Safety of Smallpox Vaccines
Substantial volumes of safety data have accumulated on first-generation vaccines through the period of widespread smallpox vaccination, the intensified eradication program and post-eradication vaccination exemplified by the recent US military and civilian healthcare worker programs. Surveillance data from the late 1960s in the USA showed serious complications of smallpox vaccination in approximately four per 100,000 individuals with an overall risk of death of one per million primary vaccinations.[56,57,58] The rate of serious adverse events may be strain related; a retrospective meta-analysis describes a sixfold increased risk of death with the Lister compared with the NYCBH strains.
Serious, albeit rare, complications of vaccination are well documented and occur with higher frequency in primary vaccinees or those with immunologic abnormalities ( Table 2 ).[56,57,60] Postvaccinial encephalitis, a rare disorder of the CNS that generally occurs in children younger than 5 years of age during the second week following vaccination, is associated with a high mortality rate and severe neurological impairment.[14,61] Other serious adverse events are associated with specific predispositions: progressive vaccinia, a frequently fatal complication of smallpox vaccination in immunocompromised hosts, involves regional and metastatic spread of vaccinia virus as a consequence of the inability to contain the localized infection; and eczema vaccinatum, characterized by extension of the local vaccinia infection to other cutaneous areas actively or remotely affected by atopic dermatitis.[14,58]
A number of other complications of smallpox vaccination, including generalized vaccinia, congenital vaccinia, inadvertent inoculation and bacterial superinfection,[3,58,63,64] are all potential causes of severe morbidity (or mortality in the case of congenital vaccinia) in vaccinees or their close contacts.[14,58] The incidence of serious adverse events expected in modern mass vaccinations using first-generation vaccinia viruses could potentially be significantly higher than historical levels due to a larger population of individuals with vaccine contraindications and a larger proportion of vaccinia-naive individuals in the population.[65,66] That this higher risk did not materialize in contemporary, posteradication programs was probably due to rigorous, risk-based contra-indication screening and extensive education. In the setting of a smallpox outbreak, however, fewer exemptions might be granted. Thus, a major focus of newer vaccine approaches is to improve upon safety while maintaining efficacy.
Live vaccinia virus vaccines are also associated with a high incidence of local and systemic symptoms. The majority of vaccinia-naive subjects experience local symptoms related to the vaccination site and as many as 40% experience mild-to-moderate constitutional symptoms, such as headache, myalgias, malaise or fever. Data from both the Lister/Elstree[59,67] and the NYCBH strains[14,56,68] of vaccinia virus confirm the higher incidence of local and systemic adverse events in primary vaccinees, compared with revaccinees. While immunogenicity and efficacy in primary vaccinees are apparently not affected by diluting unattenuated vaccinia viruses up to tenfold, fever, systemic symptom score and missed activities are significantly mitigated.
The rates of adverse events in the ongoing DoD vaccination program ( Table 2 ) are below historically anticipated levels[70,71,72] for a number of reasons, including careful screening to exclude those at predictably higher risk, enhanced vaccine education, and a generally healthy population pool. Ten military subjects with undiagnosed HIV infection, all with CD4+ counts above 280 cells/mm3, were inadvertently vaccinated and tolerated the local vaccinia infection without untoward clinical sequelae. In the concurrent DHHS program, seven cases involving the well-described, serious complications of smallpox vaccination were reported: one subject experienced suspected postvaccinial encephalitis; three had confirmed or suspected generalized vaccinia; and three subjects experienced ocular autoinoculation ( Table 2 ).[62,74,75] The relative dearth of 'expected' vaccine complications in these programs is probably multifactorial with more rigorous screening for contraindications than during the era of routine vaccine use, a lower overall denominator of vaccinees than during past routine vaccination, limiting vaccines to adults and possible reporting differences being the main reasons.
Cardiac complications of first-generation smallpox vaccines were reported, albeit infrequently, during the era of routine use decades ago. Five cases of myopericarditis were described in association with the NYCBH strain in the USA; data from Finland and Australia involving non-NYCBH vaccinia strains support rates as high as one case per 10,000 vaccinees and 1.6 per million, respectively. Up to 3% of Swedish military recruits were found to have nonspecific, asymptomatic T-wave changes on electrocardiogram following smallpox vaccination in the 1960s.[79,80] Nonetheless, a retrospective review of death certificates in New York (NY, USA) during a 4-month period in 1947 in which 6 million people were vaccinated against smallpox using the NYCBH strain failed to show a significant increase in cardiac deaths attributable to vaccination.
In the recent, posteradication vaccination programs, two forms of cardiac complications associated with smallpox vaccination were recognized: ischemic events and myopericarditis. The US military identified 24 subjects with ischemic events within 4 weeks of vaccination; the civilian program identified ten.[62,74,75,82] Of these, 19 experienced myocardial infarction, three of whom died. Both the military and civilian rates of ischemic events were within the range expected for an age-matched population, and all occurred in vaccinia-experienced individuals.[82,83] In addition, four cases of dilated cardiomyopathy in the military cohort and three cases in the civilian cohort, all but one in re-vaccinees, were recognized between 1 and 7 months after vaccination.
Despite the lack of a clear causal relationship between ischemic cardiac events and smallpox vaccination, the US CDC promulgated new recommendations regarding cardiac prescreening, surveillance and vaccine contraindications for pre-outbreak smallpox vaccination based on the temporal associations. Vaccine deferral on the basis of known heart disease or multiple cardiac risk factors was not associated with a clear reduction in ischemic cardiac events.
The DoD identified 140 cases of myopericarditis during its first 2 years of the program, largely in male, Caucasian, primary vaccinees,[75,84] representing a rate of approximately 1.2 per 10,000 - similar to the historical rates in Finnish conscripts. The rate in the civilian DHHS vaccination program in which 21 cases were identified was similar if only probable cases were considered, but was approximately 5.5 per 10,000 if both suspected and probable cases were included. Both rates were higher than age-matched, unvaccinated individuals and since cases cluster in the second week after vaccination, the appropriate conclusion is that primary smallpox vaccination of adults using first-generation vaccinia is associated with a hitherto unrecognized, increased risk of myopericarditis.
Second-generation vaccines, ACAM2000 and CCSV, show no significant differences in local or systemic adverse events compared with Dryvax. While none of the rare but well described, serious adverse events related to smallpox vaccines have been noted with these newer vaccines to date, small sample sizes preclude a relative risk determination. Seven out of 2983 (0.2%) vaccinia-naive subjects who received ACAM2000 and three out of 868 (0.3%) who received Dryvax during recent Phase II and III trials were identified as cases of suspected vaccine-induced myopericarditis.[17,22,108] These rates extrapolate to approximately fivefold higher than those noted in the DoD and DHHS efforts, possibly as a result of rigorous, active surveillance for cardiac complications informed by the findings of these posteradication vaccination programs, although the distinction between suspected and confirmed cases needs to be taken into account.[22,63]
Although no statistically significant differences were observed in the rates of myopericarditis between those who received ACAM2000 versus Dryvax, the Phase III trials of ACAM2000 were prematurely terminated on this basis. Since myopericarditis cases have occurred in subjects who had received first- or second-generation vaccines, this complication appears to be directly or indirectly related to vaccinia virus and unlikely to be related to an adventitious agent introduced in the processing of lymph. The higher incidence of myopericarditis observed in both treatment groups in the ACAM2000 studies, compared with the government-sponsored vaccination programs, probably results from active surveillance using routine assessments of cardiac symptoms, cardiac enzymes and electrocardiograms designed to identify asymptomatic individuals or cases involving only mild or transient symptoms.
The prototypical third-generation vaccines, LC16m8 and MVA, lack large-scale human safety evaluations. LC16m8 was noted to be well tolerated in both an open-label study involving 476 primary vaccinees and 552 revaccinees and in comparison with Dryvax in 153 vaccinia-naive volunteers; neither vaccinia-associated serious adverse events nor cardiovascular complications were noted, although planned cardiac evaluations were not performed. In an open-label study, one primary vaccinee developed acute sensorineural deafness and one reported chest pain ascribed by the authors to musculoskeletal causes, with no further information provided.
MVA appears to be associated with dose-related, local reactions in the majority of recipients; these self-limited events have not led to discontinuation of subjects from Phase I studies. In a small study of vaccinia-naive individuals with either a history of atopic dermatitis or with active atopic dermatitis, groups in which first-generation vaccinia vaccines are traditionally contra-indicated, all subjects receiving MVA reported mild-to-moderate local reactogenicity but no serious adverse reactions. MVA-primed subjects exhibit decreased reactogenicity and minimal systemic symptoms following Dryvax challenge compared with placebo-primed subjects, supporting a modulating effect of MVA in the context of safety, similar to that seen in efficacy studies. No vaccinia-associated serious adverse events or cardiac complications have been observed with MVA to date, although cardiac evaluations are uniformly lacking.
Expert Rev Vaccines. 2008;7(8):1225-1237. © 2008 Expert Reviews Ltd.
Cite this: Smallpox Vaccines for Biodefense: Need and Feasibility - Medscape - Oct 01, 2008.