Lyme Disease Vaccine's Safety is Questioned

Vanessa Raffio was a horsewoman and a veterinarian's helper who loved hiking and riding in the woods – hobbies that seemed to place the suburban New Jersey teenager at high risk for getting Lyme disease. So two years ago, Raffio, then 17, asked her doctor for the recently approved vaccine against the tick-borne infection.

"I'm the one who pushed for it," recalled her mother, Linda Scharf-Lurie. "It was the biggest mistake of my life."

Soon after she got her second dose of the vaccine in June 1999, Raffio began having pains in her ankles, she said. That autumn, she developed severe pain in her neck and back as well, and was eventually diagnosed with rheumatoid arthritis. She also permanently lost the peripheral vision in her left eye when her optic nerve became inflamed.

These days, Raffio, now a college freshman at the University of Missouri at Columbia, is able to ride a horse only for brief periods, and uses an electrical nerve stimulator to relieve her chronic pain.

"I have arthritis . . . pretty much everywhere but my knees," Raffio said. "I've learned to manage to the best of my ability. . .‚. My body is not like everyone else's body."

Raffio is one of more than 100 people whose arthritis or joint swelling is being investigated by the Food and Drug Administration because of possible links to the vaccine.

Such cases, and the questions they raise about the vaccine's safety, have renewed a debate on the risks and benefits of vaccines for illnesses, such as Lyme disease, that are treatable or avoidable by other means.

"This is what some people have called a 'boutique vaccine,' " said Robert Daum, a professor of pediatrics at the University of Chicago who chaired the FDA advisory committee that reviewed the vaccine.

Sidney M. Wolfe, director of the Public Citizen Health Research Group, a consumer group, said that the "vaccine is being grossly overpromoted to people who don't live in parts of the country where [Lyme disease] happens very much."

Carmel Hogan, a spokeswoman for GlaxoSmithKline Inc., which makes the vaccine, defended its safety record and the company's marketing policies. The company has distributed 1.4 million doses of the vaccine and continues to sponsor follow-up research on its safety, she said.

"Based on clinical trials to date and postmarketing surveillance . . . there is no causal link between this vaccine and arthritis," Hogan said.

When the FDA approved the vaccine, called LYMErix, in 1998, the agency concluded that the product was safe after reviewing extensive studies sponsored by GlaxoSmithKline, including a two-year trial involving almost 11,000 healthy adults and adolescents. Neither that study nor a separate safety trial in people with a previous history of Lyme disease found evidence that the vaccine could cause arthritis or other serious adverse effects.

However, members of the FDA advisory committee that reviewed LYMErix expressed concern at the time that the vaccine might have the potential to provoke arthritis in some recipients. The committee asked GlaxoSmithKline to conduct a large follow-up study after approval, and urged long-term monitoring of the health of vaccine recipients.

Earlier this year, the same committee heard emotional testimony from Scharf-Lurie and others who believe that the Lyme vaccine made them or their family members sick. What they didn't hear, either from the company or from the FDA, was sufficient scientific evidence to settle the question of whether the vaccine caused the illnesses, Daum said.

"Your heart went out to these folks who came" to testify, he said. "And yet, where's the science? The committee was presented with what they thought was less than the science that they had hoped for – from everybody."

More than 16,000 cases of Lyme disease were reported in 1999, making it the most common illness transmitted by insects, ticks or spiders in the United States. Yet, most cases are concentrated in about 115 counties in the eastern and north-central United States where animals (chiefly mice and deer) have high infection rates with the disease-causing bacteria, increasing the likelihood that a tick bite will transmit the infection to humans.

Maryland reported 899 cases of Lyme disease in 1999, or about 18 cases per 100,000 population. (For comparison, Connecticut, with the highest rate of any state, had 98 cases per 100,000 population.) Virginia reported 122 cases, or about 2 cases per 100,000, in 1999. The District reported six cases, about 1 per 100,000. Fairfax County in Virginia and 13 counties in Maryland (including Montgomery and Prince George's), as well as Baltimore City, are considered high-risk areas based on the frequency of reported cases and the prevalence of infected ticks, according to the federal Centers for Disease Control and Prevention.

People spending time outdoors in such areas can usually avoid tick bites by taking simple precautions. If infection does occur, it generally responds promptly to antibiotics. In a minority of cases, Lyme disease causes persistent arthritis, nerve abnormalities or other long-lasting symptoms.

GlaxoSmithKline has marketed the vaccine aggressively, with advertisements presenting ticks as a threat to people in many states who garden, golf or cook on the outdoor barbecue.

However, the vaccine – which costs about $200 for a series of three doses – does not provide complete protection, and recent studies suggest that periodic boosters are needed to maintain immunity. It should be considered only by people living in high-risk areas who engage in high-risk activities, according to guidelines issued by the CDC.

Hogan said the company's view on who should get the Lyme vaccine "is that people who live, work or travel in endemic areas should consider it."

The company is continuing to fund the follow-up study that was requested two years ago, although patient recruitment has been slow, and has reported all cases of suspected adverse reactions to the FDA, she added.

Scientific concerns about a possible link between the vaccine and arthritis arise from the fact that the vaccine is made from the same protein, found on the surface of the Lyme disease bacterium, that has been implicated in causing persistent arthritis in some people with the infection. The bacterial protein, Osp A, is similar to a human protein found on blood cells. High levels of antibodies to Osp A correlate with severity of joint swelling in people with Lyme arthritis, suggesting that the body's immune response against the infection somehow triggers an attack on its own joint tissues. People whose tissues carry a cell-surface protein known as HLA DR4 are more likely than others to develop persistent arthritis from Lyme disease (and some experts believe they may also be more prone to complications from the vaccine.)

Arthritis and neurological disorders are among the medical problems that have been reported to the FDA by some recipients of LYMErix, but there is no clear pattern to suggest that the vaccine was the cause, said Robert Ball, the agency's acting chief of vaccine safety. However, he cautioned, "the way we receive [reports], it's usually difficult or impossible to determine if a vaccine is causing adverse events" without doing additional studies.

A total of 1,048 adverse events in people who received LYMErix were reported to the agency from December 1998 through October 2000, representing about 0.07 percent of the approximately 1.4 million doses of the vaccine distributed. There were 133 reports of arthritis or joint swelling, but symptoms did not occur in any consistent pattern in relation to when people received the vaccine. There were 13 cases of facial paralysis (an occasional feature of Lyme disease) and 37 reports of possible allergic reactions. FDA reviewers concluded that the vaccine was probably responsible for some allergic reactions, but that most cases of facial paralysis had other possible causes.

Ball said the FDA is examining the arthritis cases in greater detail and plans to conduct a study to investigate whether arthritis is a possible side effect of the vaccine. In individual cases, it is very difficult to determine whether joint inflammation has been produced by the vaccine, by Lyme disease, or by some other cause of arthritis.

The study will take time, and meanwhile the agency isn't sure what to make of cases such as Raffio's, said Susan Ellenberg, director of the office of biostatistics and epidemiology in the FDA's Center for Biologics Evaluation and Research.

"When you get these reports, it looks very compelling. We are very concerned," she said. "These people are suffering."

Daum said the continuing uncertainty about the Lyme vaccine should serve as a reminder that even extensive testing can't guarantee that a new drug or vaccine will not produce unexpected side effects, and demonstrates the need for closer safety monitoring after products are approved.

"How big should the clinical trials be?" he asked. Even if studies involve more than 10,000 participants, as the LYMErix trial did, "they will not pick up something that occurs in 1 in a million people."