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Addressing challenges for allergists in vaccination to protect against smallpox
Guest editorial
Addressing challenges for allergists in vaccination to protect against smallpox Biodefense planners need look back no farther than 1978 in Birmingham, England, to appreciate the horrific consequences of the airborne release of smallpox virus. As a result of faulty fume hood venting and leaky inspection panels, the virus traveled to the floor above a smallpox research laboratory, leading to the infection and death of a 40-year-old photography technician despite modern medical care.1 Now, 26 years later, when the world needs to prepare for the possibility of a bioterrorist attack, there are still no antiviral drugs for general use in treating smallpox patients, and vaccination remains the foremost strategy in smallpox protection. Smallpox vaccine is of unquestionable efficacy. Its worldwide use is responsible for the eradication of endemic smallpox by 1980. However, the Dryvax vaccine, which is currently being used, is highly reactogenic, causing acute inflammatory changes following administration by multiple punctures of the skin, as well as inducing other more severe adverse reactions.2 Data from the smallpox vaccination program, which has begun anew with military personnel and first-responder health care workers, make clear that smallpox vaccination is fundamentally different now than it was in 1978. Because the smallpox vaccine contains a live poxvirus (vaccinia), which is able to infect, replicate, and cause serious illness unless the immune system responds adequately, those with compromised immune systems should not be vaccinated in nonemergency conditions. Nonemergency smallpox vaccination is now contraindicated in a much greater segment of the population compared with 1978. In the United States alone, this includes nearly 1 million patients with human immunodeficiency virus or acquired immunodeficiency syndrome (http:// www.cdc.gov/hiv/stats.htm), more than 150,000 transplant recipients taking immunosuppressive medications (http:// www.ustransplant.org/srtr.php), and a growing number of individuals treated for autoimmune diseases with certain immunosuppressive and anti-inflammatory drugs. For unknown reasons, atopic dermatitis (AD) has increased 2- to 3-fold in the last 40 years, and vaccinating those individuals is contraindicated due to risk of eczema vaccinatum (EV) (http:// www.bt.cdc.gov/training/smallpoxvaccine/reactions/ec_vac_ frequency.html). These patients are also at risk of severe
Official contribution of the National Institutes of Health; not subject to copyright in the United States.
VOLUME 94, JANUARY, 2005
secondary infections from vaccinia that may be acquired from newly vaccinated family members or coworkers. Additional differences between 2004 and 1978 contribute further to the current complexities of smallpox vaccination. For example, current vaccine recipients are all adults, and for most it is their first smallpox vaccination. Thus, it may not be possible to project expected adult vaccination risks by extrapolating from observations made more than a quarter century ago, when most adults in developed countries had been previously immunized. Currently, with few vaccinated individuals in the population, secondary spread from recent vaccinees has become a new concern. Further, although the impact on smallpox vaccine complications is not established, the widespread use of corticosteroids might increase risk. Corticosteroids are also being used intranasally and by inhalation in patients with allergic rhinitis and asthma, and this administration is thought to be safe, although it was not in practice when smallpox vaccination was routine. Of great concern is the apparent increased prevalence of cardiac adverse events in recent smallpox vaccinations, although likely in part contributed by better methods of detection. Among possible contributing differences may be the older age of primary vaccinees, underlying health state of certain recipients, unrecognized effects of the environment, or changes in the vaccine itself during storage. The smallpox vaccine Dryvax, currently used for both military and civilian vaccinations, is available only from stored material, production having ceased in 1982.3 With this background in mind, the Joint Taskforce on Smallpox Vaccination for Allergists developed the report published in this issue of the Annals to address concerns about smallpox vaccination and responses from the viewpoint of the practicing allergist-immunologist.4 The report deals with important questions that allergists-immunologists will be called on to answer for their patients or when consulting about vaccination or treatment of previously vaccinated individuals with asthma, allergies, or AD. Two complications of smallpox vaccination are particularly noteworthy: EV and myopericarditis. Eczema vaccinatum was previously the most common life-threatening complication of smallpox vaccination. Most cases occurred in individuals with a history of eczema, and it is likely that most of these individuals would now be diagnosed as having AD. The reported incidence of EV in the United States in the 1970s was between 10 and 40 per million vaccines, and the
1
cases occurred almost exclusively in children.5 Individuals with eczema were to be excluded from vaccination. Since 30% to 50% of patients with EV developed this disease after they were vaccinated—not by contacts—a substantial number of individuals must not have been adequately screened for AD in the 1970s. The most severe forms of EV, and nearly all deaths, occurred among the 50% to 70% of children younger than 9 years who acquired EV by exposure to a vaccinated household contact. Interestingly, the summary of serious adverse events from current vaccination of more than 650,000 military and civilian smallpox vaccinations cited in the report in this issue shows not a single case of EV. This welcome result may reflect well-performed screening of potential vaccinees for AD, different immunization practices (current schemes use only 3 punctures for primary vaccination), better postvaccination care, limitations of the sample size, and/or the vaccination of adults only. Current military screening results in an 11% to 34% deferral rate of vaccination,6 presumably because the potential vaccinee and/or close household contact has a history of AD. However, since it is known that many individuals with a history of AD do not provide this information,7 rigorous screening of AD patients must be continued to maintain the current excellent record of avoiding this serious consequence. To identify risks for development of EV and to identify approaches to reduce this risk, the National Institute of Allergy and Infectious Diseases (NIAID) recently awarded contracts for an Atopic Dermatitis and Vaccinia Immunization Network. Previous data suggest that despite inadvertent exposure of large numbers of individuals with AD, only a subset of AD patients is at risk. Several defects, primarily in the skin, have been identified in patients with AD, including defective skin barrier, increased production of TH2 cytokines, decreased production by the skin of antiviral peptides, and decreased plasmacytoid dendritic cells. Individuals with AD are also at increased risk of severe cutaneous infections with other viruses, including eczema herpeticum from dissemination of herpes simplex. Recent studies indicate that patients with AD and eczema herpeticum have earlier onset of AD and higher total serum IgE levels than individuals who have AD without eczema herpeticum. It is anticipated that human and animal studies through the Atopic Dermatitis and Vaccinia Immunization Network will provide considerable additional information, including biomarkers of increased risk of developing EV. In contrast to the absence of EV cases in current smallpox vaccination programs, unexpectedly bad news emerges for myopericarditis. The military reported more than 70 cases in healthy primary vaccinees aged 18 to 43 years; nearly 99% of these patients were male, and all presented with chest pain approximately 10 days after smallpox vaccination (http://www.ha.osd.mil/afeb/meeting/051104meeting/ Eckart%20-%20040506%20AFEB.ppt). What appears to be an even higher rate of suspected and probable myopericarditis, 59 per 100,000 population, was observed in civilian vaccinees (http://www.cdc.gov/nip/acip/minutes.htm, June
2
2003 meeting). At this time, there are no guidelines to screen for those who may be at higher risk of cardiac adverse events from smallpox vaccination. Of high potential significance, a recent report suggests a possible immunologic, rather than infectious, basis for post-smallpox vaccination cardiac inflammation.8 The investigators demonstrated biopsy-proven eosinophilic-lymphocytic myocarditis after smallpox vaccination and further showed that the condition was improved by corticosteroids. This novel insight points to new avenues of research that may lead to better risk evaluation for future vaccinees. Many of the current problems in smallpox vaccination likely trace back to Dryvax itself, which was produced in calf lymph and contains, in addition to live vaccinia virus, antibiotics and potentially bacteria. The NIAID funded the evaluation of vaccination with Dryvax diluted 1:5 and 1:10.9 The study reported successful vaccination with the diluted vaccines as evaluated by vaccinia vesicles and immune responses. The study also found significant reductions in local inflammation and lymphadenopathy in diluted vs undiluted vaccine, but the diluted vaccine resulted in a higher incidence of satellite lesions. The Centers for Disease Control and Prevention oversees a contract to stockpile vaccinia immunoglobulin to treat complications to smallpox vaccination. Licensure of this product is being applied for, which would include the capability of intravenous infusion to treat generalized vaccinia, progressive vaccinia, inadvertent autoinoculation, and, importantly, EV. New smallpox vaccines on the horizon may also greatly reduce risks of future vaccination. The NIAID funded the production of a next-generation live vaccinia virus vaccine grown in Vero cells under serum-free, sterile conditions.10 Batches of the new vaccine have been produced, and application for licensure will be forthcoming. Nevertheless, many adverse events may not be avoidable with vaccines composed of infectious vaccinia virus. The NIAID has recently awarded contracts to produce a supply of modified vaccinia Ankara (MVA), a highly attenuated vaccine strain that does not replicate in mammals.11 MVA is derived from vaccinia passaged more than 500 times in cultured cells. This attenuation process leads to the loss of many viral genes that are nonessential under selection conditions, yielding a virus that has been safely administered to certain at-risk groups and that has been shown to be effective in animal poxvirus challenge studies.11 Although MVA had been used in smallpox vaccination trials in the 1970s, its effectiveness was not conclusive, and use of a virus with the deletion of many genes as compared with vaccinia requires rigorous confirmation that the protective epitopes are retained. If further studies demonstrate safety and effectiveness, MVA may replace the current vaccinia virus vaccine and would, undoubtedly, be much safer to use. Further research should address whether defects in cutaneous immune responses of AD patients may limit effectiveness of MVA in these individuals, that is, whether the same defect(s) that accounts for the capacity of vaccinia
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
to replicate in the skin and cause EV may also result in inadequate immune responses to attenuated vaccines. ACKNOWLEDGMENTS We thank Drs. Gerry Kovacs of NIAID, John Becher of the Centers for Disease Control and Prevention, and D. A. Henderson, US Department of Health and Human Services, Office of the Secretary, Office of the Assistant Secretary for Public Health Emergency Preparedness, for information on vaccine strains and the status of current vaccine and vaccinia immunoglobulin programs. CHARLES J. HACKETT, PHD DANIEL ROTROSEN, MD MARSHALL PLAUT, MD Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland REFERENCES 1. Hawkes N. Smallpox death in Britain challenges presumption of laboratory safety. Science. 1979;203:855– 856. 2. Henderson DA, Borio LL, Lane JM. Smallpox and vaccinia. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia, PA: Saunders; 2004:123–153.
VOLUME 94, JANUARY, 2005
3. Smallpox vaccine no longer available for civilians–United States. MMWR Morb Mortal Wkly Rep. 1983;32:387. 4. Ein D, Gruchalla R, Baker JR, et al. Pre-event smallpox vaccination and postevent exposure and disease: a report of the Joint Task Force on Smallpox Vaccination for Allergists. Ann Allergy Asthma Immunol. 2005;94:4-7. 5. Plaut M, Tinkle SS. Risks of smallpox vaccination: 200 years after Jenner. J Allergy Clin Immunol. 2003;112:683– 685. 6. Grabenstein JD, Winkenwerder W Jr. US military smallpox vaccination program experience. JAMA. 2003;289:3278 –3282. 7. Naleway AL, Belongia EA, Greenlee RT, Kieke BA Jr, Chen RT, Shay DK. Eczematous skin disease and recall of past diagnoses: implications for smallpox vaccination. Ann Intern Med. 2003;139:1–7. 8. Murphy JG, Wright RS, Bruce GK, et al. Eosinophiliclymphocytic myocarditis after smallpox vaccination. Lancet. 2003;362:1378 –1380. 9. Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med. 2002; 346:1265–1274. 10. Weltzin R, Liu J, Pugachev KV, et al. Clonal vaccinia virus grown in cell culture as a new smallpox vaccine. Nat Med. 2003;9:1125–1130. 11. McCurdy LH, Larkin BD, Martin JE, Graham BS. Modified vaccinia Ankara: potential as an alternative smallpox vaccine. Clin Infect Dis. 2004;38:1749 –1753.
3
Addressing challenges for allergists in vaccination to protect against smallpox Biodefense planners need look back no farther than 1978 in Birmingham, England, to appreciate the horrific consequences of the airborne release of smallpox virus. As a result of faulty fume hood venting and leaky inspection panels, the virus traveled to the floor above a smallpox research laboratory, leading to the infection and death of a 40-year-old photography technician despite modern medical care.1 Now, 26 years later, when the world needs to prepare for the possibility of a bioterrorist attack, there are still no antiviral drugs for general use in treating smallpox patients, and vaccination remains the foremost strategy in smallpox protection. Smallpox vaccine is of unquestionable efficacy. Its worldwide use is responsible for the eradication of endemic smallpox by 1980. However, the Dryvax vaccine, which is currently being used, is highly reactogenic, causing acute inflammatory changes following administration by multiple punctures of the skin, as well as inducing other more severe adverse reactions.2 Data from the smallpox vaccination program, which has begun anew with military personnel and first-responder health care workers, make clear that smallpox vaccination is fundamentally different now than it was in 1978. Because the smallpox vaccine contains a live poxvirus (vaccinia), which is able to infect, replicate, and cause serious illness unless the immune system responds adequately, those with compromised immune systems should not be vaccinated in nonemergency conditions. Nonemergency smallpox vaccination is now contraindicated in a much greater segment of the population compared with 1978. In the United States alone, this includes nearly 1 million patients with human immunodeficiency virus or acquired immunodeficiency syndrome (http:// www.cdc.gov/hiv/stats.htm), more than 150,000 transplant recipients taking immunosuppressive medications (http:// www.ustransplant.org/srtr.php), and a growing number of individuals treated for autoimmune diseases with certain immunosuppressive and anti-inflammatory drugs. For unknown reasons, atopic dermatitis (AD) has increased 2- to 3-fold in the last 40 years, and vaccinating those individuals is contraindicated due to risk of eczema vaccinatum (EV) (http:// www.bt.cdc.gov/training/smallpoxvaccine/reactions/ec_vac_ frequency.html). These patients are also at risk of severe
Official contribution of the National Institutes of Health; not subject to copyright in the United States.
VOLUME 94, JANUARY, 2005
secondary infections from vaccinia that may be acquired from newly vaccinated family members or coworkers. Additional differences between 2004 and 1978 contribute further to the current complexities of smallpox vaccination. For example, current vaccine recipients are all adults, and for most it is their first smallpox vaccination. Thus, it may not be possible to project expected adult vaccination risks by extrapolating from observations made more than a quarter century ago, when most adults in developed countries had been previously immunized. Currently, with few vaccinated individuals in the population, secondary spread from recent vaccinees has become a new concern. Further, although the impact on smallpox vaccine complications is not established, the widespread use of corticosteroids might increase risk. Corticosteroids are also being used intranasally and by inhalation in patients with allergic rhinitis and asthma, and this administration is thought to be safe, although it was not in practice when smallpox vaccination was routine. Of great concern is the apparent increased prevalence of cardiac adverse events in recent smallpox vaccinations, although likely in part contributed by better methods of detection. Among possible contributing differences may be the older age of primary vaccinees, underlying health state of certain recipients, unrecognized effects of the environment, or changes in the vaccine itself during storage. The smallpox vaccine Dryvax, currently used for both military and civilian vaccinations, is available only from stored material, production having ceased in 1982.3 With this background in mind, the Joint Taskforce on Smallpox Vaccination for Allergists developed the report published in this issue of the Annals to address concerns about smallpox vaccination and responses from the viewpoint of the practicing allergist-immunologist.4 The report deals with important questions that allergists-immunologists will be called on to answer for their patients or when consulting about vaccination or treatment of previously vaccinated individuals with asthma, allergies, or AD. Two complications of smallpox vaccination are particularly noteworthy: EV and myopericarditis. Eczema vaccinatum was previously the most common life-threatening complication of smallpox vaccination. Most cases occurred in individuals with a history of eczema, and it is likely that most of these individuals would now be diagnosed as having AD. The reported incidence of EV in the United States in the 1970s was between 10 and 40 per million vaccines, and the
1
cases occurred almost exclusively in children.5 Individuals with eczema were to be excluded from vaccination. Since 30% to 50% of patients with EV developed this disease after they were vaccinated—not by contacts—a substantial number of individuals must not have been adequately screened for AD in the 1970s. The most severe forms of EV, and nearly all deaths, occurred among the 50% to 70% of children younger than 9 years who acquired EV by exposure to a vaccinated household contact. Interestingly, the summary of serious adverse events from current vaccination of more than 650,000 military and civilian smallpox vaccinations cited in the report in this issue shows not a single case of EV. This welcome result may reflect well-performed screening of potential vaccinees for AD, different immunization practices (current schemes use only 3 punctures for primary vaccination), better postvaccination care, limitations of the sample size, and/or the vaccination of adults only. Current military screening results in an 11% to 34% deferral rate of vaccination,6 presumably because the potential vaccinee and/or close household contact has a history of AD. However, since it is known that many individuals with a history of AD do not provide this information,7 rigorous screening of AD patients must be continued to maintain the current excellent record of avoiding this serious consequence. To identify risks for development of EV and to identify approaches to reduce this risk, the National Institute of Allergy and Infectious Diseases (NIAID) recently awarded contracts for an Atopic Dermatitis and Vaccinia Immunization Network. Previous data suggest that despite inadvertent exposure of large numbers of individuals with AD, only a subset of AD patients is at risk. Several defects, primarily in the skin, have been identified in patients with AD, including defective skin barrier, increased production of TH2 cytokines, decreased production by the skin of antiviral peptides, and decreased plasmacytoid dendritic cells. Individuals with AD are also at increased risk of severe cutaneous infections with other viruses, including eczema herpeticum from dissemination of herpes simplex. Recent studies indicate that patients with AD and eczema herpeticum have earlier onset of AD and higher total serum IgE levels than individuals who have AD without eczema herpeticum. It is anticipated that human and animal studies through the Atopic Dermatitis and Vaccinia Immunization Network will provide considerable additional information, including biomarkers of increased risk of developing EV. In contrast to the absence of EV cases in current smallpox vaccination programs, unexpectedly bad news emerges for myopericarditis. The military reported more than 70 cases in healthy primary vaccinees aged 18 to 43 years; nearly 99% of these patients were male, and all presented with chest pain approximately 10 days after smallpox vaccination (http://www.ha.osd.mil/afeb/meeting/051104meeting/ Eckart%20-%20040506%20AFEB.ppt). What appears to be an even higher rate of suspected and probable myopericarditis, 59 per 100,000 population, was observed in civilian vaccinees (http://www.cdc.gov/nip/acip/minutes.htm, June
2
2003 meeting). At this time, there are no guidelines to screen for those who may be at higher risk of cardiac adverse events from smallpox vaccination. Of high potential significance, a recent report suggests a possible immunologic, rather than infectious, basis for post-smallpox vaccination cardiac inflammation.8 The investigators demonstrated biopsy-proven eosinophilic-lymphocytic myocarditis after smallpox vaccination and further showed that the condition was improved by corticosteroids. This novel insight points to new avenues of research that may lead to better risk evaluation for future vaccinees. Many of the current problems in smallpox vaccination likely trace back to Dryvax itself, which was produced in calf lymph and contains, in addition to live vaccinia virus, antibiotics and potentially bacteria. The NIAID funded the evaluation of vaccination with Dryvax diluted 1:5 and 1:10.9 The study reported successful vaccination with the diluted vaccines as evaluated by vaccinia vesicles and immune responses. The study also found significant reductions in local inflammation and lymphadenopathy in diluted vs undiluted vaccine, but the diluted vaccine resulted in a higher incidence of satellite lesions. The Centers for Disease Control and Prevention oversees a contract to stockpile vaccinia immunoglobulin to treat complications to smallpox vaccination. Licensure of this product is being applied for, which would include the capability of intravenous infusion to treat generalized vaccinia, progressive vaccinia, inadvertent autoinoculation, and, importantly, EV. New smallpox vaccines on the horizon may also greatly reduce risks of future vaccination. The NIAID funded the production of a next-generation live vaccinia virus vaccine grown in Vero cells under serum-free, sterile conditions.10 Batches of the new vaccine have been produced, and application for licensure will be forthcoming. Nevertheless, many adverse events may not be avoidable with vaccines composed of infectious vaccinia virus. The NIAID has recently awarded contracts to produce a supply of modified vaccinia Ankara (MVA), a highly attenuated vaccine strain that does not replicate in mammals.11 MVA is derived from vaccinia passaged more than 500 times in cultured cells. This attenuation process leads to the loss of many viral genes that are nonessential under selection conditions, yielding a virus that has been safely administered to certain at-risk groups and that has been shown to be effective in animal poxvirus challenge studies.11 Although MVA had been used in smallpox vaccination trials in the 1970s, its effectiveness was not conclusive, and use of a virus with the deletion of many genes as compared with vaccinia requires rigorous confirmation that the protective epitopes are retained. If further studies demonstrate safety and effectiveness, MVA may replace the current vaccinia virus vaccine and would, undoubtedly, be much safer to use. Further research should address whether defects in cutaneous immune responses of AD patients may limit effectiveness of MVA in these individuals, that is, whether the same defect(s) that accounts for the capacity of vaccinia
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
to replicate in the skin and cause EV may also result in inadequate immune responses to attenuated vaccines. ACKNOWLEDGMENTS We thank Drs. Gerry Kovacs of NIAID, John Becher of the Centers for Disease Control and Prevention, and D. A. Henderson, US Department of Health and Human Services, Office of the Secretary, Office of the Assistant Secretary for Public Health Emergency Preparedness, for information on vaccine strains and the status of current vaccine and vaccinia immunoglobulin programs. CHARLES J. HACKETT, PHD DANIEL ROTROSEN, MD MARSHALL PLAUT, MD Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland REFERENCES 1. Hawkes N. Smallpox death in Britain challenges presumption of laboratory safety. Science. 1979;203:855– 856. 2. Henderson DA, Borio LL, Lane JM. Smallpox and vaccinia. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia, PA: Saunders; 2004:123–153.
VOLUME 94, JANUARY, 2005
3. Smallpox vaccine no longer available for civilians–United States. MMWR Morb Mortal Wkly Rep. 1983;32:387. 4. Ein D, Gruchalla R, Baker JR, et al. Pre-event smallpox vaccination and postevent exposure and disease: a report of the Joint Task Force on Smallpox Vaccination for Allergists. Ann Allergy Asthma Immunol. 2005;94:4-7. 5. Plaut M, Tinkle SS. Risks of smallpox vaccination: 200 years after Jenner. J Allergy Clin Immunol. 2003;112:683– 685. 6. Grabenstein JD, Winkenwerder W Jr. US military smallpox vaccination program experience. JAMA. 2003;289:3278 –3282. 7. Naleway AL, Belongia EA, Greenlee RT, Kieke BA Jr, Chen RT, Shay DK. Eczematous skin disease and recall of past diagnoses: implications for smallpox vaccination. Ann Intern Med. 2003;139:1–7. 8. Murphy JG, Wright RS, Bruce GK, et al. Eosinophiliclymphocytic myocarditis after smallpox vaccination. Lancet. 2003;362:1378 –1380. 9. Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med. 2002; 346:1265–1274. 10. Weltzin R, Liu J, Pugachev KV, et al. Clonal vaccinia virus grown in cell culture as a new smallpox vaccine. Nat Med. 2003;9:1125–1130. 11. McCurdy LH, Larkin BD, Martin JE, Graham BS. Modified vaccinia Ankara: potential as an alternative smallpox vaccine. Clin Infect Dis. 2004;38:1749 –1753.
3