Special Feature

Adverse Reactions to the Smallpox Vaccine

By John R. Lonks, MD, and Maria D. Mileno, MD

Synopsis: Infectious disease experts and their colleagues in government continue to struggle to determine just who should receive smallpox vaccine in approaching the bioterrorism threat. While the vaccine is not available for use in travel clinics, the risks and benefits surrounding the process of smallpox vaccination should be known and are described here, based upon the most recent published experience.

Sources: Grabenstein JD, Winkenwerder W. US military smallpox vaccination program experience. JAMA. 2003; 289(24):3278-3282; Halsell JS, et al. Myopericarditis following smallpox vaccination among vaccinia-naïve US military personnel. JAMA. 2003;289(24):3283-3289; Frey SE, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med. 2002;346(17):1265-1274.

Smallpox vaccine (vaccinia virus) consists of a live virus vaccine that replicates locally within the skin. Successful vaccination provides protection against infection with smallpox. Some vaccine recipients (27-77%) develop local symptoms such as pain at the vaccination site. Systemic symptoms may also occur. High rates of successful vaccination, which include full skin reactions as defined by WHO response rates, were reported recently from the US military immunization program clinics. Four sites conducted the vaccinations: Walter Reed Army Medical Center, Washington, DC; Aberdeen Proving Ground, Maryland; Wilford Hall Air Force Medical Center, Lackland Air Force Base, San Antonio, Tex; and the National Naval Medical Center, Bethesda, Md. Nine hundred seventy-one of 1017 (95.5%) primary vaccinees were successfully vaccinated with a single vaccination. Nine hundred thirty-four of 975 (95.8%) previously vaccinated individuals also achieved successful responses.

A study reported in the New England Journal of Medicine in 2002 indicated that adults showed adverse reactions between days 7 and 9 following vaccination, 8.9% had fever > 100°F, 3.0% had fever > 101°F, and 0.8% had fever > 102°F. From days 0 to 14 after vaccination, 16-44% of vaccine recipients had headache, 17-53% had fatigue, 9-50% had muscle aches, 2-18% had chills, and 4-16% had nausea. The majority of patients categorized these symptoms as mild or moderate, while the minority (3% or less) were severe.

Data obtained in 1963 provide us with some insight and perspective regarding a number of additional serious adverse reactions and their rates of occurrence in primary vaccinees. Note that all of these adverse events were much less common after revaccination than after primary vaccination. Inadvertent inoculation occurred in 14 per 1 million; generalized vaccinia in 21 per 1 million; eczema vaccinatum in 9 per 1 million; progressive vaccinia in 1 per 1 million; and postvaccinial encephalopathy/postvaccinial encephalitis in 2 per 1 million. Inadvertent inoculation (accidental implantation) refers to the transfer of vaccinia, usually via the hands, from the vaccination site to other parts of the body such as the face, eyelid, genitalia, and rectum where the virus reproduces and a lesion develops. Historically, accidental implantation was the most common adverse event. Vaccinia keratitis is the result of accidental implantation of vaccinia into the cornea and could result in blindness. Generalized vaccinia occurs when vesicular or pustular lesions occur beyond the vaccination site. It is self-limited when it occurs in those who are not immunocompromised. Eczema vaccinatum refers to localized or systemic spread beyond the vaccination site of vaccinia virus to areas of the skin affected by eczema or atopic dermatitis. This includes areas of skin with inactive or active eczema/atopic dermatitis. However, it may also occur in those with chronic exfoliative skin lesions such as moderate or severe psoriasis, severe acne, epidermolysis bullosa, pemphigus vulgaris; or acute self-limited disorders that disrupt the epidermis such as impetigo, varicella, varicella zoster, acute burns, acute contact dermatitis and pityriasis rosea; or a history of Darier’s disease (keratosis follicularis). The severity of eczema vaccinatum ranges from a mild self-limited reaction to a severe and sometimes fatal illness.

Progressive vaccinia (vaccinia necrosum) is characterized by continuing and progressive necrosis at the vaccination site. Lesions may develop at other body sites. It is both a severe and potentially fatal adverse event. Progressive vaccinia usually occurs in persons with some form of immunodeficiency. Other rare adverse events affecting the skin include generalized rashes (erythematous, urticarial, nonspecific), erythema multiforme (Stevens-Johnson syndrome) and secondary bacterial infections at the site of vaccination.

Neurological complications include postvaccinial encephalopathy and postvaccinial encephalitis; the distinction between these 2 entities is based on pathologic findings. Postvaccinial encephalopathy usually occurs in children younger than 2 years, resulting in fevers and convulsions beginning 6-10 days after vaccination. Postvaccinial encephalitis usually affects those older than 2 years and begins 11-15 days after vaccination. Both postvaccinial encephalopathy and postvaccinial encephalitis can be fatal, and those who survive may have permanent sequelae. Some studies have referred to both processes as postvaccinial encephalitis. Death has occurred in 1 or 2 persons per million vaccinated and was most often due to postvaccinial encephalitis or progressive vaccinia.

Smallpox vaccine has not caused congenital malformations. Rare reports describe fetal infection in pregnant women who experienced stillbirths or infant deaths shortly after delivery. These events usually occurred after primary vaccination. Women of childbearing potential should be instructed not to become pregnant for at least 4 weeks after vaccination.

Vaccinia, because it is a live virus, can be spread to unvaccinated contacts such as those living in the same household (contact vaccinia) or sexual partners. Besides developing lesions at the accidental implantation site, the individual is at risk for developing other complications. Historically, accidental implantation (inadvertent inoculation) and eczema vaccinatum were the 2 most common complications of contact vaccinia. In 1963, there were 22 cases of inadvertent inoculation, mostly children age 1-4 years old, and 54 reported cases of eczema vaccinatum in contacts. During the same year, 6.239 million individuals received primary vaccination and 7.775 million received revaccination.

Of the 35,903 civilians who received the smallpox vaccine from Jan. 24 to May 2, 2003, there were no cases of eczema vaccinatum, progressive vaccinia, postvaccinial encephalitis or postvaccinial encephalomyelitis, fetal vaccinia, or erythema multiforme major. There were 12 suspected and 3 confirmed cases of inadvertent inoculations that did not involve the eye, 2 confirmed cases of ocular vaccinia and 2 suspected and 1 confirmed case of generalized vaccinia. There were no cases of transmission from vaccinees to others in the health care setting or other settings while there were 9 cases spread from military vaccinees to civilian contacts. More than 430,000 individuals in the military received the vaccine since December 2002. There were 36 cases of generalized vaccinia all of which were mild, 48 cases of autoinoculation, 19 cases of transmission to others, and no cases of eczema vaccinatum or progressive vaccinia. According to the National Smallpox Vaccine in Pregnancy Registry, 6 women in the civilian population and 85 in the military were inadvertently exposed to the smallpox vaccine during pregnancy.

In the past, myocarditis was reported as an adverse vaccine event in a European cohort only. In the United States, where a different vaccine strain was used, myocarditis had not been a well-recognized complication. During the recent vaccination program, there have been 14 suspected, 1 probable, and no confirmed cases of myocarditis/pericarditis among 35,903 civilian vaccinees as a result of the smallpox vaccine. In the military study, there were 26 probable and 1 confirmed case of myocarditis and/or pericarditis among more than 430,000 vaccinees. There were 18 primary vaccinees among the US military personnel with probable myocardial disease. All cases survived and all returned to duty or are on short-term leave. The mechanistic relationship between vaccination and myocarditis/pericarditis is still not clear and is under investigation. Angina and myocardial infarctions have been reported following receipt of the smallpox vaccine. It is not known whether the vaccine actually caused these problems.

Treatment with Vaccinia Immune globulin (VIG) is available from the CDC for some of the complications of the smallpox vaccine. It is indicated for treatment of the following complications: progressive vaccinia, eczema vaccinatum, severe or recurrent cases of generalized vaccinia, and extensive accidental implantation. VIG is not indicated for mild cases of accidental implantation, mild cases of generalized vaccinia, erythema multiforme, postvaccinial encephalitis, and vaccinia keratitis. Patients with vaccinia keratitis should be treated with topical antiviral agents by a knowledgeable ophthalmologist.


Hundreds of millions of people have died of smallpox throughout history. Soldiers and sailors were often targets of this disease. Civilian outbreaks also occurred and vaccinated service members spread vaccinia to several civilians as recently as the 1980s. The disease begins with fever, aches, and nausea and later develops into a blistering rash. Death is due to overwhelming viremia and hypotension. To prepare against biological attacks using this agent, the United States Department of Defense implemented the US military smallpox vaccination program in December 2002. The experience described here suggests that a broad smallpox vaccination program may be implemented safely, with expected temporary symptoms. However, some individuals who set out to be first responders should avoid vaccination. Practitioners should identify those individuals who have susceptibilities known or thought to predispose to adverse events for themselves (the vaccinees) or their close contacts. These include pregnancy or breast-feeding; extensive skin eruptions present at the time of vaccination; atopic dermatitis (active or history of atopic dermatitis or "eczema"); presence or probability of T-cell immune defects or disease, congenital, or acquired; immunosuppressive therapy; inflammatory or disruptive diseases of the cornea or surrounding structures; and age < 1 year. Antibody deficiency generally has not led to adverse events, except in very few instances, usually in association with temporary loss of T-cell function. Nevertheless, such individuals should not be vaccinated in situations in which no risk of contact with smallpox is present.

Myopericarditis should be considered an expected adverse event associated with smallpox vaccination. Clinicians should consider myopericarditis in the differential diagnosis of patients presenting with chest pain 4 to 30 days following smallpox vaccination. Echocardiography to document decreased ventricular function and an elevated serum troponin level suggest significant myocyte injury and may indicate the need for diagnostic endomyocardial biopsy. Such specimens should be tested for the presence of vaccinia virus. Persons with known cardiac disease or serious potential risk factors for cardiac disease should also be considered exempt from vaccination.

Dr. Mileno is Director, Travel Medicine, The Miriam Hospital, Assistant Professor of Medicine, Brown University, Providence, RI.

Suggested Reading

1. Neff JM, et al. Complications of smallpox vaccination. I. National survey in the United States, 1963. N Engl J Med. 1967;276(3):125-132.

2. Update: Adverse events following civilian smallpox vaccination—United States, 2003. MMWR Morb Mortal Wkly Rep. 2003;52(19):444-446.

3. Fulginiti VA, et al. Smallpox vaccination: A review, part II. Adverse events. Clin Infect Dis. 2003;37: 251-271.