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The national smallpox vaccine program proved last year to be a bumpy road; it was also especially spotty for about 10 percent Vanderbilt's vaccinated volunteers who broke out in a curious acne-like rash.

"Several of the volunteers said their acne worsened, and we weren't sure it was the vaccine," said Dr. Tom Talbot, an Infectious Diseases fellow and co-investigator in Vanderbilt's smallpox vaccine clinical trials. (The national trials also were coordinated here.)

He set the claims aside -- this type of reaction hadn't been documented in previous vaccinations -- but the investigative side of his public health brain kept it simmering.

"Then in late October (2002, during the clinical trial), we saw two volunteers with generalized rashes on their backs and legs and we became more attuned to a possible association with the vaccine," Talbot said. "The second light bulb to go off was in a news story in which one volunteer noted new "acne" on his back after vaccination. He said he 'felt like a teen-ager again'."

That's all the evidence Talbot needed to start his own sleuthing. He documented the outbreaks and biopsied pustules on seven patients, and compiled the data into a rash study that ran in the June 25 issue of the Journal of the American Medical Association

From October to the first of December last year, his study reports, 148 volunteers participated in the most recent of Vanderbilt's smallpox vaccine trial. All were between 18 and 32 years old, had never received the vaccine and passed a health battery. Talbot and Dr. Kathryn Edwards, professor of Pediatrics and vice chair for Pediatric Research, were testing the efficacy of the Aventis Pasteur smallpox vaccine at full strength and in dilutions of one-to-five and one-to-10.

Between eight and 10 days post-vaccination, the time of maximal viral replication, four people had a generalized rash of pustules on their arms, legs, face, back and trunk; 11 had a similar, but more focal, reaction.

Historical accounts of smallpox vaccine side effects listed "non-descript rashes or general vaccinia," a spreading of the virus throughout the body, a sometimes fatal side effect, Talbot said. But, he added, "they were never well described."

Samples of the lesions seen at Vanderbilt tested negative for the virus, ruling out vaccinia and possibly establishing a new, less serious, reaction to the vaccine: folliculitis, benign eruptions like pimples.

"We wanted to see if this eruption was common in adults after vaccination, and if it could be mistaken for general vaccinia," Talbot said. The paper, he said, was an effort to lessen anxiety and provide some clarity for physicians who might see the rash on patients and confuse the less serious reaction with a fatal one.

"Tom conducted a meticulous study of reactions after vaccination," said Edwards, a co-author on the study. "Many investigators saw small blisters after vaccination and believed that they represented disseminated vaccinia. However, Tom discovered that much to the contrary, the lesions were a folliculitis and did not represent infectious virus at all. His findings are reassuring for our upcoming studies and for the military population who continues to be immunized."

The reasons for folliculitis, Talbot suggests, might lie in the differences between the adults in the smallpox vaccine trial population and the children who routinely received the vaccine until 1972.

"Children don't have as many hair follicles as adults, which may explain the high incidence in the study population of adults," Talbot said. He and his colleagues propose that the eruption may be related to the vigorous immune response seen after vaccination. Reassuringly, volunteers had minimal to no symptoms related to the eruption, which was also short-lived and resolved without scarring.

Three other smallpox vaccine studies, in civilian and military populations, ran in the same JAMA issue that carried Talbot's. An editorial by Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said Talbot's study "illustrates the value of reevaluating seemingly established phenomena when new (diagnostic and technological) tools become available."

"If these cases had occurred 40 years ago, when cultures were not routinely performed on lesions occurring after vaccination, these individuals might have been diagnosed as having generalized vaccinia," Fauci and co-author Dr. Mary E. Wright, also of the NIAID, wrote.