Researchers have reported four cases of temporary arthritis they believe are associated with a controversial Lyme disease vaccine.
Since the vaccine LYMErix was approved in December 1998, there have been questions about whether it might cause arthritis in some people. GlaxoSmithKline, the vaccine maker, has maintained that there have been no higher incidence of arthritis than seen in a normal population.
Although there have been dozens of anecdotal reports of arthritis-like reactions to the vaccine — some of them quite serious and lasting — these four cases are the first fully documented reports followed by experts “that we are aware of,” said Paul Fawcett, head of the immunology laboratories at the duPont Hospital for Children in Wilmington, Del., who conducted the research.
All four cases were reported at the national scientific meeting of the American College of Rheumatology in Philadelphia in November and at the Lyme Disease Foundation annual meeting at Farmington, Conn., on April 22. Fawcett said the cases also have been reported to the manufacturer.
Two cases involved employees of the Wilmington hospital, one a pulmonary specialist and the other a surgeon, who volunteered for a study of the vaccine for the tick-borne disease.
The other two cases involved children, ages 9 and 16, who participated in a pediatric Lyme vaccine trial and were referred to Fawcett and his fellow researcher, Dr. Carlos Rose, an associate professor of pediatrics.
The vaccine has been approved for those 15 and older, but not for those younger. The company has conducted a pediatric clinical trial of 4,087 children ages 4-18 and is seeking approval of the vaccine for use among children.
In an e-mail, company spokeswoman Carmel Hogan said she could not comment on any individual cases but “we reaffirm our position that all evidence to date from clinical trials and post marketing data establishes LYMErix to be safe and effective.”
Hogan also said the pediatric trial found “no increase in the reports of arthritis in the vaccine recipients when compared with placebo recipients. Submissions for a pediatric indication and other applications are currently before the FDA and the company continues to support these applications.”
Lyme disease can in most cases be effectively treated with antibiotics. Some have questioned whether vaccine protection against a generally treatable disease is worth the potential risk of a severe adverse reaction.
The two adult cases occurred in a study of 20 volunteers at the hospital, designed to look at the evolution of the immune response to the vaccine. In both cases, the participants developed severe swelling, redness and pain in their fingers within 24 hours of the second dose of the vaccine. Three doses are needed to confer immunity.
The surgeon, 53, also developed flu-like symptoms, achiness, swelling in his toes and severe pain in his shoulders. His symptoms subsided within four or five days, the researchers reported.
Like the surgeon, the pulmonary specialist, 43, reported pain throughout his body within 24 hours of his second dose and was unable to work for three days. His symptoms went away after seven weeks.
Tests before and during the study showed no signs that the participants had Lyme disease, and swelling in the hands is not typical of Lyme disease, which tends to cause swelling in joints such as the knee.
“There’s absolutely no question these are the result of the vaccine. This manifestation is really unusual for Lyme disease and there’s definitely no serologic sign of infection,” Fawcett said.
Fawcett also was a member of the data monitoring safety board for the clinical trial of a Lyme vaccine made by Pasteur Merieux Connaught. Connaught never sought approval of the vaccine, which was similar to GlaxoSmithKline’s, and it was never brought to market.
The pediatric cases are more complicated. In one, a 9-year-old boy developed severe pain in both knees and swelling in the right knee several weeks after the third dose of the vaccine.
About a month later, he developed swelling in his right elbow; several months after that, he developed arthritis in his hip. Weeks after that, his right thumb became swollen.
A Western blot, a technique used to identify specific proteins, coupled with his widespread arthritis, made researchers suspect that the boy had asymptomatic Lyme disease, and that the vaccine had set off a form of arthritis not commonly seen in Lyme disease.
The boy also had the HLA-DR4+ gene found in about 20 percent of people. A test tube study by Dr. Allan Steere, lead investigator for the GlaxoSmithKline adult vaccine trial, showed part of the Lyme vaccine has the potential for “cross-reacting” with people who have this gene type — that is, the body’s immune system could theoretically attack its own protein, thinking it was the invading Lyme bacteria.
In the fourth case, a 16-year-old boy, who had been diagnosed and treated for Lyme disease three years earlier, had pain in both knees and swelling in his right knee several months after his third dose of the vaccine.
There appeared to be no other explanation for the swelling and no sign that he had been recently exposed to Lyme disease, Fawcett said.
The Western blot showed no signs of actual infection but showed “excess ” reactivity to other proteins” than the vaccine protein, Fawcett said. “We concluded that the swelling was related to the vaccine,” Fawcett said.
Both boys were treated with antibiotics and their symptoms subsided.
The vaccine works by stimulating the immune system to produce antibodies to a protein on the outer surface of the Lyme-causing bacterium B. Burgdorferi, called outer surface protein A, or OspA.
“We believe that the immune response to OspA is resulting in an autoreactive response. We do not know the nature of that response and we’ve seen in individuals who have only received the vaccine a frank arthritis,” Fawcett said. “In individuals with a prior history of infection or ongoing infection it appears it can result in an aggravated arthrogenic response.”
Fawcett said part of the problem in the two pediatric cases was that the Western blot tests supplied by the vaccine maker were confusing, showing a cross reaction with other proteins beside OspA. This made it hard to determine whether the response was just to the vaccine, Fawcett said.
Two tests are typically used to diagnose Lyme disease, an ELISA test, another assay that tests for antibodies, and a Western blot. It is known that someone who has had the vaccine will test positive on an ELISA. The vaccine maker, however, has maintained that a Western blot is able to distinguish between someone who had had Lyme disease and someone who has had the vaccine. Fawcett, though, believes the commercially available Western blots are not always able to do that.
In January, the Food and Drug Administration convened a meeting of its vaccine advisory panel. Although there was no formal vote, every member expressed concern about the vaccine’s safety and called for better follow-up studies.