Smallpox Vaccines for Biodefense: Need and Feasibility

Andrew W Artenstein; John D Grabenstein

Disclosures

Expert Rev Vaccines. 2008;7(8):1225-1237. 

In This Article

Feasibility & Acceptability of Smallpox Vaccination

As smallpox is no longer a cause of naturally occurring disease in humans and there is no known animal reservoir for this pathogen in nature, any human case of smallpox occurring outside of a known laboratory exposure would be tantamount to bioterrorism.[86] Thus, any discussion of smallpox mitigation strategies, specifically pre-event or postevent vaccination, hinges on the concept of 'risk'. Risk refers to the likelihood that exposure to a hazard will lead to a negative consequence.[87] In the context of a smallpox threat, it is essential to consider both the probabilities of exposure and the potential range of consequences associated with the disease and with its vaccines in order to attempt to objectively gauge risk of this type. The probability of exposure to smallpox outside of a laboratory setting is believed to be low but not zero. It has been suggested that unreported smallpox stocks may have existed in the former Soviet Union; if this is accurate, the whereabouts of such viruses would not be known.[88] Since the exposure variable is dependent on the unpredictable tactics of terrorists, accurate, quantifiable risk appraisal is not possible.[89] However, the potential consequences of a bioterrorist attack using smallpox would be devastating.

Multiple characteristics of smallpox ensure that its deliberate reintroduction into the human population would be a global health catastrophe of profound dimensions. Smallpox is stable in aerosol form, raising the possibility of a large-scale attack; it has a low infective dose, requiring minimal viral inocula to cause productive infection in humans[3]; and case-fatality rates historically approached 30%. Morbidity from smallpox was substantial and included prolonged duration of illness, scarring of survivors, secondary soft-tissue infections and blindness.[3] Secondary attack rates among unvaccinated close contacts ranged from 37-88%, although these data derive from historical studies in developing countries and may not be analogous to current circumstances.[3,86,90] Additionally, much of the world's population is susceptible to smallpox due to the cessation of routine vaccination in the early 1970s and the absence of low-level, boosting exposures that would be expected if variola circulated naturally in the environment. Finally, other orthopoxviruses, such as monkeypox, may be pathogenic for humans in either naturally occurring outbreaks or bioterrorism scenarios and may be partially ameliorated by vaccinia immunity.[88,91,92]

While improvements in medical care and infection-control procedures, and advances in health technology may mitigate some of the expected morbidity and mortality from smallpox in the 21st Century, they represent a double-edged sword. These same advancements have increased the prevalence of immunocompromised hosts, a population at higher risk of serious morbidity and mortality from smallpox. Similarly, the prevalence of atopic dermatitis in the population has increased markedly since the discontinuation of routine smallpox vaccination; up to 10% of adults and 30% of children in industrialized countries are now diagnosed with this disorder.[93] Live-virus smallpox vaccines are traditionally contraindicated in this population as well. Furthermore, mass casualties due to a smallpox outbreak could rapidly overwhelm healthcare resources.

It has been variably estimated that the number of deaths in the USA after implementation of mass vaccination, using first-generation smallpox vaccines presumably in response to a realized threat, would conservatively range between 125 and 500, accompanied by thousands of serious adverse events.[65,66] In a postevent setting, where the actual smallpox 'event' was realized anywhere throughout the world, the risks associated with the disease would probably far outweigh the potential risks associated with vaccination; thus the benefits of vaccination would favor its deployment, although the relative merits of various strategies, ranging from mass vaccination to a more targeted, ring vaccination approach, are debatable.[66,94]

In an outbreak scenario, some combination of ring and mass vaccination would probably be implemented. Dilution studies that have expanded the existing supply of first-generation vaccines in concert with the licensure of a second-generation vaccine, ACAM2000,[109] have resulted in stockpiles of clinically effective vaccines sufficient to vaccinate the entire US population, serving as a fail-safe posture in the event of a biologic attack using smallpox.

In addition to the US stockpile, smallpox vaccine stockpiles are also being developed by other nations.[95] Recent experiences with posteradication vaccination and previous mass smallpox vaccination efforts[17,81] have demonstrated the feasibility of this approach. Japan has limited stockpiles of the attenuated LC16m8 vaccine, although more data would be needed to assure its efficacy and safety in individuals with vaccinia contraindications.[95] Many other nations have developed stockpiles of first- and, in some cases, second-generation vaccines; it is estimated that current capabilities would be sufficient to vaccinate approximately 10% of the world's population.[95] To assure vaccine availability to poorer nations and provide for a nimble response by the international public-health community, the WHO has recently implemented a plan to develop a strategic smallpox vaccine stockpile of at least 200 million doses, largely derived from pledged donations from member countries and reminiscent of the WHO's efforts during the global smallpox eradication program of the 1970s.[111]

By contrast, the concept of pre-event vaccination presents a more problematic analysis. Despite the relative dearth of serious adverse events in both the recent DoD and DHHS smallpox vaccination programs,[62,75] there was a low but meaningful incidence of complications related to first-generation vaccines. While the risks can be mitigated via careful screening and exclusion of those in selected higher risk categories, they cannot be completely abrogated. For instance, it has been demonstrated that more than a third of subjects with atopic dermatitis or other vaccine contra-indications were unrecognized using various screening strategies.[96,97] In a setting of a very low perceived risk of smallpox, are any levels of significant vaccine-related risks acceptable? Data from the civilian healthcare worker vaccination program of 2003 address this issue.[62]

Multiple, detailed evaluations of the DHHS program have been reported elsewhere.[62,74,82,98,99] While there appears to be general agreement that many aspects of the program were instructive from an operational public health standpoint, it remains unclear whether the program achieved the stated goal of enhancing national biodefense preparedness.[100] Certainly the number of civilians actually vaccinated fell far short, approximately 8%, of the 500,000 target set at the program's inception.[62] However, this in and of itself does not necessarily constitute failure, to the extent that the program served as a pilot study to explore the feasibility, acquire experience and reveal hitherto unrecognized issues.

Perhaps the most instructive aspects of the posteradication DHHS smallpox vaccination program, however, relate to the acceptability of vaccination among the targeted civilian groups, largely healthcare workers and others potentially involved in the initial response to a bioterrorist event. Revelations from this experience should inform future vaccination programs in the arena of biodefense. One contemporary study that modeled various smallpox attack scenarios demonstrates that the risk associated with pre-event vaccination of healthcare workers generally outweighs the potential health benefits when the probability of a smallpox attack is less than 22%; in order for mass pre-event vaccination of the public to be beneficial, the probability of an attack would have to be significantly higher, above 47%.[101]

In large part, healthcare workers and traditional first responders who declined voluntary smallpox vaccination determined that their personal risk associated with vaccination using first-generation smallpox vaccine outweighed the perceived risk of smallpox.[102,103] A number of additional factors contributed to the risk equation that ultimately limited the acceptability of pre-event smallpox vaccination in the 2003 setting: uncertainties regarding liability for vaccine-induced injury; sources of compensation and mechanisms of remedy for illness or injury related to vaccination; inadequate education concerning the risks and potential benefits of the program; the recognition of novel cardiac adverse events; and the lack of biological weapon caches in Iraq.[104,105] Individuals will generally act according to their personal perceptions of risk, but since it is inherently impossible to quantify the probability that a terrorist will release a biological weapon, the perceived risks associated with smallpox vaccination apparently dominated the equation in 2003.

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