The smallpox immunization program: scientific knowledge gained

July 2003

The military and civilian smallpox immunization programs are now about six months old. The civilian program, directed primarily at health care workers (HCW), has fallen far short of the stated goal of 500,000 HCWs; to date only about 38,000 have been immunized. The next phase of the civilian immunization program has officially begun; this phase is directed broad immunization of all health care personnel, as well as first-responders, emergency service personnel, police, fire fighters, and others. The goal for this phase is 10,000,000 individuals. At this writing, however, the future of the civilian program is not clear, and mixed messages are being received from various governmental bodies.

My purpose in these comments, however, is not to discuss the political or social issues involved in smallpox immunization, but rather to highlight some of the scientific observations that have been made to date within both the military and civilian programs. The key information appears in four reports published in the June 25, 2003 issue of The Journal of the American Medical Association, together with an accompanying editorial by Drs. Wright and Fauci. Space will permit me to discuss only three of these reports.

Military adverse reactions

The first of these, by John Grabenstein and his colleagues, details the adverse reaction experience in the military from Dec. 13, 2002 through May 28, 2003. A total of 450,293 personnel were vaccinated, and slightly over 70% of the group were primary vaccinees; 87% were male. The adverse event experience was generally the same as the experience reported 30 to 40 years ago. Among events generally considered as mild or temporary, there were 36 cases of generalized vaccinia, one case of erythema multiforme, 48 instances of inadvertent self-inoculation and 21 cases of contact inoculation. The incidence of generalized vaccinia and contact inoculation was within historical norms; the incidence of self-inoculation appeared to be lower than the norm, although the reliability of the historical norm may not be well established.

Among the moderate or severe adverse events, there were 37 instances of myopericarditis, one case of encephalitis and no cases of eczema vaccinatum or progressive vaccinia; there were no deaths. All of the moderate/severe adverse events were within historic norms, including perhaps myopericarditis. (Vide infra for more comment on myopericarditis.)

There were, however, eight additional cardiac events that occurred in this population, including four myocardial infarctions, two instances of angina and one each with coronary artery spasm and atrial fibrillation. One of the patients with myocardial infarction died.

There were several other important observations in this report. Vaccinated HCWs remained on the job with no interruption of their duties, including surgery, labor and delivery and care of immunocompromised patients; no transmission within the health care setting was detected. Rates of time off beccause of local or systemic symptoms varied from 0.5% to 3%, depending on the setting, and usually occurred eight to 12 days after vaccination. Finally, 10 males with undiagnosed HIV infection were vaccinated, and each responded normally without incident. Their CD4 cell counts subsequently were found to range from 303 to 751.

Myopericarditis frequency

The frequency of myopericarditis as an adverse event following smallpox vaccination was probably the most surprising of the events encountered, at least to a U.S. population. Detailed observations of this complication were published in a second paper, by Jeffrey Hadsell and his co-authors. Among 203,734 primary vaccinees, 18 cases of myopericarditis occurred during the 30-day period following vaccination, an incidence of 7.8/100,000. No cases occurred among over 95,000 people who had been previously vaccinated.

Clinically, the cases were generally typical of myopericarditis complicating other viral infections, such as those caused by enteroviruses or influenza viruses. Patients typically presented with chest pain and developed characteristic electrocardiogram changes, transient cardiac enzyme elevations, and often wall-motion changes observed on echocardiograms. All patients recovered and have either returned to active duty or are on convalescent leave. There was a marked temporal association of the onset of symptoms with vaccination; all cases had onset between days 7 to19 after vaccination.

The vaccinia strain used in the vaccine, the New York City Board of Health strain, has not been previously associated with this frequency of myopericarditis. Other strains, however, have been associated with a higher incidence: the strain used to vaccinate the Finnish military in 1883 appeared to result in myopericarditis with an incidence as high as 1/10,000, not appreciably higher than the recent U.S. experience. Could this increased incidence in the United States result from improved surveillance and better diagnostic techniques? That may be possible, but the question simply cannot be answered at this time.

Civilian experiences

The third report on which I wish to comment came not from the military, but rather the civilian population. Talbot and his associates reported experience from healthy adult primary vaccinees studied at Vanderbilt University. Among 148 participants studied, skin eruptions developed in 15, generalized in four and focal in 11. All cases had onset between days 9 to 11 after vaccination, and all resolved without scarring. Cases occurred about equally in males and females. Seventeen lesion samples were taken from seven of the patients; all cultures were negative for vaccinia virus. One skin biopsy specimen taken from one of the patients with generalized eruptions showed suppurative folliculitis with no evidence to suggest viral replication. Treatment was symptomatic.

Note that about 10% of this population of young, healthy primary vaccinees developed folliculitis, as described. These occurrences were notable for at least two reasons. First, their development was a cause of considerable concern, both to the patients and to their providers, as they sought to be confident this was not a serious adverse event such as progressive vaccinia. Second, it is very easily confused with generalized vaccinia. The latter, not generally a serious adverse event, has its onset five to 10 days postvaccination, just slightly earlier on average than the follicular lesions described, although there is considerable overlap.

The differences between the two entities are subtle, though real. In generalized vaccinia, the lesions all appear similar; in folliculitis, they appear in several stages of development. Vaccinia virus can be recovered from severe lesions of generalized vaccinia, but cultures are uniformly negative in folliculitis. Finally, scarring may occur with severe generalized vaccinia lesions, but there is no scarring at all with folliculitis. It is quite possible, however, that the incidence of generalized vaccinia has been overestimated in the past because of erroneous inclusion of patients with folliculitis.

These are all important observations, and reassuring ones at that. Smallpox vaccine is still as safe – or not – as was true 30 to 40 years ago. Nonetheless, I, and I think most readers, continue to hope that the next generation of smallpox vaccines, currently in the pipeline, proves to be safer than the current product, yet equally protective.