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The US smallpox vaccination program: a review of a large modern era smallpox vaccination implementation program
Vaccine 23 (2005) 2078–2081
The US smallpox vaccination program: a review of a large modern era smallpox vaccination implementation program Gregory A. Poland a, ∗ , John D. Grabenstein b , John M. Neff c a
Mayo Vaccine Research Group, and Department of Medicine, Program in Translational Immunovirology and Biodefense, 611 C Guggenheim Building, 200 First Street, SW, Mayo Clinic and Foundation, Rochester, Minnesota, MN, USA b Military Vaccine Agency, United States Army Surgeon General’s Office, Falls Church, VA, USA c Center for Children with Special Needs, Children’s Hospital and Regional Medical Center, Seattle, WA, USA Available online 4 February 2005
Abstract We describe the US experience with a large-scale smallpox vaccination program in the modern era and quantify the anticipated and unanticipated local and systemic side-effects of smallpox vaccination. In addition, we review unexpected issues, such as the development of myopericarditis discovered during the implementation of this program. These results constitute the largest dataset of a vaccinia vaccination program utilizing calf-lymph derived New York City Board of Health strain vaccine (Dryvax, Wyeth) since the 1970s. These results should inform current and future vaccinia vaccination programs and provide a historical rate of complications against which candidate vaccine side-effects can be compared in future clinical trials. © 2005 Elsevier Ltd. All rights reserved. Keywords: Smallpox vaccine; Smallpox; Smallpox vaccine side effects
1. Introduction It is important to understand the historical context for the use of calf-derived smallpox vaccine. Routine smallpox vaccination ceased in the US by the mid 1970s. Smallpox was declared eradicated from the world by the World Health Organization (WHO) in 1980 [1]. US military use of smallpox vaccine was restricted to new trainees in 1984 and then discontinued entirely in 1990. Restoration of the US National Smallpox Vaccination Program was announced on 13 December 2002 by President George W. Bush.
夽 Disclaimer: The views expressed are those of the authors and do not represent the official position of the United States Government, the Centers for Disease Control, or the Armed Forces Epidemiological Board. ∗ Corresponding author. Tel.: +1 507 284 4456; fax: +1 507 266 4187. E-mail address: [email protected] (G.A. Poland).
0264-410X/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2005.01.012
The major concern regarding implementation of a largescale smallpox vaccination program was serious adverse events. A literature review suggested that the total incidence of major complications was 572 out of 14,168,000 vaccinations during a US surveillance program in 1968 [2]. An examination of worldwide reports from 1924 through the 1960s demonstrated a strain-dependent incidence of encephalitis between 2 and 1200 per million vaccinations, an incidence of encephalopathy between 3 and 50 per million vaccinations, eczema vaccinatum between 8 and 80 per million vaccinations, progressive vaccinia at 1 per million vaccinations, and generalized vaccinia at an incidence of 1–70 per million vaccinations [3]. Notably, only five cases of myopericarditis were reported in the literature between 1955 and 1986 utilizing the US vaccine (Dryvax, Wyeth). The Finnish strain of smallpox vaccine was reported to have an estimated incidence of postvaccination clinical myopericarditis as high as 1 in 10,000 among Finnish military conscripts in 1983 [4]. Finally, myopericarditis following smallpox vaccination was reported in
G.A. Poland et al. / Vaccine 23 (2005) 2078–2081
only 8 suspected cases of over 5,000,000 vaccinees in Australia [5]. In response to concerns about the use of smallpox as a weapon of biologic terrorism, President Bush announced the initiation of the two-pronged US Smallpox Vaccination Program in December 2002. The first program would be carried out under the auspices of the Department of Health and Human Services (DHHS) and was designed to immunize a cohort of health care workers and first responders who could respond in the event of a smallpox outbreak. Hence, this program would involve members of the US Public Health Service (PHS) and civilians. The DHHS Smallpox Vaccination Program vaccinated ∼39,500 people. Thirtysix percent of these individuals received primary vaccination while 64% were revaccinees. Approximately 36% of the DHHS vaccinees were male (64% female) with a median age of 48 years with a mean of 47.1 years (±9.5 years). In contrast, the second and larger program would be carried out under the auspices of the US Department of Defense (DoD). For the military population, stage 1A was designed to provide vaccine to smallpox epidemic response teams and involve 2000 to 5000 people beginning in mid-December 2002. Stage 1b was designed to immunize medical teams numbering 10,000–25,000 people beginning in early January 2003. Stage 2 was designed initially to provide vaccine protection to 500,000 mission-critical forces beginning in early January 2003 [6]. As of January 2005, the DoD program had screened 790,000 service members, of which 730,580 actually received smallpox vaccine. Seventy-one percent (515,351) received primary immunization, and 29% (215,229) were revaccinated. Eighty-nine percent (646,676) of the vaccinees were male (11% female). The median age of all vaccine recipients was 26 years with a mean of 28.5 years (±8.5 years). Notably, both the DoD and DHHS smallpox vaccination programs started in December 2002 and peaked by March 2003. Since that time, smaller numbers of vaccinees, in a maintenance phase, have been immunized.
2079
2. Anticipated preventable adverse events Both programs were highly successful in terms of the safety with which they were implemented. Multiple concerns had been raised publicly and in the literature regarding fears of large numbers of people suffering severe systemic effects and of both contact and nosocomial transmission of vaccinia virus. In fact, screening and education successes were such that not a single case of eczema vaccinatum, progressive vaccinia, fetal vaccinia, or workplace contact transmission occurred, despite implementation of the vaccination program at hundreds, if not thousands, of different vaccination clinics. As of January 2005, noteworthy events among 730,580 DoD vaccinees included one case of encephalitis, now fully recovered, (note: there is one case of post-vaccinal encephalitis in the civilian population and that individual has some persistent memory loss and has not fully recovered); 43 cases of generalized vaccinia, all of which were mild and recovered, (a careful review of the reported cases of generalized vaccines by consulting dermatologists suggest that these cases represent hypersensitivity reactions); inadvertent infection occurring in the skin among 62 vaccinees and 50 contacts of vaccinees; inadvertent infection of the eye occurring in 16 vaccinees and in 2 contacts of vaccinees. Of note, the main risks for contact transfer were family and intimate contacts occurring in 22 family members, 18 adult intimate contacts, 12 friends, and no patients or coworkers of vaccinees. Also of note, vaccinia immune globulin treatment was instituted in only three cases: one burn patient and two with auto-inoculation of the eye (one auto-inoculation, one contact). Table 1 provides details of the anticipated adverse events reports both for the DoD and DHHS Smallpox Vaccination Programs.
3. Unanticipated effects of smallpox vaccination Unanticipated effects of smallpox vaccination also occurred. As of October 2004, 24 DoD vaccinees were admitted to the hospital with myocardial ischemia 2–24 days after
Table 1 Anticipated smallpox vaccine events DoD (n = 730,580) as of 4 January 2005
DHHS (n = 40,422) as of 31 January 04
Preventable Eczema vaccinatum Progressive vaccinia Fetal vaccinia Contact transmission-nosocomial Contact transmission-not Nosocomial Auto-inoculation—non-ocular Auto-inoculation—ocular
0 0 0 0 50 Secondary 2 Tertiary 62 16
0 0 0 0 0
Not preventable Generalized vaccinia All mild, no sequela Post-vaccination encephalitis
35 Suspect 8 Probable 1
2 Suspect 1 Confirmed 1
20 3
2080
G.A. Poland et al. / Vaccine 23 (2005) 2078–2081 Table 4 Unanticipated cardiac event-myopericarditis after smallpox vaccination
Table 2 Cardiac ischemic events after smallpox vaccination DoD* Ischemic events as admission Diagnosis Angina Myocardial infarction Fatal MI
DHHS+
24 5 13 1/13
9 3 6 2/6
DoD*: expected ischemic admissions in a 2-week window = 40 (upper 95% CI: 48); expected cardiac deaths per year—US Army = 50. DHHS+: expected rate of MI in a 3-week window = 2 (upper 95% CI: 5.4); expected rate of angina in a 3-week window = 10.
receiving vaccine. Myocardial infarction incurred in 13 subjects, 1 with fatality, 5 with angina, and 6 with atherosclerotic coronary vascular disease, with 2 of those cases being fatal. The admission diagnosis was changed to myocarditis in 6 of these cases. Of note, the expected incidence of admission for ischemia age-adjusted for this population over a 14-day window was 40 admissions with an upper 95% confidence limit of 48. Among the four fatalities, it is clear that these individuals had significant pre-existing cardiovascular disease. One was a 55-year-old smoker with three-vessel occlusion, left ventricular hypertrophy and cardiomegaly. Another was a 47-year-old who died after physical exertion and was found to have severe atherosclerotic cardiovascular disease with twovessel occlusion. This individual had a 15-year history of smoking. Yet another was a 31-year-old with three-vessel occlusion, left ventricular hypertrophy and a significant family history of his father dying of an MI at age 39. After reviewing their medical records, a committee of experts concluded that ischemia after smallpox vaccination did not exceed the expected level in unvaccinated people within the DoD population. Table 2 provides details of the ischemic cardiac events among vaccinees in the DoD and the DHHS smallpox vaccination programs. An additional unanticipated adverse event was dilated cardiomyopathy including four cases in the DoD program and three in the DHHS program. Table 3 provides details of this condition. Notably, an unanticipated adverse event was myopericarditis. Table 4 provides details of the number of known cases in both DoD and DHHS programs. Table 3 Unanticipated events under investigation after smallpox vaccination-dilated cardiomyopathy DoD (n = 730,580) as of 4 January 2005 Dilated cardiomyopathy 4 3 Re-vaccinees 1 Primary 4 Male Ages 34, 37, 42, 44 Onset recognized 5, 22, 23, 29 Weeks after smallpox vaccination
DHHS (n = 40,449) as of 13 February 04 3* (*1 Still pending review) 3 Re-vaccinees 2 Female, 1 male* Ages 53, 55, 56* Onsets recognized ∼2*, 2.6, and 3.3 months after smallpox vaccination
DoD (n = 730,580) as of 4 January 2005
DHHS (n = 40,422) as of 31 January 04
Myopericarditis 86
21
8 Suspected 74 Probable 4 Confirmed
16 Suspected 5 Probable 0 Confirmed
Overall, 86 cases of myopericarditis have occurred among DoD vaccinees, graded as 8 suspect, 74 probable, and 4 biopsy-confirmed (see Table 4). A report of the details of the first 18 cases has been published [7]. In US military personnel vaccinated against smallpox, the observed incidence of 16.11 per 100,000 vaccinees of myopericarditis over a 30-day observation window among 347,516 primary vaccinees was nearly 7.5-fold higher than the expected rate of 2.16 per 100,000 (95% confidence intervals 1.90–2.34) among non-vaccinated active duty military personnel. Also notable was that the incidence of myopericarditis among revaccinees (2.07 per 100,000 among 145,155 revaccinees) was not statistically different from the expected background rate. In the DoD cohort, cases of myopericarditis occurred predominantly among males (98%) and those of Caucasian race (86.4%) both statistically significant associations P = 0.015 and P = 0.005, respectively [8]. In the 64 subjects who have been intensively followed, all have recovered normal heart function based on ECG, echocardiogram and treadmill stress tests [9]. Again, these cases were intensively reviewed by a committee of experts and the conclusion was the smallpox vaccination increased the risk of myopericarditis among adult primary vaccinees, specifically and disproportionately among male vaccinees. Interestingly, 22 cases of myopericarditis have been recognized among participants in the DHHS program. As opposed to the DoD program, 90% of these cases occurred in revaccinees and 71% of cases occurred in females. Why the results should be so opposite in the two cohorts remains unclear. Nevertheless, the conclusion is that smallpox vaccination does appear to increase the risk of myopericarditis. Previous scattered reports of myopericarditis are to be found in the literature, primarily with vaccinia strains used in Europe. As noted previously, myopericarditis had been reported in Finnish army conscripts who received a vaccinia vaccine that did not use the New York City Board of Health strain [4]. Similarly, reports from Australia also document cases of myopericarditis [5]. Thus, myopericarditis should be considered an expected adverse event associated with smallpox vaccination, though it is usually self-limited. A causal relationship is supported in this regard by the close temporal clustering (2–25 days post-vaccination), wide geographic and cross-seasonal distribution, and the occurrence predominantly in primary vaccinees [8]. Of note, Acambis PLC has documented 8
G.A. Poland et al. / Vaccine 23 (2005) 2078–2081
clinical and subclinical cases of myocarditis in a prospective study of 1162 na¨ıve vaccinees who received ACAM 2000 tissue culture vaccine or Dryvax. Myocarditis occurred at the same rate for both vaccines. This suggests that the occurrence of myocarditis may be as high as 1 per 145 primary vaccinees and may be directly related to the vaccinia virus (unpublished, ACIP meeting, October 28, 2004). Finally, there was a single case of Stevens-Johnson syndrome reported in a military recipient. This individual recovered. To date, 190 women enrolled in a smallpox vaccine pregnancy registry have been followed to term. These women were vaccinated in the DoD and DHHS programs before they were recognized to be pregnant. The anticipated rate of exposed pregnancies in the absence of a screening and education program was 8–12 per 1000 vaccinated women [10]. The recognized rate of exposed pregnancies in this largescale program was less than 2 per 1000 vaccinated women. About 75% of these women were vaccinated before conception or so soon after conception that pregnancy would not have been identified by testing. To date rates of spontaneous abortions and ectopic pregnancies do not appear to be higher than anticipated when adjusted for age and risk history and among four products of conception available for testing, no vaccinia was identifiable. In addition, no fetal vaccinia has been reported to date.
4. Conclusions Excellent screening and educational activities implemented by both the DoD and the DHHS prevented serious adverse events. The unexpected occurrence of cardiac conditions does raise concerns. In particular, epidemiologic studies indicate that myopericarditis is causally related to vaccinia. The available data do not support a causal association between ischemic cardiac events and receipt of smallpox vaccine; however, this possibility cannot be excluded. Our observations also suggest that a potential association between dilated cardiomyopathy and smallpox vaccination deserves further study. However, without further evidence, the data remains insufficient to move clearly away from neutrality to favor or reject a causal association between smallpox vaccination and dilated cardiomyopathy. In the interim, the precautionary practice of deferring from vaccination persons with pre-existing cardiac conditions or three or more risk factors continues. This practice, however, would not be warranted in an outbreak setting. The smallpox vaccination program described in this paper during the modern era demonstrates that a large-scale program can be safely carried out with rates of adverse events below historical rates. In particular, no healthcare worker to patient transmission of vaccinia virus occurred, with no resultant deaths or serious injuries. No serious events occurred that could have been prevented. Myopericarditis, however, was an unexpected occurrence and further follow-up and more research into the mechanism of this condition is important.
2081
Fortunately, all such known cases have recovered with no progression to dilated cardiomyopathy. In addition, it is worth noting that the current live-viral smallpox vaccine has significant limitations, including extensive contraindications to receipt of the vaccine, the potential for transmission of the vaccine virus to others who might suffer serious morbidity or mortality, serious and occasional lethal adverse events, and unanticipated cardiac effects. It would seem clear that a much further attenuated or even peptide-based vaccine is needed [11,12]. Once newer and safer vaccines are developed, variola would lessen substantially as a biologic weapon of concern.
Acknowledgements We wish to thank the talented and hard working team of DoD clinicians and scientists of the Military Vaccine Agency, Vaccine Healthcare Center Network, the Centers for Disease Control and Prevention, the Advisory Committee on Immunization Practices, and the Armed Forces Epidemiological Board.
References [1] World Health Organization. The global eradication of smallpox: final report of the Global Commission for the Certification of Smallpox Eradication, Geneva, December, 1979. World Health Organization; 1980. p. 1–122. [2] Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination. N Engl J Med 1969;281:1201–8. [3] Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Switzerland: World Health Organization; 1998. [4] Karjalainen J, Heikkila J, Nieminen MS, Jalanko H, Kleemola M, Lapinleimu K, et al. Etiology of mild acute infectious myocarditis. Relation to clinical features. Acta Med Scand 1983;213:65–73. [5] MacAdam D, Whitaker W. Cardiac complications after vaccination for smallpox. Br Heart J 1962;2:1099–100. [6] Grabenstein JD, Winkenwerder Jr W. US military smallpox vaccination program experience. JAMA 2003;289:3278–82. [7] Halsell 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: 3283–9. [8] Arness MK, Eckart RE, Love SS, Atwood JE, Wells TS, Engler RJ, et al. Myopericarditis following smallpox vaccination. Am J Epidemiol 2004;160:642–51. [9] Eckart RE, Love SS, Atwood JE, Arness MK, Cassimatis DC, Campbell CL, et al. Incidence and follow-up of inflammatory cardiac complications after smallpox vaccination. J Am Coll Cardiol 2004;44:201–5. [10] Centers for Disease Control and Prevention. Women with smallpox vaccine exposure during pregnancy reported to the National Smallpox Vaccine in Pregnancy Registry, United States, 2003. MMWR 2003;52:386–388. [11] Bonilla-Guerrero R, Poland GA. Smallpox vaccines: current and future. J Lab Clin Med 2003;142:252–7. [12] Poland GA, Neff JM. Smallpox vaccines: problems and prospects. In: Poland GA, editor. Immunology and allergy clinics of North America: vaccines in the 21st century. Philadelphia: WB Saunders Company; 2003. p. 731–43.
The US smallpox vaccination program: a review of a large modern era smallpox vaccination implementation program Gregory A. Poland a, ∗ , John D. Grabenstein b , John M. Neff c a
Mayo Vaccine Research Group, and Department of Medicine, Program in Translational Immunovirology and Biodefense, 611 C Guggenheim Building, 200 First Street, SW, Mayo Clinic and Foundation, Rochester, Minnesota, MN, USA b Military Vaccine Agency, United States Army Surgeon General’s Office, Falls Church, VA, USA c Center for Children with Special Needs, Children’s Hospital and Regional Medical Center, Seattle, WA, USA Available online 4 February 2005
Abstract We describe the US experience with a large-scale smallpox vaccination program in the modern era and quantify the anticipated and unanticipated local and systemic side-effects of smallpox vaccination. In addition, we review unexpected issues, such as the development of myopericarditis discovered during the implementation of this program. These results constitute the largest dataset of a vaccinia vaccination program utilizing calf-lymph derived New York City Board of Health strain vaccine (Dryvax, Wyeth) since the 1970s. These results should inform current and future vaccinia vaccination programs and provide a historical rate of complications against which candidate vaccine side-effects can be compared in future clinical trials. © 2005 Elsevier Ltd. All rights reserved. Keywords: Smallpox vaccine; Smallpox; Smallpox vaccine side effects
1. Introduction It is important to understand the historical context for the use of calf-derived smallpox vaccine. Routine smallpox vaccination ceased in the US by the mid 1970s. Smallpox was declared eradicated from the world by the World Health Organization (WHO) in 1980 [1]. US military use of smallpox vaccine was restricted to new trainees in 1984 and then discontinued entirely in 1990. Restoration of the US National Smallpox Vaccination Program was announced on 13 December 2002 by President George W. Bush.
夽 Disclaimer: The views expressed are those of the authors and do not represent the official position of the United States Government, the Centers for Disease Control, or the Armed Forces Epidemiological Board. ∗ Corresponding author. Tel.: +1 507 284 4456; fax: +1 507 266 4187. E-mail address: [email protected] (G.A. Poland).
0264-410X/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2005.01.012
The major concern regarding implementation of a largescale smallpox vaccination program was serious adverse events. A literature review suggested that the total incidence of major complications was 572 out of 14,168,000 vaccinations during a US surveillance program in 1968 [2]. An examination of worldwide reports from 1924 through the 1960s demonstrated a strain-dependent incidence of encephalitis between 2 and 1200 per million vaccinations, an incidence of encephalopathy between 3 and 50 per million vaccinations, eczema vaccinatum between 8 and 80 per million vaccinations, progressive vaccinia at 1 per million vaccinations, and generalized vaccinia at an incidence of 1–70 per million vaccinations [3]. Notably, only five cases of myopericarditis were reported in the literature between 1955 and 1986 utilizing the US vaccine (Dryvax, Wyeth). The Finnish strain of smallpox vaccine was reported to have an estimated incidence of postvaccination clinical myopericarditis as high as 1 in 10,000 among Finnish military conscripts in 1983 [4]. Finally, myopericarditis following smallpox vaccination was reported in
G.A. Poland et al. / Vaccine 23 (2005) 2078–2081
only 8 suspected cases of over 5,000,000 vaccinees in Australia [5]. In response to concerns about the use of smallpox as a weapon of biologic terrorism, President Bush announced the initiation of the two-pronged US Smallpox Vaccination Program in December 2002. The first program would be carried out under the auspices of the Department of Health and Human Services (DHHS) and was designed to immunize a cohort of health care workers and first responders who could respond in the event of a smallpox outbreak. Hence, this program would involve members of the US Public Health Service (PHS) and civilians. The DHHS Smallpox Vaccination Program vaccinated ∼39,500 people. Thirtysix percent of these individuals received primary vaccination while 64% were revaccinees. Approximately 36% of the DHHS vaccinees were male (64% female) with a median age of 48 years with a mean of 47.1 years (±9.5 years). In contrast, the second and larger program would be carried out under the auspices of the US Department of Defense (DoD). For the military population, stage 1A was designed to provide vaccine to smallpox epidemic response teams and involve 2000 to 5000 people beginning in mid-December 2002. Stage 1b was designed to immunize medical teams numbering 10,000–25,000 people beginning in early January 2003. Stage 2 was designed initially to provide vaccine protection to 500,000 mission-critical forces beginning in early January 2003 [6]. As of January 2005, the DoD program had screened 790,000 service members, of which 730,580 actually received smallpox vaccine. Seventy-one percent (515,351) received primary immunization, and 29% (215,229) were revaccinated. Eighty-nine percent (646,676) of the vaccinees were male (11% female). The median age of all vaccine recipients was 26 years with a mean of 28.5 years (±8.5 years). Notably, both the DoD and DHHS smallpox vaccination programs started in December 2002 and peaked by March 2003. Since that time, smaller numbers of vaccinees, in a maintenance phase, have been immunized.
2079
2. Anticipated preventable adverse events Both programs were highly successful in terms of the safety with which they were implemented. Multiple concerns had been raised publicly and in the literature regarding fears of large numbers of people suffering severe systemic effects and of both contact and nosocomial transmission of vaccinia virus. In fact, screening and education successes were such that not a single case of eczema vaccinatum, progressive vaccinia, fetal vaccinia, or workplace contact transmission occurred, despite implementation of the vaccination program at hundreds, if not thousands, of different vaccination clinics. As of January 2005, noteworthy events among 730,580 DoD vaccinees included one case of encephalitis, now fully recovered, (note: there is one case of post-vaccinal encephalitis in the civilian population and that individual has some persistent memory loss and has not fully recovered); 43 cases of generalized vaccinia, all of which were mild and recovered, (a careful review of the reported cases of generalized vaccines by consulting dermatologists suggest that these cases represent hypersensitivity reactions); inadvertent infection occurring in the skin among 62 vaccinees and 50 contacts of vaccinees; inadvertent infection of the eye occurring in 16 vaccinees and in 2 contacts of vaccinees. Of note, the main risks for contact transfer were family and intimate contacts occurring in 22 family members, 18 adult intimate contacts, 12 friends, and no patients or coworkers of vaccinees. Also of note, vaccinia immune globulin treatment was instituted in only three cases: one burn patient and two with auto-inoculation of the eye (one auto-inoculation, one contact). Table 1 provides details of the anticipated adverse events reports both for the DoD and DHHS Smallpox Vaccination Programs.
3. Unanticipated effects of smallpox vaccination Unanticipated effects of smallpox vaccination also occurred. As of October 2004, 24 DoD vaccinees were admitted to the hospital with myocardial ischemia 2–24 days after
Table 1 Anticipated smallpox vaccine events DoD (n = 730,580) as of 4 January 2005
DHHS (n = 40,422) as of 31 January 04
Preventable Eczema vaccinatum Progressive vaccinia Fetal vaccinia Contact transmission-nosocomial Contact transmission-not Nosocomial Auto-inoculation—non-ocular Auto-inoculation—ocular
0 0 0 0 50 Secondary 2 Tertiary 62 16
0 0 0 0 0
Not preventable Generalized vaccinia All mild, no sequela Post-vaccination encephalitis
35 Suspect 8 Probable 1
2 Suspect 1 Confirmed 1
20 3
2080
G.A. Poland et al. / Vaccine 23 (2005) 2078–2081 Table 4 Unanticipated cardiac event-myopericarditis after smallpox vaccination
Table 2 Cardiac ischemic events after smallpox vaccination DoD* Ischemic events as admission Diagnosis Angina Myocardial infarction Fatal MI
DHHS+
24 5 13 1/13
9 3 6 2/6
DoD*: expected ischemic admissions in a 2-week window = 40 (upper 95% CI: 48); expected cardiac deaths per year—US Army = 50. DHHS+: expected rate of MI in a 3-week window = 2 (upper 95% CI: 5.4); expected rate of angina in a 3-week window = 10.
receiving vaccine. Myocardial infarction incurred in 13 subjects, 1 with fatality, 5 with angina, and 6 with atherosclerotic coronary vascular disease, with 2 of those cases being fatal. The admission diagnosis was changed to myocarditis in 6 of these cases. Of note, the expected incidence of admission for ischemia age-adjusted for this population over a 14-day window was 40 admissions with an upper 95% confidence limit of 48. Among the four fatalities, it is clear that these individuals had significant pre-existing cardiovascular disease. One was a 55-year-old smoker with three-vessel occlusion, left ventricular hypertrophy and cardiomegaly. Another was a 47-year-old who died after physical exertion and was found to have severe atherosclerotic cardiovascular disease with twovessel occlusion. This individual had a 15-year history of smoking. Yet another was a 31-year-old with three-vessel occlusion, left ventricular hypertrophy and a significant family history of his father dying of an MI at age 39. After reviewing their medical records, a committee of experts concluded that ischemia after smallpox vaccination did not exceed the expected level in unvaccinated people within the DoD population. Table 2 provides details of the ischemic cardiac events among vaccinees in the DoD and the DHHS smallpox vaccination programs. An additional unanticipated adverse event was dilated cardiomyopathy including four cases in the DoD program and three in the DHHS program. Table 3 provides details of this condition. Notably, an unanticipated adverse event was myopericarditis. Table 4 provides details of the number of known cases in both DoD and DHHS programs. Table 3 Unanticipated events under investigation after smallpox vaccination-dilated cardiomyopathy DoD (n = 730,580) as of 4 January 2005 Dilated cardiomyopathy 4 3 Re-vaccinees 1 Primary 4 Male Ages 34, 37, 42, 44 Onset recognized 5, 22, 23, 29 Weeks after smallpox vaccination
DHHS (n = 40,449) as of 13 February 04 3* (*1 Still pending review) 3 Re-vaccinees 2 Female, 1 male* Ages 53, 55, 56* Onsets recognized ∼2*, 2.6, and 3.3 months after smallpox vaccination
DoD (n = 730,580) as of 4 January 2005
DHHS (n = 40,422) as of 31 January 04
Myopericarditis 86
21
8 Suspected 74 Probable 4 Confirmed
16 Suspected 5 Probable 0 Confirmed
Overall, 86 cases of myopericarditis have occurred among DoD vaccinees, graded as 8 suspect, 74 probable, and 4 biopsy-confirmed (see Table 4). A report of the details of the first 18 cases has been published [7]. In US military personnel vaccinated against smallpox, the observed incidence of 16.11 per 100,000 vaccinees of myopericarditis over a 30-day observation window among 347,516 primary vaccinees was nearly 7.5-fold higher than the expected rate of 2.16 per 100,000 (95% confidence intervals 1.90–2.34) among non-vaccinated active duty military personnel. Also notable was that the incidence of myopericarditis among revaccinees (2.07 per 100,000 among 145,155 revaccinees) was not statistically different from the expected background rate. In the DoD cohort, cases of myopericarditis occurred predominantly among males (98%) and those of Caucasian race (86.4%) both statistically significant associations P = 0.015 and P = 0.005, respectively [8]. In the 64 subjects who have been intensively followed, all have recovered normal heart function based on ECG, echocardiogram and treadmill stress tests [9]. Again, these cases were intensively reviewed by a committee of experts and the conclusion was the smallpox vaccination increased the risk of myopericarditis among adult primary vaccinees, specifically and disproportionately among male vaccinees. Interestingly, 22 cases of myopericarditis have been recognized among participants in the DHHS program. As opposed to the DoD program, 90% of these cases occurred in revaccinees and 71% of cases occurred in females. Why the results should be so opposite in the two cohorts remains unclear. Nevertheless, the conclusion is that smallpox vaccination does appear to increase the risk of myopericarditis. Previous scattered reports of myopericarditis are to be found in the literature, primarily with vaccinia strains used in Europe. As noted previously, myopericarditis had been reported in Finnish army conscripts who received a vaccinia vaccine that did not use the New York City Board of Health strain [4]. Similarly, reports from Australia also document cases of myopericarditis [5]. Thus, myopericarditis should be considered an expected adverse event associated with smallpox vaccination, though it is usually self-limited. A causal relationship is supported in this regard by the close temporal clustering (2–25 days post-vaccination), wide geographic and cross-seasonal distribution, and the occurrence predominantly in primary vaccinees [8]. Of note, Acambis PLC has documented 8
G.A. Poland et al. / Vaccine 23 (2005) 2078–2081
clinical and subclinical cases of myocarditis in a prospective study of 1162 na¨ıve vaccinees who received ACAM 2000 tissue culture vaccine or Dryvax. Myocarditis occurred at the same rate for both vaccines. This suggests that the occurrence of myocarditis may be as high as 1 per 145 primary vaccinees and may be directly related to the vaccinia virus (unpublished, ACIP meeting, October 28, 2004). Finally, there was a single case of Stevens-Johnson syndrome reported in a military recipient. This individual recovered. To date, 190 women enrolled in a smallpox vaccine pregnancy registry have been followed to term. These women were vaccinated in the DoD and DHHS programs before they were recognized to be pregnant. The anticipated rate of exposed pregnancies in the absence of a screening and education program was 8–12 per 1000 vaccinated women [10]. The recognized rate of exposed pregnancies in this largescale program was less than 2 per 1000 vaccinated women. About 75% of these women were vaccinated before conception or so soon after conception that pregnancy would not have been identified by testing. To date rates of spontaneous abortions and ectopic pregnancies do not appear to be higher than anticipated when adjusted for age and risk history and among four products of conception available for testing, no vaccinia was identifiable. In addition, no fetal vaccinia has been reported to date.
4. Conclusions Excellent screening and educational activities implemented by both the DoD and the DHHS prevented serious adverse events. The unexpected occurrence of cardiac conditions does raise concerns. In particular, epidemiologic studies indicate that myopericarditis is causally related to vaccinia. The available data do not support a causal association between ischemic cardiac events and receipt of smallpox vaccine; however, this possibility cannot be excluded. Our observations also suggest that a potential association between dilated cardiomyopathy and smallpox vaccination deserves further study. However, without further evidence, the data remains insufficient to move clearly away from neutrality to favor or reject a causal association between smallpox vaccination and dilated cardiomyopathy. In the interim, the precautionary practice of deferring from vaccination persons with pre-existing cardiac conditions or three or more risk factors continues. This practice, however, would not be warranted in an outbreak setting. The smallpox vaccination program described in this paper during the modern era demonstrates that a large-scale program can be safely carried out with rates of adverse events below historical rates. In particular, no healthcare worker to patient transmission of vaccinia virus occurred, with no resultant deaths or serious injuries. No serious events occurred that could have been prevented. Myopericarditis, however, was an unexpected occurrence and further follow-up and more research into the mechanism of this condition is important.
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Fortunately, all such known cases have recovered with no progression to dilated cardiomyopathy. In addition, it is worth noting that the current live-viral smallpox vaccine has significant limitations, including extensive contraindications to receipt of the vaccine, the potential for transmission of the vaccine virus to others who might suffer serious morbidity or mortality, serious and occasional lethal adverse events, and unanticipated cardiac effects. It would seem clear that a much further attenuated or even peptide-based vaccine is needed [11,12]. Once newer and safer vaccines are developed, variola would lessen substantially as a biologic weapon of concern.
Acknowledgements We wish to thank the talented and hard working team of DoD clinicians and scientists of the Military Vaccine Agency, Vaccine Healthcare Center Network, the Centers for Disease Control and Prevention, the Advisory Committee on Immunization Practices, and the Armed Forces Epidemiological Board.
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