Public Release: 

Serious adverse reactions to smallpox vaccine appear to be limited

The JAMA Network Journals

There was a low rate of life-threatening adverse reactions to the smallpox vaccine administered to potential first responders to a bioterrorism incident, possibly attributable to rigorous vaccine safety screening and educational programs, according to a study in the December 7 issue of JAMA.

Routine childhood immunization against smallpox in the United States ceased in 1971, according to background information in the article. Although the World Health Organization declared in 1980 that smallpox had been eradicated worldwide, there is concern that smallpox virus may exist outside the World Health Organization−designated repository laboratories and may be used as a bioweapon. Detection of a smallpox case could represent an intentional bioterrorism event requiring an immediate, coordinated response by public health, medical, and law enforcement personnel to control the outbreak and protect the public.

In January 2003, the U.S. Department of Health and Human Services (DHHS) implemented a voluntary civilian smallpox vaccination program, in which vaccine was administered to federal, state, and local volunteers who might be first responders during a bioterrorism event.

Christine G. Casey, M.D., of the Centers for Disease Control and Prevention, Atlanta, and colleagues examined the vaccine safety profile among civilians who received smallpox vaccine between January 24 and October 31, 2003. The researchers evaluated adverse events reported via the Vaccine Adverse Event Reporting System (VAERS) and the Centers for Disease Control and Prevention.

A total of 37,901 volunteers in 55 jurisdictions received at least 1 dose of smallpox vaccine. VAERS received 822 reports of adverse events following smallpox vaccination (overall reporting rate, 217 per 10,000 vaccinees). A total of 590 adverse events (72 percent) were reported within 14 days of vaccination. Nonserious adverse events (n = 722) included multiple signs and symptoms of mild and self-limited local reactions. One hundred adverse events (12 percent) were designated as serious, resulting in 85 hospitalizations, 2 permanent disabilities, 10 life-threatening illnesses, and 3 deaths. Among the serious adverse events, 21 cases were classified as myocarditis (inflammation of the muscular tissue of the heart) and/or pericarditis (inflammation of a membrane that surrounds the heart) and 10 as ischemic cardiac events that were not anticipated based on historical data. Two cases of generalized vaccinia (a skin eruption in reaction to vaccination) and 1 case of postvaccinial encephalitis (inflammation of the brain) were detected. No preventable life-threatening adverse reactions, contact transmissions, or adverse reactions that required treatment with vaccinia immune globulin were identified. Serious adverse events were more common among older revaccinees than younger first-time vaccinees.

"The absence of preventable serious adverse reactions provides indirect evidence of effective vaccination screening and education, as well as attentive vaccination site care and monitoring," the authors write.

"This comprehensive smallpox vaccine safety monitoring and response system can serve as an effective model for vaccine campaigns that may occur in response to public health emergencies. Unique aspects included rapid detection, investigation, and response to rare and potentially serious adverse events. Our report highlights the success of education, screening, and clinical investigations and reviews in augmenting a robust safety monitoring system to minimize preventable adverse events. Additional reduction of overall vaccinia adverse events might be achievable through study of cardiac and dermatological risk factors, a better understanding of vaccinia host-pathogen interaction, and development of a less reactogenic vaccinia vaccine," the researchers conclude.


(JAMA.2005; 294:2734-2743. Available pre-embargo to the media at

Editor's Note: All financial and material support for the surveillance efforts was conducted as part of the CDC and state health department public health response. No additional funding was sought to support these activities.

Neurologic Adverse Events From Smallpox Vaccine Generally Mild

In a related study in this issue of JAMA, adverse neurologic reactions from smallpox vaccination were generally mild and the rate of specific syndromes did not exceed baseline estimates.

Rare adverse events causally associated with smallpox vaccination include neurologic syndromes such as central nervous system (CNS) and peripheral nervous system (PNS) complications, according to background information in the article. The most common CNS complication after smallpox vaccination is encephalitis (postvaccinial encephalomyelitis - inflammation of the brain and spinal cord). Other infrequent events can include headache, Guillain-Barré syndrome (a temporary inflammation of the nerves, causing pain, weakness, and paralysis in the extremities), Bell palsy (paralysis of the facial muscles), and myelitis (inflammation of the spinal cord).

James J. Sejvar, M.D., of the Centers for Disease Control and Prevention, Atlanta, and colleagues assessed reports of postvaccinial encephalomyelitis and other neurologic adverse events between December 16, 2002, and March 11, 2004, among DHHS and DoD smallpox vaccinees, to clinically characterize them and assess their frequency. Information on the events was obtained through active case reporting and review of data submitted to the Vaccine Adverse Event Reporting System among 665,000 persons vaccinated against smallpox by the Departments of Defense (n = 590,400) and Health and Human Services (n = 64,600) during the 2002-2004 U.S. Smallpox Vaccination Program.

The researchers found that there were 214 neurologic adverse events temporally associated with smallpox vaccination; 111 reports involved DHHS and 103 involved DoD vaccinees. Fifty-four percent of these events occurred within 1 week of vaccination, and 53 percent were among primary vaccinees. The most common neurologic adverse event was headache (95 cases), followed by nonserious limb paresthesias (n = 17) or pain (n = 13) and dizziness or vertigo (n = 13). Serious neurologic adverse events included 13 cases of suspected meningitis, 3 cases of suspected encephalitis or myelitis, 11 cases of Bell palsy, 8 seizures (including 1 death), and 3 cases of Guillain-Barré syndrome. Among these 39 events, 27 (69 percent) occurred in primary vaccinees and all but 2 occurred within 12 days of vaccination.

"Our findings identified many milder neurologic adverse events temporally but not necessarily causally associated with smallpox vaccination. They suggest that such events are generally self-limited, nonserious, and not associated with severe morbidity or mortality when screening defers persons with high-risk conditions," the authors write.

"Smallpox vaccine was given to healthy people, which creates a low tolerance for associated risk. Risks associated with vaccines are best identified through population-based assessments. New, possibly less reactogenic smallpox vaccines are currently under development. Continued monitoring for neurologic events is needed to assess the safety of smallpox vaccines and to better characterize the spectrum of neurologic illness associated with them," the researchers conclude.

(JAMA.2005; 294:2744-2750. Available pre-embargo to the media at

Editor's Note: This study was supported by the CDC and the U.S. Department of Defense.

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