of smallpox investiga- tion and care and will be available to go immediately 1. Focused and immunization com- to the site of a suspected or proven smallpox case. bined with extensive surveillance and isolation of With teams available in every state, approximately cases was the strategy used to eradicate smallpox 10 000 to 20 000 carefully screened individuals will in the successful worldwide program in the 1960s receive smallpox vaccine. and 1970s. For the general population, the ring vaccination 2. In a universal immunization campaign, the num- strategy is recommended for managing those ex- ber of adverse events would be expected to be posed to smallpox. The development of safer vac- higher than in the past because of the number of cines or substantial evidence that a bioterrorism persons with contraindications, some of which threat is more likely than currently believed should might be undiagnosed or unrecognized at the lead to a reevaluation of this policy, including the time of immunization or exposure to individuals possibility of a postattack expansion of the ring of who have recently been immunized (eg, undiag- vaccine recipients. nosed immunosuppressive disorders such as HIV infection or receiving cytotoxic or immunosup- pressive agents for , transplantation, or au- RECOMMENDATIONS toimmune or inflammatory disorders). Severe 1. At present, the AAP supports the ring vaccination vaccinia infections may occur in such vulnerable approach to contain smallpox cases that might individuals and in persons with skin conditions, develop as a result of bioterrorism. including atopic dermatitis, if they come in close 2. Ongoing reassessment of the risk of smallpox as a contact with immunized immunocompetent per- bioterrorism agent is critical; any change in that sons who are shedding vaccinia virus. assessment should be shared with public health 3. In the past, individuals with complications of im- munization were treated with VIG. Current sup- authorities. plies of VIG are not sufficient to treat the number 3. Ongoing attempts to develop a safer and more of patients expected to experience adverse effects effective smallpox vaccine should continue and with a universal immunization campaign. should be supported. Smallpox , includ- 4. In the past, immunization focused on young chil- ing those presently available and those developed dren. Senescence of the could in the future, should be evaluated for safety and make the elderly more susceptible to vaccine-re- immunogenicity in children as well as adults. lated complications, but there is little information 4. Health care professionals throughout the country available regarding the immune response and should be educated regarding identification of complication rate in older individuals. There is smallpox. some experimental evidence to suggest that they 5. The CDC and regional and local public health may have a higher rate of certain complications authorities should have a plan in place to respond from smallpox immunization.18 immediately to a suspected or confirmed case of 5. Current supplies of smallpox vaccine would be smallpox. exhausted quickly if a universal campaign were 6. The public should be educated that the concept of initiated, potentially leaving no vaccine for use if ring vaccination means that some individuals will smallpox cases occurred. be immunized according to a mandatory (no non- 6. Mass preevent immunization would require large medical exemptions) protocol and that quarantine numbers of health care and public health profes- may have to be used (including, possibly, separat- sionals to perform immunization and to monitor ing family members). for and deal with the high number of adverse 7. The public should be educated about the possible events. serious adverse effects of smallpox immunization, 7. Should an outbreak of smallpox occur, initiation especially for children, because surveillance stud- of mass immunization may lead to improper reli- ies demonstrate that they have a higher incidence ance on this strategy to control the outbreak with of adverse effects. less focus on other essential outbreak control mea- sures, such as careful surveillance, contact tracing, Committee on Infectious Diseases, 2001–2002 and isolation of cases. If an outbreak occurred in a Jon S. Abramson, MD, Chairperson locale where there had not been preemptive im- Carol J. Baker, MD munization, there could be inadequate supplies of *Robert S. Baltimore, MD vaccine for areas with the greatest need, and that Margaret C. Fisher, MD *Julia A. McMillan, MD potentially could prolong the epidemic instead of H. Cody Meissner, MD controlling it. Gary D. Overturf, MD Keith R. Powell, MD The AAP supports the opinion of the CDC’s Ad- Charles G. Prober, MD visory Committee on Immunization Practices that it Margaret B. Rennels, MD

844 SMALLPOX VACCINEDownloaded from www.aappublications.org/news by guest on September 26, 2021 Thomas N. Saari, MD weapon: medical and public health management. JAMA. 1999;281: Leonard B. Weiner, MD 2127–2137 4. O’Toole T. Smallpox: an attack scenario. Emerg Infect Dis. 1999;5: 540–546 Ex Officio 5. Meltzer MI, Damon I, LeDuc JW, Millar JD. Modeling potential re- Larry K. Pickering, MD sponses to smallpox as a bioterrorist weapon. Emerg Infect Dis. 2001;7: Red Book Editor 959–969 6. Fauci AS. Smallpox —the need for dialogue. N Engl J Med. 2002;346:1319–1320 Liaisons 7. Breman JG, Henderson DA. Diagnosis and management of smallpox. Lance Chilton, MD N Engl J Med. 2002;346:1300–1308 AAP Practice Action Group 8. Frey SE, Newman FK, Cruz J, et al. Dose-related effects of smallpox Marc Fischer, MD vaccine. N Engl J Med. 2002;346:1275–1280 Centers for Disease Control and Prevention 9. Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and Joanne Embree, MD diluted smallpox vaccine. N Engl J Med. 2002;346:1265–1274 10. Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox Canadian Paediatric Society vaccination, 1968. N Engl J Med. 1969;281:1201–1208 Martin C. Mahoney, MD 11. Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox American Academy of Family Physicians vaccination, 1968: results of ten statewide surveys. J Infect Dis. 1970;122: Dikoe Makhene, MD 303–309 National Institutes of Health 12. Lane JM, Millar JD. Risks of smallpox vaccination complications in the Walter A. Orenstein, MD United States. Am J Epidemiol. 1971;93:238–240 Centers for Disease Control and Prevention 13. Rudikoff D, Lebwohl M. Atopic dermatitis. Lancet. 1998;351:1715–1721 Douglas Pratt, MD 14. Centers for Disease Control and Prevention. Vaccinia (smallpox) Food and Drug Administration vaccine: recommendations of the Advisory Committee on Immuniza- Jeffrey R. Starke, MD tion Practices (ACIP), 2001. MMWR Morb Mortal Wkly Rep. 2001;50(RR- 10):1–25 American Thoracic Society 15. Pear R. A nation challenged: the bioterrorism threat. Frozen smallpox vaccine is still potent, officials say. The New York Times. March 30, Consultant 2002:A8 Edgar O. Ledbetter, MD 16. Bicknell WJ. The case for voluntary smallpox vaccination. N Engl J Med. 2002;346:1323–1325 17. Centers for Disease Control and Prevention, Public Health Emergency Staff Preparedness and Response. Interim smallpox response plan and Martha Cook, MS guidelines. Atlanta, GA: Centers for Disease Control and Prevention; November 2001. Available at: http://www.bt.cdc. gov/DocumentsApp/ *Lead authors Smallpox/RPG/index. asp. Accessed July 18, 2002 18. Koplan JP, Marton KI. Smallpox vaccination revisited. Some observa- REFERENCES tions on the biology of vaccinia. Am J Trop Med Hyg. 1975;24:656–663 1. Koplan JP, Foster SO. Smallpox: clinical types, causes of death, and treatment. J Infect Dis. 1979;140:440–441 2. 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 All policy statements from the American Academy of It. New York, NY: Random House; 1999 Pediatrics automatically expire 5 years after publication unless 3. Henderson DA, Inglesby TV, Bartlett JG, et al. Smallpox as a biological reaffirmed, revised, or retired at or before that time.

Downloaded from www.aappublications.org/news by AMERICANguest on September ACADEMY 26, 2021 OF PEDIATRICS 845 Smallpox Vaccine Committee on Infectious Diseases Pediatrics 2002;110;841 DOI: 10.1542/peds.110.4.841

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/110/4/841 References This article cites 15 articles, 1 of which you can access for free at: http://pediatrics.aappublications.org/content/110/4/841#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Vaccine/Immunization http://www.aappublications.org/cgi/collection/vaccine:immunization_ sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 26, 2021 Smallpox Vaccine Committee on Infectious Diseases Pediatrics 2002;110;841 DOI: 10.1542/peds.110.4.841

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2002 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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