Article

Safety of Smallpox Vaccine among Military Recipients Questioned_JAMA

Mon, 3 Nov 2003

The government’s hasty and ill-advised smallpox vaccination policy for US civilians was roundly rejected by scientists and the public alike. Scientists agreed that public concerns about the vaccine’s adverse effects were valid. Military personnel, however, were given no choice–500,000 were inoculated. Surely their reactions to the vaccine are not appreciably different from what civilians might have experienced–unless it is claimed they are of a different species.

An exchange of letters in The Journal of the American Medical Society (see below) by Dr. Meryl Nass, a board member of the Alliance for Human Research Protection, and  Drs Grabenstein and Winkenwerder et al, revolves around the veracity of the military claims about the safety of the smallpox vaccine.

Dr. Nass disputes the claim by Dr. Grabenstein that the adverse event rates following smallpox vaccine were derived from active surveillance of 500,000 soldiers. Active surveillance means after you give a drug or vaccine you go back periodically and ask the recipients if they are okay or having any symptoms. It is expensive and time-consuming, and you then need to look into which symptoms might be vaccine-related. It would have cost many millions to do active surveillance on 500,000 soldiers–it is simply never done with such large groups. Since Dr. Grabenstein is a PhD pharmacoepidemiologist there’s no question that he knows the difference between active and passive surveillance.

Dr. Nass is contacted by sick soldiers every day, she can, therefore, vouch for the fact there has been no active surveillance, and when they got sick, they heard only denials the vaccine might have any relationship to their illness.

Dr. Nass’ response to Dr. Grabenstein’s published letter follows.

Safety of the Smallpox Vaccine Among Military Recipients

To the Editor: Dr Halsell and colleagues [1] reported that myopericarditis occurred at a rate of 1 per 12 819 primary vaccinees in the US military. Similarly, Drs Grabenstein and Winkenwerder [2] found that between 0.5% and 3.0% of military vaccine recipients needed short-term sick leave. Both groups of authors concluded that adverse events occurred at rates below historical rates, and that a mass vaccination program could be carried out safely. In both reports, however, vaccine complications were derived using passive rather than active surveillance. Therefore, the very favorable comparison of military adverse effect rates to historical rates is misleading.

Furthermore, claims that no deaths were associated with the military vaccination program and that no women developed myopericarditis are incorrect. Two military deaths have in fact been reported to be associated with smallpox vaccination. [3-4] One occurred in a previously healthy 22-year-old female reservist who died 1 month after receiving both anthrax and smallpox vaccines. According to the autopsy report, this was associated with pericarditis.

Similarly, the rate of myopericarditis found by the US Centers for Disease Control and Prevention (CDC) in civilians under active surveillance was more than 7 times higher than the military rate: 1 in 1725 vaccinees, of whom 71% were women. [5] Furthermore, the CDC reports that 2 women are now known to have developed dilated cardiomyopathy following smallpox vaccination. [6] The total number of serious adverse events among civilians from January 24 through June 20, 2003, is 71, or a rate of 1 in 500 smallpox vaccinations. [6] These events included 5 myocardial infarctions and 1 stroke.

The letter by Dr Nass, as originally submitted to THE JOURNAL, was previously posted at http://www.cbsnews.com/htdocs/pdf/nassletter.pdf. – ED.

Meryl Nass, MD
Mount Desert Island Hospital
Bar Harbor, Me

1. Halsell JS, Riddle JR, Atwood JE, et al. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. JAMA. 2003;289:3283-3289. ABSTRACT/FULL TEXT

2. Grabenstein JD, Winkenwerder W Jr. US military smallpox vaccination program experience. JAMA. 2003;289:3278-3282. ABSTRACT/FULL TEXT

3. Roos R. Military smallpox vaccinee dies of heart attack; ACIP considers options. March 28, 2003. Available at: http://www.cidrap.umn.edu/cidrap/content/bt/smallpox/news/acipheart.html. Accessibility verified September 26, 2003.

4. Meincke P. Soldier dies after smallpox vaccination [transcript]. Chicago local news. ABC television. April 9, 2003. Available at: http://abclocal.go.com/wls/news/040903_ns_smallpoxdeath.html. Accessibility verified September 26, 2003.

5. Centers for Disease Control and Prevention. Update: cardiac-related events during the civilian smallpox vaccination program – United States, 2003. MMWR Morb Mortal Wkly Rep. 2003;52:492-496. MEDLINE

6. Centers for Disease Control and Prevention. Update: cardiac and other adverse events following civilian smallpox vaccination – United States, 2003. MMWR Morb Mortal Wkly Rep. 2003;52:639-642. MEDLINE

Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2003;290:2123-2124.

Safety of the Smallpox Vaccine Among Military Recipients – Reply

In Reply: Contrary to Dr Nass’s assertion, active surveillance was the primary source for the published military data on smallpox vaccine safety. [1] Of 18 myopericarditis cases reported, [2] only 3 were found using the Vaccine Adverse Event Reporting System. Most were first identified among well-observed military personnel via reports to headquarters or from the Defense Medical Surveillance System. [3]

The death of a 22-year-old female soldier was reported, [1] but pericarditis had not been diagnosed at that time. At the time of this writing, her death is classified as “unexplained” by the CDC. The Department of Defense is consulting with civilian medical experts to determine if this death was related to smallpox vaccination.

There are considerable differences between the military and civilian vaccinee populations in age and sex mix, underlying health, and access to medical care. Most military myopericarditis cases are classified as “probable,” whereas most civilian cases are “suspect.” [4] It is not known if the 2 civilian cases of dilated cardiomyopathy are incident cases after vaccination or prevalent cases predating vaccination. [5] Both had multiple risk factors independent of vaccination. Notably, after smallpox vaccination of 490 000 military personnel, the Department of Defense has identified no elevated rates of cardiac disorders other than myopericarditis. [1-2]

Adverse events occur among unvaccinated people at certain rates. We would expect these events to occur in similar vaccinated people at similar rates. The Department of Defense uses scientific methods to determine whether those rates are exceeded. Managers of vaccination programs also must use reliable scientific practices.

We also disagree with Nass that the smallpox safety reports issued by the Department of Defense are misleading. Military reporting began at a public session of the Institute of Medicine on December 19, 2002. Regular periodic reports followed, as information accumulated. One of the physicians who analyzed much of the 1960s smallpox vaccine safety data chairs today’s Smallpox Vaccine Safety Working Group, evaluating both military and civilian safety data. He considers modern data collection superior to earlier efforts. “Surveillance techniques used in 2003 are much more comprehensive and sophisticated than those used in the 1960s” (J.M. Neff, written communication, August 27, 2003).

John D. Grabenstein, RPh, PhD; James R. Riddle, DVM, MPH; Mark K. Arness, MD, MT&MH; William Winkenwerder, Jr, MD Department of Defense Washington, DC

1. Grabenstein JD, Winkenwerder W. US military smallpox vaccination program experience. JAMA. 2003;289:3278-82. ABSTRACT/FULL TEXT

2. Halsell JS, Riddle JR, Atwood JE, et al. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. JAMA. 2003;289:3283-3289. ABSTRACT/FULL TEXT

3. Rubertone MV, Brundage JF. The Defense Medical Surveillance System and the Department of Defense serum repository: glimpses of the future of public health surveillance. Am J Public Health. 2002;92:1900-1904. ABSTRACT/FULL TEXT

4. Centers for Disease Control & Prevention. Update: adverse events following civilian smallpox vaccination – United States, 2003. MMWR Morb Mortal Wkly Rep. 2003;52:819-820. MEDLINE

5. Centers for Disease Control & Prevention. Update: cardiac and other adverse events following civilian smallpox vaccination – United States, 2003. MMWR Morb Mortal Wkly Rep. 2003;52:639-642. MEDLINE

Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2003;290:2124.

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Dr. Meryl Nass’ response:

The incorrect claims in the authors’ original two papers are magnified in their Author Response. The following discusses six misleading statements in their reply.

1. They implausibly claim that the adverse event rates following smallpox vaccine were derived from active surveillance — of 490,000 mostly deployed soldiers! Since Grabenstein has a PhD in epidemiology, he should know the difference between active and passive surveillance. Active surveillance means that after you give a drug or vaccine you go back periodically and ask the recipients if they are having any symptoms that may be adverse reactions. It is expensive and time-consuming, and it necessitates looking into which symptoms might be vaccine-related.  This is why active surveillance is simply never done with such large groups. Yet Grabenstein et al claim that "reports to headquarters" and data from the Defense Medical Surveillance System (a database of outpatient visits and hospitalizations) are forms of active surveillance, when both are unquestionably passive.

2. The military authors support the claim in their June 25, 2003 JAMA article that no women in the military have developed pericarditis following smallpox vaccination, by saying that in the case of deceased reservist Rachel Lacey, "pericarditis had not been diagnosed at that time." Rachel Lacey, a 22 year old in excellent health, was placed on active duty February 24, 2003. She received five vaccinations in one day in early March, including both anthrax and smallpox vaccinations. She became ill almost immediately, was first hospitalized on March 19, and died April 4.

After an autopsy, the Mayo Clinic pathologist diagnosed "lymphocytic pericarditis with eosinophils, post-vaccination and diffuse alveolar damage" on both the autopsy report and death certificate. Although it is conceivable that someone at CDC who never examined the patient has called her death "unexplained," the diagnosis of pericarditis had been established well before Grabenstein et al’s article was published.

3. Grabenstein et al point out that most military cases of vaccine-related myopericarditis are "probable" according to CDC’s case definition, and most civilian cases are "suspect." The only way to confirm a case using CDC’s case definition is with positive viral titres, a test not routinely available. In standard medical practice, pericarditis is a clinical diagnosis. The difference between the military "probable" and civilian "suspect" classifications really means that military cases had to meet a higher burden of proof in order to be counted, which is another reason relatively few cases were identified. This allowed the authors to claim the vaccine was much safer than what the Morbidity and Mortality Weekly Report, the CDC Advisory Committee on Immunization Practices and the Institute of Medicine concluded.

4. Next, Grabenstein et al assert that two civilian cases of dilated cardiomyopathy may be prevalent (pre-existing) conditions, predating vaccination. But that is not what CDC reported. Both women developed symptoms shortly after vaccination, both had new onset of left bundle branch block on EKG and both developed new heart murmurs. Did both have multiple (non-vaccine) risk factors as Grabenstein claimed? One had untreated borderline hypertension and obesity at age 52. Not a high-risk patient for congestive heart failure, as the DoD authors implied.

5. Grabenstein et al say, "The Department of Defense uses scientific methods to determine whether baseline adverse event rates are exceeded" in the vaccinated. But they fail to reveal any validated research to support their claim, unlike CDC’s findings in 38,000 vaccinated civilians, that no elevated rates of any other cardiac conditions were found in 490,000 vaccinated soldiers.

6. Finally, Grabenstein et al cite a personal communication from a JM Neff who said, "Surveillance techniques used in 2003 are much more comprehensive and sophisticated than those used in the 1960s." Granted – but is Neff referring to military surveillance or civilian surveillance? When the military adverse event rate for myopericarditis is only 14% of the civilian rate, when the rate for other adverse events is zero, and when case-finding is limited to ICD-9 codes and reports to FDA, military surveillance is neither comprehensive nor sophisticated.

The problem here is not merely the lack of surveillance for vaccine adverse events. The problem is a military medical culture in which the mission trumps good medical practice. In this case, the "mission" dictates putting a good face on a very bad program. By publishing these articles in the JAMA, the aim of the military authors was to send the wrong message about smallpox vaccine’s safety to half the physicians in America. Yet CDC has belatedly acknowledged the civilian vaccination program as failed. Both the Institute of Medicine and CDC’s Advisory Committee on Immunization Practices have suggested that routine smallpox vaccinations for civilians should be halted, due to unacceptable rates of serious adverse reactions.

Colonel Grabenstein’s coauthors include the Assistant Secretary of Defense for Health Affairs, Dr. William Winkenwerder, M.D. Dr. Winkenwerder is the top physician in the Department of Defense, and is responsible for exercising civilian control over military medicine. Yet he has signed his name to an article and subsequent rebuttal that are steeped in obfuscation, not science. What message does that send to the entire military medical corps?

Dr. Winkenwerder completed medical school, obtained an MBA at the Wharton School of Business, and has a record as an able hospital administrator. An Assistant Secretary of Defense for Health Affairs who is known for ethical conduct, clinical knowledge and intellectual honesty would be a welcome change.

Meryl Nass, MD
H 207 276-5092
W 207 288-5082 ext 220 or pager 441
C 207 522-5229

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