Smallpox vaccination: neurologic complications

Douglas J Lanska MD FAAN MS MSPH (Dr. Lanska of the Great Lakes VA Healthcare System and the University of Wisconsin School of Medicine and Public Health has no relevant financial relationships to disclose.)
Originally released May 21, 2003; last updated March 6, 2014; expires March 6, 2017


The author explains the clinical presentation, pathophysiology, prevention, and diagnostic work-up of suspected encephalomyelitis following smallpox vaccination. Active efforts are underway to develop a safer vaccine for smallpox with fewer and less serious neurologic complications.

Key points


• Various neurologic complications of smallpox vaccination have been reported, including encephalitis, transverse myelitis, meningitis, and polyneuritis.


• Smallpox vaccination with the New York City Board of Health vaccine previously used in the United States was associated with a low rate of postvaccination encephalitis (3 cases per 1 million vaccinations).


• Postvaccination encephalitis usually occurs 10 to 14 days after vaccination, but it may occur from 7 to 21 days after vaccination.


• Headache, vomiting, drowsiness, and fever are often the first symptoms observed in postvaccination encephalitis. In mild cases, these may be the only symptoms, and in such cases recovery is often rapid and complete. In more severe cases, symptoms progress to include disorientation, confusion, stupor or coma, paralysis, incontinence, urinary retention, and seizures.


• Case-fatality rates for postvaccination encephalomyelitis vary considerably, from approximately 10% to 50%. Death can occur suddenly, usually within a week of onset of symptoms.


• Approximately 25% to 30% of all survivors of postvaccination encephalitis have some residual neurologic defect.

Historical note and terminology

Smallpox is a serious, often fatal, highly contagious viral disease that has killed millions of people over the past several thousand years.

Image: Child infected with smallpox

Variolation with live smallpox was practiced prior to the development of cowpox vaccination by Edward Jenner (1749-1823) in 1796 (Stewart and Devlin 2006).

Image: Edward Jenner
Image: Cowpox in "M" (or mulberry) form (transmission electron micrograph)
Although medical practitioners were initially skeptical of Jenner's vaccination, smallpox vaccination was compulsory in England and Wales by 1853.

The last indigenous case of smallpox in the United States was in 1934, and the last imported outbreak was in 1949. Routine smallpox vaccination was stopped in 1972 for most United States civilians (ie, nonhealthcare workers), and in 1976 for healthcare workers (Cleri et al 2003; Lane and Goldstein 2003). The last case of naturally acquired smallpox occurred in Somalia in 1977 and the World Health Organization declared smallpox eradicated from the World in 1980 (Booss and Davis 2003; Cleri et al 2003; Johnson 2003). Vaccination of United States military recruits stopped in 1990.

Although naturally acquired smallpox was finally eradicated from the entire world by 1980, stocks of the virus have been maintained in at least 2 laboratories in the United States and the former Soviet Union. The United States government is now concerned that the smallpox virus may have been acquired by several other countries and could be used as an agent of bioterrorism.

At this time most people in the United States probably have little resistance to smallpox virus, even if they were vaccinated prior to 1972 when routine smallpox vaccination stopped in the United States. Currently, there is no effective treatment for smallpox, and the only available prevention is vaccination.

The Dryvax® smallpox vaccine previously used in the United States was 90% to 95% effective in preventing smallpox among those exposed to the virus. It provided good levels of protection for at least 5 years, but then protection gradually decreased. Unfortunately, the vaccine had serious potential side effects. Based on past experience with the vaccine, for every 1 million individuals vaccinated, between 15 and 50 individuals suffered severe complications, and 1 or 2 were likely to die from the vaccine (Kemper et al 2002; Cono et al 2003). Severe complications were more likely among people being vaccinated for the first time, among infants, and in those with recognized contraindications to vaccination (Cono et al 2003). Dryvax® was last manufactured in 1978 (Wyeth Laboratories, Marietha, PA). There were only 15 million doses of the smallpox vaccine left after the suspension of all smallpox vaccinations. The remaining doses of Dryvax® were destroyed in 2008.

Encephalitis as a complication of smallpox vaccination was initially recognized in 1905 (Roos and Eckerman 2002). Since then, the estimated incidence of encephalitis and other neurologic complications of smallpox vaccination has varied considerably over time and across countries (Kretzschmar et al 2006). Some of the variation reflects use of different strains of virus in the vaccines: vaccination with the New York City Board of Health strain is associated with a low rate of postvaccination encephalitis (3 cases per 1 million vaccinations), whereas the Lister and Copenhagen strains are associated with intermediate rates (26 and 33 cases per 1 million vaccinations, respectively), and the Bern strain is associated with very high rates (45 cases per 1 million vaccinations). Some additional variation in reported rates over time is explained by changes in vaccine production methods, quality control, vaccination procedures, health care, and case ascertainment (eg, better ascertainment procedures may have reduced the number of adverse events misdiagnosed as postvaccination encephalitis) (Kretzschmar et al 2006).

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