Smallpox Immunization in the 21st Century: Title and subTitle BreakThe Old and the New

Just over 6 months ago a decision was made to reinstitute smallpox vaccination for selected segments of the US population.¹ This decision to implement a pre-event smallpox vaccination program was based on the concern that smallpox could be used as an agent of bioterrorism; however, certain questions about the risk of smallpox vaccination in a 21st-century setting arose.^{2 - 3} Among these was the possibility that the current United States population might be more vulnerable to serious adverse effects of the smallpox vaccine due to a relative increase—compared with 3 to 4 decades ago—in conditions affecting the immune system such as the use of immunosuppressive drugs and the presence of human immunodeficiency virus infection in the community. A consequence of this change in population profile could be an increased incidence of established adverse events as well as the emergence of heretofore unrecognized adverse events. At the same time that these issues were being raised, there was also an appreciation that the immunization of a new generation of individuals provided an opportunity to apply 21st-century technology to the study of vaccinia-induced immunity.

Addressing these topics, this issue of THE JOURNAL contains reports from the first large-scale experience with smallpox vaccination in the United States in 30 years, as well as data from 2 research studies in civilian populations. In a timely and well-conducted surveillance study by the Department of Defense, Grabenstein and Winkenwerder⁴ evaluate the incidence of adverse events in 450 293 (70.5% primary vaccinees and 29.5% revaccinees) military personnel vaccinated between December 2002 and May 2003 with a live vaccine consisting of the New York City Board of Health strain of vaccinia (Dryvax, Wyeth Laboratories, Marietta, Pa). Also from the military population, Halsell and colleagues⁵ detail the characteristics of 18 cases of myopericarditis among 326 356 US military personnel immunized through March 14, 2003. In separate civilian research studies, a potential new clinical finding, postvaccination folliculitis, is described by Talbot and colleagues⁶ while Frey and colleagues⁷ examine the impact of diluted smallpox vaccine on successful vaccination rates in vaccinia non-naive recipients who had been vaccinated decades previously, the duration of viral shedding, and the kinetics of neutralizing antibody production.

The observation that this smallpox vaccine can be administered safely in a 21st-century population with a very low adverse-event rate is a critically important piece of new information.⁴ Although the military population is relatively young and carefully screened, suggesting that the findings in this cohort may not be generalizable to the population as a whole, the denominator of more than 450 000 gives considerable power to the conclusions. Furthermore, careful screening is and will be applied to the ongoing civilian pre-event vaccination program of smallpox response teams and first responders. By adjusting the observed incidence rate to events per million, the authors⁴ show that not only did the adverse events of generalized vaccinia, encephalitis, and self-inoculation occur at frequencies similar to or less than those of the 1960s,^{8 - 10} perhaps more importantly, they also report that there were no cases of progressive vaccinia, eczema vaccinatum, or vaccine-attributed deaths.

Several other outcomes of the US military smallpox vaccination program are worth emphasizing. First, despite close person-to-person contact and minimal lesion coverage (in some instances only a simple Band-Aid was used when military personnel returned to assigned duties immediately following vaccination), the rate of contact transmission was low, 43 per million overall and 0 per million among 19 333 health care workers. Second, of 10 inadvertently vaccinated individuals infected with human immunodeficiency virus, none experienced complications. Although this number is admittedly small, it nonetheless demonstrates that smallpox vaccination can be administered safely to at least some individuals infected with human immunodeficiency virus without evidence of severe immunodeficiency. Third, and perhaps most compelling, the spectrum of complications was different in primary vs revaccinated individuals (ie, those immunized in the distant past). In the military program, generalized vaccinia and myopericarditis cases occurred only in primary vaccinees.

Myopericarditis after vaccination with the New York City Board of Health strain of vaccina virus, as reported by Halsell and colleagues,⁵ is not a new observation. However, for the many clinicians who have spent the last year familiarizing themselves with photographs of patients with progressive vaccinia, eczema vaccinatum, or other widely documented adverse events, this complication may not have been fully appreciated. As noted by the authors,⁵ a small number of cases of myopericarditis associated with the New York City Board of Health strain of vaccinia virus had actually been previously reported and myopericarditis had also been observed with the use of other smallpox vaccines in Europe and Australia. It is unclear whether the apparent increase of this adverse effect currently reported is a function of tighter modern day surveillance and diagnostic capability or a true increase in incidence. The ability to determine a true difference in incidence of myopericarditis between the past and present is also complicated because there is no single uniform case definition for this condition. In describing the limitations of their study, Halsell et al⁵ note the importance of developing a standard case definition. At present, the Centers for Disease Control and Prevention is developing a refined definition as cases of myopericarditis continue to be reported in both vaccinia naive and revaccinated civilians.^{11 - 12}

Talbot and colleagues⁶ report a papulovesicular rash that mimics generalized vaccinia in 15 of 148 vaccinia-naive participants following their vaccination (Aventis Pasteur Smallpox Vaccine, Swiftwater, Pa). Both generalized vaccinia and this newly described postvaccination folliculitis⁶ can appear at multiple sites, including the face, neck, back, and extremities, and both occur at the time of maximal viral replication (approximately 9 days after vaccination). Although it has been reported that vaccinia can be cultured from generalized vaccinia and from another vaccinial-related folliculitis, acne vaccinatum,¹³ viral cultures from all 7 of the patients cultured in this study were negative for vaccinia; polymerase chain reaction assays were not performed. The single lesion that was biopsied revealed only folliculitis with no evidence of virus. If these cases had occurred 40 years ago, when cultures were not routinely performed on lesions occurring after vaccination, these individuals might have been diagnosed as having generalized vaccinia. This study illustrates the importance of re-evaluating seemingly established phenomena when new tools become available.

The absence of established laboratory correlates of protective immunity against smallpox continues to drive the need for studies evaluating the nature of the immune response to vaccinia and the projected duration of protection against smallpox infection and disease. The clinical efficacy of smallpox vaccine has been clearly established through the worldwide eradication of naturally occurring smallpox; however, the degree and duration of protection in previously vaccinated individuals are not well understood. The presence of a cutaneous take, a vesicular lesion that progresses to a pustule followed by scabbing at the site of vaccination, remains the only widely accepted marker of protection and successful vaccination. In this regard, Frey and colleagues⁷ report in their study of 90 participants receiving the New York City Board of Health strain of smallpox vaccine that non-naive (previously immunized) participants developed smaller skin lesions, experienced a shorter duration of viral shedding, and had higher antibody levels following vaccination than those who were receiving their first immunization. With the caveat of relatively large confidence intervals, Frey et al also note that an adequate successful vaccination rate (up to 86%) and substantial boost in antibody production can be achieved with a vaccine dilution of 1:10 in non-naive individuals. Of note is the observation that the preboost titers of neutralizing antibody in the non-naive recipients were comparable with the titers in the vaccinia-naive individuals after immunization, thus suggesting long-term persistence of specific immunity in previously vaccinated individuals. This may have important implications in determining the degree of already existing herd immunity in the population.

The 4 reports in this issue of THE JOURNAL highlight the ongoing challenge to clinicians to be mindful of the old while being vigilant for the new. Before 2002, virtually all that was known about the efficacy and safety of smallpox vaccination had been documented in studies conducted a minimum of 30 years earlier. This was an era prior to the availability of technological advances, such as flow cytometry, polymerase chain reaction, and magnetic resonance imaging and before modern-day computer systems made it possible to perform diagnostic surveillance and statistical analyses in close to real time. The continued application of these and other new technologies to this historic public health issue should be of great value in furthering the understanding of the nature of smallpox protection induced by vaccination.

By rapidly sharing the data from their smallpox vaccination experience with the general medical community, the Department of Defense has provided the civilian population with critical information pertaining to an important general public health issue and should be commended for this effort. This is a model for how military and civilian cooperation can effectively serve the public health of the entire nation.