Table 3. Risk-versus-benefit considerations for pre-event smallpox vaccination.

Risks/concerns	Benefit/mitigating factors	Unresolved issues	Ref.
• Probability of exposure to smallpox is difficult to reliably quantify, but is greater than zero – Weaponized viruses may be available – Growth and expansion of terrorist activities	• Currently available first- and second-generation vaccines are efficacious • Variola virus is difficult to manipulate in the laboratory • No known animal or natural reservoir of infection	• Second-generation vaccines demonstrate surrogate efficacy in humans; in the absence of a smallpox outbreak, their clinical effectiveness cannot be ascertained • Exposure to smallpox depends on the unpredictable acts of terrorists	[14,17,89]
• Reintroduction of smallpox into the human population would be potentially catastrophic, especially in settings with inadequate public health infrastructure – Variola virus can be aerosolized – Air-borne transmission has been documented – Mortality can exceed 30% – High secondary attack rates in some settings (e.g., healthcare environments) – Most people are either immunologically naive or were vaccinated decades ago – High transmission risk in healthcare settings – Genetic or molecular technology could be used to enhance virulence	• Effective vaccines are available • Postexposure vaccination, within 4 days, is protective • Aerosol transmission is not the predominant route • Improvements in supportive medical care may mitigate excess mortality • Remote vaccination may afford at least partial protection • Possible role for antivirals that were not available when smallpox occurred naturally	• Advances in medical care and health technology have also served to increase the prevalence of immunocompromised hosts and other subgroups in whom currently licensed smallpox vaccines are contraindicated • Medical resources may be overwhelmed by a large number of cases • Durability of vaccine-induced immunity is ill-defined in clinical settings	[3,89,107]
• Smallpox vaccines are associated with significant safety issues (Table 2) • Public acceptance will depend on scenario	• Post-eradication programs show that careful screening can minimize some serious adverse effects but may not avert myopericarditis	• Newer-generation vaccines may be associated with improved safety profiles, but currently there are insufficient data to demonstrate this