Portal de Periódicos da CAPES

Risks of smallpox vaccination 200 years after Jenner

2003; Elsevier BV; Volume: 112; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2003.07.002

1097-6825

Marshall Plaut,

Dermatology and Skin Diseases

It has been more than 200 years since Dr Edward Jenner performed the first experiment to demonstrate the efficacy of cowpox in preventing smallpox.1Mullin D. Prometheus in Goucestershire: Edward Jenner 1749-1823. J Allergy Clin Immunol. 2003;112:nnn-nnn.Google Scholar Jenner realized that his approach might eventually lead to the eradication of smallpox; indeed, this vision did come true. Because of immunologic cross-reactivity among orthopox viruses, inoculation of cowpox or vaccinia virus protects against smallpox, and smallpox was eradicated throughout the world by 1980. The risk of vaccination exceeded the benefits in the United States, and routine vaccination was discontinued in 1972.Unfortunately, events early in the 21st century have raised the possibility that terrorists will initiate epidemics of smallpox or other severe infectious diseases. Ironically, the remarkable success of vaccination has led to the current situation, in which most of the world has never been vaccinated against smallpox. If terrorists have access to viable smallpox, then much of the world's population is once again at risk for acquiring this contagious disease, which has a mortality rate of 20% to 40%.2Bray M Pathogenesis and potential antiviral therapy of complications of smallpox vaccination.Antiviral Res. 2003; 58: 101-114Crossref PubMed Scopus (86) Google Scholar Vaccinia immunization is also needed for laboratory workers exposed to vaccinia and for protection against other orthopox viruses, such as monkeypox.Effective vaccination against smallpox requires epicutaneous administration of viable vaccinia virus (“scarification”). Immunization results in both an antibody response and a cell-mediated immune response, including cytotoxic T cells.3Engler RJM Kenner J Leung DYM Smallpox vaccination: risk considerations for patients with atopic dermatitis.J Allergy Clin Immunol. 2002; 110: 357-365Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar The relative roles of innate immunity, antibody immunity, and cell-mediated immunity in protection from adverse effects of inoculated vaccinia and smallpox exposure are uncertain.The virulence of vaccinia virus and its epicutaneous route of administration result in a number of adverse effects, including life-threatening complications. The current issue of this Journal presents 4 reviews of topics central to an understanding of the risk of smallpox vaccination. Mullin1Mullin D. Prometheus in Goucestershire: Edward Jenner 1749-1823. J Allergy Clin Immunol. 2003;112:nnn-nnn.Google Scholar provides a historical perspective on Jenner's contributions to the development of an effective vaccine for smallpox. Gruchalla and Jones4Gruchalla RS Jones J Combating high-priority biological agents: what to do with drug-allergic patients and those for whom vaccination is contraindicated?.J Allergy Clin Immunol. 2003; 112: nnn-nnnAbstract Full Text Full Text PDF Scopus (10) Google Scholar review the adverse events associated with prevention and treatment of infectious diseases induced by agents of bioterrorism; they include a discussion of allergic reactions to antibiotics and of adverse reactions to smallpox and other vaccines. Hackett5Hackett CJ Innate immune activation as a broad-spectrum biodefense strategy: prospects and research challenges.J Allergy Clin Immunol. 2003; 112: nnn-nnnAbstract Full Text Full Text PDF Scopus (60) Google Scholar reviews the role of innate immunity in protection against infectious agents. Wollenberg6Wollenberg A Viral infections in atopic dermatitis: pathogenic aspects and clinical management.J Allergy Clin Immunol. 2003; 112: nnn-nnnAbstract Full Text Full Text PDF Scopus (219) Google Scholar reviews cutaneous viral infections in patients with atopic dermatitis (AD) and the abnormalities in cutaneous immunity in these patients that enhance their risk of eczema vaccinatum (EV) from immunization with vaccinia.The adverse effects associated with vaccinia administration have been reviewed by Engler et al,3Engler RJM Kenner J Leung DYM Smallpox vaccination: risk considerations for patients with atopic dermatitis.J Allergy Clin Immunol. 2002; 110: 357-365Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar by Bray,2Bray M Pathogenesis and potential antiviral therapy of complications of smallpox vaccination.Antiviral Res. 2003; 58: 101-114Crossref PubMed Scopus (86) Google Scholar and, in this issue of the Journal, by Gruchalla.4Gruchalla RS Jones J Combating high-priority biological agents: what to do with drug-allergic patients and those for whom vaccination is contraindicated?.J Allergy Clin Immunol. 2003; 112: nnn-nnnAbstract Full Text Full Text PDF Scopus (10) Google Scholar Careful epidemiologic studies in the 1960s identified 3 major life-threatening reactions: postvaccinial encephalitis, progressive vaccinia, and EV. Recent studies have identified a fourth adverse event that is potentially life-threatening: myopericarditis.7Halsell JS Riddle JR Atwood JE Gardner P Shope R Poland GA et al.Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel.JAMA. 2003; 289: 3283-3289Crossref PubMed Scopus (222) Google Scholar Progressive vaccinia occurs in immune-deficient recipients of vaccinia. Much of the risk is associated with a cellular immunodeficiency, though rare individuals with apparent B-cell deficiency are also at risk.3Engler RJM Kenner J Leung DYM Smallpox vaccination: risk considerations for patients with atopic dermatitis.J Allergy Clin Immunol. 2002; 110: 357-365Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 8Kempe CH Studies on smallpox and complications of smallpox vaccination.Pediatrics. 1960; 26: 176-189PubMed Google Scholar The prevalence rates of at-risk individuals, such as those who are carriers of HIV and those who are on immunosuppressive medications, are much higher than they were 30 to 40 years ago.3Engler RJM Kenner J Leung DYM Smallpox vaccination: risk considerations for patients with atopic dermatitis.J Allergy Clin Immunol. 2002; 110: 357-365Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar Most cases of EV occurred in individuals with histories of “eczema,” and most of these individuals probably had what would now be diagnosed as AD. The prevalence of AD has increased substantially in recent years; more than 10% of the population might have histories of this disease, and even greater numbers have household contacts with AD.3Engler RJM Kenner J Leung DYM Smallpox vaccination: risk considerations for patients with atopic dermatitis.J Allergy Clin Immunol. 2002; 110: 357-365Abstract Full Text Full Text PDF PubMed Scopus (127) Google ScholarEV was the most common life-threatening complication of smallpox vaccination, occurring in approximately 10 vaccinees per million in a national survey9Lane JM Ruben FL Neff JM Millar JD Complications of smallpox vaccination, 1968.National surveillance in the United States. N Engl J Med. 1969; 281: 1201-1208PubMed Google Scholar and in approximately 40 vaccinees per million in a more detailed survey that probably identified milder cases.10Lane JM Ruben FL Neff JM Millar JD Complications of smallpox vaccination, 1968: results of ten statewide surveys.J Infect Dis. 1970; 122: 303-309Crossref PubMed Scopus (246) Google Scholar EV is 10-fold more frequent in primary vaccinees than in those revaccinated.9Lane JM Ruben FL Neff JM Millar JD Complications of smallpox vaccination, 1968.National surveillance in the United States. N Engl J Med. 1969; 281: 1201-1208PubMed Google Scholar, 10Lane JM Ruben FL Neff JM Millar JD Complications of smallpox vaccination, 1968: results of ten statewide surveys.J Infect Dis. 1970; 122: 303-309Crossref PubMed Scopus (246) Google Scholar The mortality estimates from untreated EV vary widely—from 1% to 6% to 30% in children under the age of 2 years.3Engler RJM Kenner J Leung DYM Smallpox vaccination: risk considerations for patients with atopic dermatitis.J Allergy Clin Immunol. 2002; 110: 357-365Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 8Kempe CH Studies on smallpox and complications of smallpox vaccination.Pediatrics. 1960; 26: 176-189PubMed Google Scholar Deaths from EV were among children less than 9 years of age, and nearly all cases were from exposure to a vaccinated household contact.11Lane JM Ruben FL Abrutyn E Millar JD Deaths attributable to smallpox vaccination.JAMA. 1970; 212: 441-444Crossref PubMed Scopus (83) Google Scholar There are limited treatments available for life-threatening complications of vaccinia immunization. Whereas anecdotal data suggest that vaccinia immune globulin is effective in treating EV, there are no controlled studies to demonstrate the efficacy of vaccinia immune globulin or of antivirals for EV or other adverse effects of vaccinia.2Bray M Pathogenesis and potential antiviral therapy of complications of smallpox vaccination.Antiviral Res. 2003; 58: 101-114Crossref PubMed Scopus (86) Google ScholarRecent studies have not identified any cases of EV among 450,000 military personnel and 37,000 civilian personnel.12Grabenstein JD Winkenwerder W US military smallpox vaccination program experience.JAMA. 2003; 289: 3278-3282Crossref PubMed Scopus (179) Google Scholar, 13Centers for Disease Control and Prevention Update: cardiac and other adverse events following civilian smallpox vaccinationUnited States, 2003.MMWR Morb Mortal Wkly Rep. 2003; 52: 639-642PubMed Google Scholar This low rate might reflect the modified vaccination scheme (only 3 punctures for primary vaccinees), better postvaccination care of the scarified site, and better screening for individuals with AD and individuals with household contacts with AD. In 2003, the clinical diagnosis of AD is defined by a set of questionnaires, and recent military experience demonstrates that 11% to 34% of eligible personnel deferred vaccination, skin condition being the major reason for deferral.12Grabenstein JD Winkenwerder W US military smallpox vaccination program experience.JAMA. 2003; 289: 3278-3282Crossref PubMed Scopus (179) Google Scholar However, the success of the military experience might need to be interpreted cautiously, inasmuch as recent civilian surveys suggest that 30% to 40% of individuals with histories of AD will not correctly report this history.14Naleway AL Belongia EA Greenlee RT Burney AK Chen RT Shay DK Eczematous skin disease and recall of past diagnoses: implications for smallpox vaccination.Ann Int Med. 2003; 139: 1-7Crossref PubMed Scopus (35) Google ScholarThe number of patients with AD who were vaccinated is unknown, so the risk of EV among these patients is also unknown. Although individuals with “eczema” were supposed to be excluded from mass vaccination campaigns, approximately one half to one third of individuals who developed EV acquired it after vaccinia immunization,9Lane JM Ruben FL Neff JM Millar JD Complications of smallpox vaccination, 1968.National surveillance in the United States. N Engl J Med. 1969; 281: 1201-1208PubMed Google Scholar, 15Copeman PWM Wallace HJ Eczema vaccinatum.Br Med J. 1964; 2: 906-908Crossref PubMed Scopus (76) Google Scholar suggesting that substantial numbers of patients with AD must have been vaccinated inadvertently. The remaining one half to two-thirds of EV cases developed after exposure to household contacts who had been vaccinated.9Lane JM Ruben FL Neff JM Millar JD Complications of smallpox vaccination, 1968.National surveillance in the United States. N Engl J Med. 1969; 281: 1201-1208PubMed Google Scholar, 15Copeman PWM Wallace HJ Eczema vaccinatum.Br Med J. 1964; 2: 906-908Crossref PubMed Scopus (76) Google Scholar It is likely that only a small subset of patients with AD develop EV after exposure to vaccinia. Unfortunately, there are no biomarkers to identify this high-risk subpopulation. The most intriguing approach to identifying the subpopulation is suggested by the data of Wollenberg.6Wollenberg A Viral infections in atopic dermatitis: pathogenic aspects and clinical management.J Allergy Clin Immunol. 2003; 112: nnn-nnnAbstract Full Text Full Text PDF Scopus (219) Google Scholar Individuals with AD who are infected with cutaneous viruses, including both eczema molluscum due to chronic molluscum contagiosum and eczema herpeticum due to disseminated herpes simplex, represent a subset of patients with AD who are likely to be at increased risk for EV, and this subset should be compared with patients with AD who do not have such viral infections.There are at least 4 abnormalities in cutaneous and/or immune function in patients with AD that might be markers of predisposition to EV: defective skin barrier, high TH2 responses, decreased antimicrobial peptides, and decreased plasmacytoid dendritic cells (PDCs). Defective barrier properties of the stratum corneum are associated with greater skin irritancy and inflammation and a lower irritancy threshold. The lower irritancy threshold is attributed in part to the increased number of cutaneous nerve fibers found in AD skin. The increased sensation of itch might cause scratching of the skin and mechanical release of Substance P from nerve endings, which in turn induces cutaneous mast cell release of histamine.16Urashima R Mihara M Cutaneous nerves in atopic dermatitis.A histological and electron microscopic study. Virchows Arch. 1998; 432: 363-370PubMed Google Scholar Other results have identified an increase in TH2 cytokines in acute AD lesions, and these cytokines inhibit antiviral defense in the skin. Furthermore, antimicrobial peptides, a major component of innate antimicrobial/antiviral lytic mechanisms, are relatively diminished in AD skin.17Ong PY Ohtake T Brandt C Strickland I Boguniewicz M Ganz T et al.Endogenous antimicrobial peptides and skin infections in atopic dermatitis.N Engl J Med. 2002; 347: 1151-1160Crossref PubMed Scopus (1620) Google ScholarThrough their overlapping inflammatory and antigen-presenting properties, dendritic cells link innate and adaptive immunity. One subpopulation of dendritic cells, the PDCs, is thought to be viral antigen-presenting cells. PDCs are markedly reduced in the skin of patients with AD, possibly because IL-4 and IL-10, 2 cytokines that are increased in the AD skin, inhibit PDC recruitment.18Wollenberg A Wagner M Gunther S Towarowski A Tuma E Moderer M et al.Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin disease.J Invest Derm. 2002; 119: 1096-1102Crossref PubMed Scopus (373) Google ScholarPoxvirus-induced blockade of immune pathways might act synergistically with AD-induced compromise of adaptive and innate immune pathways to predispose patients with AD to cutaneous viral infections. For example, vaccinia produces homologs of the host interferon pathway, viral IFN α/β binding protein and a soluble viral IFN receptor, that block IFN signaling and promote a virally permissive environment.5Hackett CJ Innate immune activation as a broad-spectrum biodefense strategy: prospects and research challenges.J Allergy Clin Immunol. 2003; 112: nnn-nnnAbstract Full Text Full Text PDF Scopus (60) Google ScholarNew generations of vaccines are intended to protect against threats of bioterrorism and be safe for immunocompromised individuals. Attempts to improve the safety of vaccination against smallpox have focused on developing attenuated versions of vaccinia. One attenuated virus, modified vaccinia Ankara (MVA), is derived from a vaccinia virus that was passaged more than 500 times. Compared to wild-type vaccinia, MVA has many gene deletions and has limited ability to proliferate in mammalian tissue.19Stittelaar KJ Kuiken T de Swart RL van Amerongen G Vos HW Niesters HG et al.Safety of modified vaccinia virus Ankara (MVA) in immune-suppressed macaques.Vaccine. 2001; 19: 3700-3709Crossref PubMed Scopus (158) Google Scholar MVA underwent clinical trials in Europe in the 1970s with some success, but it is difficult to determine which at-risk groups received the vaccine. Should attenuated vaccinia preparations induce adequate immune responses, they might be useful either as an alternate vaccine to wild-type vaccinia or as a pretreatment. Administration of attenuated vaccinia might induce protective antivaccinia immune responses that would permit safer administration of wild-type vaccinia several weeks after administration of the attenuated virus.The effectiveness and long-term protective value of attenuated viruses directed against smallpox in patients with AD and other immunocompromised individuals remain to be determined. It is noteworthy that current research into improvement of smallpox vaccination is limited by our success in eradicating smallpox. Until the 1970s, smallpox vaccine efficacy was evaluated in populations naturally exposed to smallpox. Since then, vaccine efficacy has not been evaluated because there has been no population exposed to smallpox. In contrast, in the late 1700s the only available protection against smallpox was variolation, or inoculation of a small amount of smallpox. The mortality rate from variolation was initially approximately 2% and subsequently somewhat lower, but variolation apparently protected against the high mortality of natural exposure to smallpox.1Mullin D. Prometheus in Goucestershire: Edward Jenner 1749-1823. J Allergy Clin Immunol. 2003;112:nnn-nnn.Google Scholar Jenner evaluated the success of his new therapy by a challenge with live smallpox, an approach that would now be considered unethical.The complexity of vaccine development for immunocompromised individuals is highlighted by the inability of the at-risk population to mount an adequate antivaccinia immune response, so they almost certainly do not make an adequate anti-smallpox response. Research on smallpox vaccination had been performed before recent advances in immunology. New immunologic knowledge, as well as substantial technical advances in fields such as genomics, molecular biology, and bioinformatics, should in the future provide an array of tools by which we can understand the immune and gene expression response to viruses of normal and susceptible individuals, including responses in subsets of patients with AD.20Wright ME Fauci AS Smallpox immunization in the 21st century: the old and the new.JAMA. 2003; 289: 3306-3308Crossref PubMed Scopus (8) Google Scholar These data should result in the identification of biomarkers of susceptibility to adverse events and in the development of improved vaccines. Athough the reemergence of smallpox is potentially devastating to the world community, future research promises to develop new immunotherapeutic approaches so that even at-risk individuals will be able to be protected from smallpox. It has been more than 200 years since Dr Edward Jenner performed the first experiment to demonstrate the efficacy of cowpox in preventing smallpox.1Mullin D. Prometheus in Goucestershire: Edward Jenner 1749-1823. J Allergy Clin Immunol. 2003;112:nnn-nnn.Google Scholar Jenner realized that his approach might eventually lead to the eradication of smallpox; indeed, this vision did come true. Because of immunologic cross-reactivity among orthopox viruses, inoculation of cowpox or vaccinia virus protects against smallpox, and smallpox was eradicated throughout the world by 1980. The risk of vaccination exceeded the benefits in the United States, and routine vaccination was discontinued in 1972. Unfortunately, events early in the 21st century have raised the possibility that terrorists will initiate epidemics of smallpox or other severe infectious diseases. Ironically, the remarkable success of vaccination has led to the current situation, in which most of the world has never been vaccinated against smallpox. If terrorists have access to viable smallpox, then much of the world's population is once again at risk for acquiring this contagious disease, which has a mortality rate of 20% to 40%.2Bray M Pathogenesis and potential antiviral therapy of complications of smallpox vaccination.Antiviral Res. 2003; 58: 101-114Crossref PubMed Scopus (86) Google Scholar Vaccinia immunization is also needed for laboratory workers exposed to vaccinia and for protection against other orthopox viruses, such as monkeypox. Effective vaccination against smallpox requires epicutaneous administration of viable vaccinia virus (“scarification”). Immunization results in both an antibody response and a cell-mediated immune response, including cytotoxic T cells.3Engler RJM Kenner J Leung DYM Smallpox vaccination: risk considerations for patients with atopic dermatitis.J Allergy Clin Immunol. 2002; 110: 357-365Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar The relative roles of innate immunity, antibody immunity, and cell-mediated immunity in protection from adverse effects of inoculated vaccinia and smallpox exposure are uncertain. The virulence of vaccinia virus and its epicutaneous route of administration result in a number of adverse effects, including life-threatening complications. The current issue of this Journal presents 4 reviews of topics central to an understanding of the risk of smallpox vaccination. Mullin1Mullin D. Prometheus in Goucestershire: Edward Jenner 1749-1823. J Allergy Clin Immunol. 2003;112:nnn-nnn.Google Scholar provides a historical perspective on Jenner's contributions to the development of an effective vaccine for smallpox. Gruchalla and Jones4Gruchalla RS Jones J Combating high-priority biological agents: what to do with drug-allergic patients and those for whom vaccination is contraindicated?.J Allergy Clin Immunol. 2003; 112: nnn-nnnAbstract Full Text Full Text PDF Scopus (10) Google Scholar review the adverse events associated with prevention and treatment of infectious diseases induced by agents of bioterrorism; they include a discussion of allergic reactions to antibiotics and of adverse reactions to smallpox and other vaccines. Hackett5Hackett CJ Innate immune activation as a broad-spectrum biodefense strategy: prospects and research challenges.J Allergy Clin Immunol. 2003; 112: nnn-nnnAbstract Full Text Full Text PDF Scopus (60) Google Scholar reviews the role of innate immunity in protection against infectious agents. Wollenberg6Wollenberg A Viral infections in atopic dermatitis: pathogenic aspects and clinical management.J Allergy Clin Immunol. 2003; 112: nnn-nnnAbstract Full Text Full Text PDF Scopus (219) Google Scholar reviews cutaneous viral infections in patients with atopic dermatitis (AD) and the abnormalities in cutaneous immunity in these patients that enhance their risk of eczema vaccinatum (EV) from immunization with vaccinia. The adverse effects associated with vaccinia administration have been reviewed by Engler et al,3Engler RJM Kenner J Leung DYM Smallpox vaccination: risk considerations for patients with atopic dermatitis.J Allergy Clin Immunol. 2002; 110: 357-365Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar by Bray,2Bray M Pathogenesis and potential antiviral therapy of complications of smallpox vaccination.Antiviral Res. 2003; 58: 101-114Crossref PubMed Scopus (86) Google Scholar and, in this issue of the Journal, by Gruchalla.4Gruchalla RS Jones J Combating high-priority biological agents: what to do with drug-allergic patients and those for whom vaccination is contraindicated?.J Allergy Clin Immunol. 2003; 112: nnn-nnnAbstract Full Text Full Text PDF Scopus (10) Google Scholar Careful epidemiologic studies in the 1960s identified 3 major life-threatening reactions: postvaccinial encephalitis, progressive vaccinia, and EV. Recent studies have identified a fourth adverse event that is potentially life-threatening: myopericarditis.7Halsell JS Riddle JR Atwood JE Gardner P Shope R Poland GA et al.Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel.JAMA. 2003; 289: 3283-3289Crossref PubMed Scopus (222) Google Scholar Progressive vaccinia occurs in immune-deficient recipients of vaccinia. Much of the risk is associated with a cellular immunodeficiency, though rare individuals with apparent B-cell deficiency are also at risk.3Engler RJM Kenner J Leung DYM Smallpox vaccination: risk considerations for patients with atopic dermatitis.J Allergy Clin Immunol. 2002; 110: 357-365Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 8Kempe CH Studies on smallpox and complications of smallpox vaccination.Pediatrics. 1960; 26: 176-189PubMed Google Scholar The prevalence rates of at-risk individuals, such as those who are carriers of HIV and those who are on immunosuppressive medications, are much higher than they were 30 to 40 years ago.3Engler RJM Kenner J Leung DYM Smallpox vaccination: risk considerations for patients with atopic dermatitis.J Allergy Clin Immunol. 2002; 110: 357-365Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar Most cases of EV occurred in individuals with histories of “eczema,” and most of these individuals probably had what would now be diagnosed as AD. The prevalence of AD has increased substantially in recent years; more than 10% of the population might have histories of this disease, and even greater numbers have household contacts with AD.3Engler RJM Kenner J Leung DYM Smallpox vaccination: risk considerations for patients with atopic dermatitis.J Allergy Clin Immunol. 2002; 110: 357-365Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar EV was the most common life-threatening complication of smallpox vaccination, occurring in approximately 10 vaccinees per million in a national survey9Lane JM Ruben FL Neff JM Millar JD Complications of smallpox vaccination, 1968.National surveillance in the United States. N Engl J Med. 1969; 281: 1201-1208PubMed Google Scholar and in approximately 40 vaccinees per million in a more detailed survey that probably identified milder cases.10Lane JM Ruben FL Neff JM Millar JD Complications of smallpox vaccination, 1968: results of ten statewide surveys.J Infect Dis. 1970; 122: 303-309Crossref PubMed Scopus (246) Google Scholar EV is 10-fold more frequent in primary vaccinees than in those revaccinated.9Lane JM Ruben FL Neff JM Millar JD Complications of smallpox vaccination, 1968.National surveillance in the United States. N Engl J Med. 1969; 281: 1201-1208PubMed Google Scholar, 10Lane JM Ruben FL Neff JM Millar JD Complications of smallpox vaccination, 1968: results of ten statewide surveys.J Infect Dis. 1970; 122: 303-309Crossref PubMed Scopus (246) Google Scholar The mortality estimates from untreated EV vary widely—from 1% to 6% to 30% in children under the age of 2 years.3Engler RJM Kenner J Leung DYM Smallpox vaccination: risk considerations for patients with atopic dermatitis.J Allergy Clin Immunol. 2002; 110: 357-365Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 8Kempe CH Studies on smallpox and complications of smallpox vaccination.Pediatrics. 1960; 26: 176-189PubMed Google Scholar Deaths from EV were among children less than 9 years of age, and nearly all cases were from exposure to a vaccinated household contact.11Lane JM Ruben FL Abrutyn E Millar JD Deaths attributable to smallpox vaccination.JAMA. 1970; 212: 441-444Crossref PubMed Scopus (83) Google Scholar There are limited treatments available for life-threatening complications of vaccinia immunization. Whereas anecdotal data suggest that vaccinia immune globulin is effective in treating EV, there are no controlled studies to demonstrate the efficacy of vaccinia immune globulin or of antivirals for EV or other adverse effects of vaccinia.2Bray M Pathogenesis and potential antiviral therapy of complications of smallpox vaccination.Antiviral Res. 2003; 58: 101-114Crossref PubMed Scopus (86) Google Scholar Recent studies have not identified any cases of EV among 450,000 military personnel and 37,000 civilian personnel.12Grabenstein JD Winkenwerder W US military smallpox vaccination program experience.JAMA. 2003; 289: 3278-3282Crossref PubMed Scopus (179) Google Scholar, 13Centers for Disease Control and Prevention Update: cardiac and other adverse events following civilian smallpox vaccinationUnited States, 2003.MMWR Morb Mortal Wkly Rep. 2003; 52: 639-642PubMed Google Scholar This low rate might reflect the modified vaccination scheme (only 3 punctures for primary vaccinees), better postvaccination care of the scarified site, and better screening for individuals with AD and individuals with household contacts with AD. In 2003, the clinical diagnosis of AD is defined by a set of questionnaires, and recent military experience demonstrates that 11% to 34% of eligible personnel deferred vaccination, skin condition being the major reason for deferral.12Grabenstein JD Winkenwerder W US military smallpox vaccination program experience.JAMA. 2003; 289: 3278-3282Crossref PubMed Scopus (179) Google Scholar However, the success of the military experience might need to be interpreted cautiously, inasmuch as recent civilian surveys suggest that 30% to 40% of individuals with histories of AD will not correctly report this history.14Naleway AL Belongia EA Greenlee RT Burney AK Chen RT Shay DK Eczematous skin disease and recall of past diagnoses: implications for smallpox vaccination.Ann Int Med. 2003; 139: 1-7Crossref PubMed Scopus (35) Google Scholar The number of patients with AD who were vaccinated is unknown, so the risk of EV among these patients is also unknown. Although individuals with “eczema” were supposed to be excluded from mass vaccination campaigns, approximately one half to one third of individuals who developed EV acquired it after vaccinia immunization,9Lane JM Ruben FL Neff JM Millar JD Complications of smallpox vaccination, 1968.National surveillance in the United States. N Engl J Med. 1969; 281: 1201-1208PubMed Google Scholar, 15Copeman PWM Wallace HJ Eczema vaccinatum.Br Med J. 1964; 2: 906-908Crossref PubMed Scopus (76) Google Scholar suggesting that substantial numbers of patients with AD must have been vaccinated inadvertently. The remaining one half to two-thirds of EV cases developed after exposure to household contacts who had been vaccinated.9Lane JM Ruben FL Neff JM Millar JD Complications of smallpox vaccination, 1968.National surveillance in the United States. N Engl J Med. 1969; 281: 1201-1208PubMed Google Scholar, 15Copeman PWM Wallace HJ Eczema vaccinatum.Br Med J. 1964; 2: 906-908Crossref PubMed Scopus (76) Google Scholar It is likely that only a small subset of patients with AD develop EV after exposure to vaccinia. Unfortunately, there are no biomarkers to identify this high-risk subpopulation. The most intriguing approach to identifying the subpopulation is suggested by the data of Wollenberg.6Wollenberg A Viral infections in atopic dermatitis: pathogenic aspects and clinical management.J Allergy Clin Immunol. 2003; 112: nnn-nnnAbstract Full Text Full Text PDF Scopus (219) Google Scholar Individuals with AD who are infected with cutaneous viruses, including both eczema molluscum due to chronic molluscum contagiosum and eczema herpeticum due to disseminated herpes simplex, represent a subset of patients with AD who are likely to be at increased risk for EV, and this subset should be compared with patients with AD who do not have such viral infections. There are at least 4 abnormalities in cutaneous and/or immune function in patients with AD that might be markers of predisposition to EV: defective skin barrier, high TH2 responses, decreased antimicrobial peptides, and decreased plasmacytoid dendritic cells (PDCs). Defective barrier properties of the stratum corneum are associated with greater skin irritancy and inflammation and a lower irritancy threshold. The lower irritancy threshold is attributed in part to the increased number of cutaneous nerve fibers found in AD skin. The increased sensation of itch might cause scratching of the skin and mechanical release of Substance P from nerve endings, which in turn induces cutaneous mast cell release of histamine.16Urashima R Mihara M Cutaneous nerves in atopic dermatitis.A histological and electron microscopic study. Virchows Arch. 1998; 432: 363-370PubMed Google Scholar Other results have identified an increase in TH2 cytokines in acute AD lesions, and these cytokines inhibit antiviral defense in the skin. Furthermore, antimicrobial peptides, a major component of innate antimicrobial/antiviral lytic mechanisms, are relatively diminished in AD skin.17Ong PY Ohtake T Brandt C Strickland I Boguniewicz M Ganz T et al.Endogenous antimicrobial peptides and skin infections in atopic dermatitis.N Engl J Med. 2002; 347: 1151-1160Crossref PubMed Scopus (1620) Google Scholar Through their overlapping inflammatory and antigen-presenting properties, dendritic cells link innate and adaptive immunity. One subpopulation of dendritic cells, the PDCs, is thought to be viral antigen-presenting cells. PDCs are markedly reduced in the skin of patients with AD, possibly because IL-4 and IL-10, 2 cytokines that are increased in the AD skin, inhibit PDC recruitment.18Wollenberg A Wagner M Gunther S Towarowski A Tuma E Moderer M et al.Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin disease.J Invest Derm. 2002; 119: 1096-1102Crossref PubMed Scopus (373) Google Scholar Poxvirus-induced blockade of immune pathways might act synergistically with AD-induced compromise of adaptive and innate immune pathways to predispose patients with AD to cutaneous viral infections. For example, vaccinia produces homologs of the host interferon pathway, viral IFN α/β binding protein and a soluble viral IFN receptor, that block IFN signaling and promote a virally permissive environment.5Hackett CJ Innate immune activation as a broad-spectrum biodefense strategy: prospects and research challenges.J Allergy Clin Immunol. 2003; 112: nnn-nnnAbstract Full Text Full Text PDF Scopus (60) Google Scholar New generations of vaccines are intended to protect against threats of bioterrorism and be safe for immunocompromised individuals. Attempts to improve the safety of vaccination against smallpox have focused on developing attenuated versions of vaccinia. One attenuated virus, modified vaccinia Ankara (MVA), is derived from a vaccinia virus that was passaged more than 500 times. Compared to wild-type vaccinia, MVA has many gene deletions and has limited ability to proliferate in mammalian tissue.19Stittelaar KJ Kuiken T de Swart RL van Amerongen G Vos HW Niesters HG et al.Safety of modified vaccinia virus Ankara (MVA) in immune-suppressed macaques.Vaccine. 2001; 19: 3700-3709Crossref PubMed Scopus (158) Google Scholar MVA underwent clinical trials in Europe in the 1970s with some success, but it is difficult to determine which at-risk groups received the vaccine. Should attenuated vaccinia preparations induce adequate immune responses, they might be useful either as an alternate vaccine to wild-type vaccinia or as a pretreatment. Administration of attenuated vaccinia might induce protective antivaccinia immune responses that would permit safer administration of wild-type vaccinia several weeks after administration of the attenuated virus. The effectiveness and long-term protective value of attenuated viruses directed against smallpox in patients with AD and other immunocompromised individuals remain to be determined. It is noteworthy that current research into improvement of smallpox vaccination is limited by our success in eradicating smallpox. Until the 1970s, smallpox vaccine efficacy was evaluated in populations naturally exposed to smallpox. Since then, vaccine efficacy has not been evaluated because there has been no population exposed to smallpox. In contrast, in the late 1700s the only available protection against smallpox was variolation, or inoculation of a small amount of smallpox. The mortality rate from variolation was initially approximately 2% and subsequently somewhat lower, but variolation apparently protected against the high mortality of natural exposure to smallpox.1Mullin D. Prometheus in Goucestershire: Edward Jenner 1749-1823. J Allergy Clin Immunol. 2003;112:nnn-nnn.Google Scholar Jenner evaluated the success of his new therapy by a challenge with live smallpox, an approach that would now be considered unethical. The complexity of vaccine development for immunocompromised individuals is highlighted by the inability of the at-risk population to mount an adequate antivaccinia immune response, so they almost certainly do not make an adequate anti-smallpox response. Research on smallpox vaccination had been performed before recent advances in immunology. New immunologic knowledge, as well as substantial technical advances in fields such as genomics, molecular biology, and bioinformatics, should in the future provide an array of tools by which we can understand the immune and gene expression response to viruses of normal and susceptible individuals, including responses in subsets of patients with AD.20Wright ME Fauci AS Smallpox immunization in the 21st century: the old and the new.JAMA. 2003; 289: 3306-3308Crossref PubMed Scopus (8) Google Scholar These data should result in the identification of biomarkers of susceptibility to adverse events and in the development of improved vaccines. Athough the reemergence of smallpox is potentially devastating to the world community, future research promises to develop new immunotherapeutic approaches so that even at-risk individuals will be able to be protected from smallpox.