FDA questions safety of Lyme disease vaccine

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FDA questions safety of Lyme disease vaccine

Manufacturer defends record, says arthritis not tied to doses


Washington Post

WASHINGTON 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, Ms. 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, Ms. Raffio began having pains in her ankles, she said. That autumn, she developed severe pain in her neck and backand wasfound to have rheumatoid arthritis. She also permanently lost the peripheral vision in her left eye when her optic nerve became inflamed.

These days, Ms. Raffio, now a college freshman at the University of Missouri at Columbia, can 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," she said. "I've learned to manage to the best of my ability. ... My body is not like everyone else's body."

Ms. 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," Ms. 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 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.

This year the same committee heard emotional testimony from Ms. Scharf-Lurie and others who think 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, Mr. 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.

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. Only people living in high-risk areas who engage in high-risk activities, according to guidelines issued by the Centers for Disease Control and Prevention should consider it.

Ms. 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."


-- Martin Thompson (mthom1927@aol.com), April 09, 2001


THIS IS NOT ACTUALLY A NEW ISSUE: Note date of article below. Also note year (1998) of some of the lab work that supports the possibility. I don't know what the "truth" is on this question, but there are legitimate concerns. ***************************************************************

Headline: Lyme Vaccine Fears: Concerns newly approved drug can cause arthritis

Source: By Ridgely Ochs, Staff Writer, New York Newsday, 10 March 2000

[No URL, sorry]

[Photo] New Jersey minister Zelma Johnson is filing a lawsuit against the drug company, alleging that the vaccine caused her arthritis.

LYME DISEASE VACCINATIONS led to 298 reports of adverse reactions last year, the first year the vaccine was on the market, according to reports to the Food and Drug Administration obtained by Newsday under the Freedom of Information Act. Of those, about 10 percent reported symptoms of chronic arthritis, which some doctors and scientists fear could be a potential side effect of the vaccine.

The theoretical possibility of the vaccine's prompting such an autoimmune response, in which the body attacks its own tissue, was known to the scientists, drug makers and the FDA before the vaccine was approved, although it is not included in the warning label.

"I'm stunned. Looking at these data, I'm highly concerned by the number of ther eactions and the severity of the reactions," said Karen Vanderhoof-Forschner, chairwoman of the board of directors of the nonprofit Lyme Disease Foundation in Hartford. Vanderhoof- Forschner testified in May, 1998, before the FDA advisory panel urging the vaccine's approval by the FDA. "This is a voluntary reporting system, so this is probably the tip of the iceberg. How is the public supposed to evaluate this data?"

Most of the other events reported -- a very small number of the 600,000 people who took the vaccine in its first year -- appear to be allergic reactions, some quite severe, or failures of the vaccine to work. About one-third of the patients who had a reaction ended up in the emergency room.

Both the FDA and SmithKline Beecham Pharmaceuticals of Philadelphia, maker of the vaccine marketed as LYMErix, say that the reports of adverse events don't raise any red flags. An FDA spokeswoman, Lenore Gelbsaid the reports are not proof the adverse events were caused by the vaccine. "If we do have concerns, we make an effort to change the labeling to reflect that ... There is no effort to change the label," she said. She declined to comment further.

Dennis Parenti, group director of adult vaccines for SmithKline Beecham, said 600,000 people got the vaccine in 1999, after it was approved in December, 1998; 20,000 more had participated in trials testing it, and there is no evidence of an increase in arthritis because of it. "We've sliced it and diced it and every way looked at it and repeated some tests, and we and the FDA found there was no association," Parenti said.

But several lawsuits, including a class action suit in Pennsylvania, have been filed against SmithKline Beecham alleging the vaccine can cause arthritis in some people. The suit charges that the drug-maker failed to warn doctors and the public that LYMErix exposes people of a certain genetic type -- 20 to 30 percent of the population -- "to the risk of a chronic, degenerative and incurable autoimmune disease which is much greater than the risk posed to these individuals by an ordinary Lyme-carrier tick bite."

The suit wants the company to relabel its vaccine, warn the public and tell doctors to screen for those who might be susceptible to a reaction. And it wants the drug manufacturer to create a trust fund to pay for blood tests for those who already have had the vaccine to see if they are at risk. "There is a lot of smoke here, and underneath we believe there is a fire. This is a chance for SmithKline Beecham to do the right thing and do it early on their liability," said Albert Brooks of Sheller, Lugwig & Bader of Philadephia, which filed the suit.

A New Jersey minister, Zelma Johnson, is also in the process of filing a lawsuit against the drug company alleging that the vaccine caused her arthritis.

Ira Maurer, a White Plains lawyer representing Johnson as well as three others who were in the clinical trials for the vaccine, said, "You go under the assumption that side effects will be the typical aches and pains, but when you look at these reports [of adverse events], many are far more serious."

All drugs have potential side effects that may not show up until used in a large population. What is unusual about this vaccine is that the chief researcher, the drug company, the FDA advisory panel that recommended its approval and the FDA knew beforehand there was the theoretical possibility this one could lead to arthritis.

The question, some say, is whether the risks of the vaccine's side effects outweigh the potential benefits.

"I wouldn't take the vaccine," said Ronald Schell, a Lyme disease researcher from the University of Wisconsin. "I recognize that's a prejudice based on my animal research." He recently published a study that found hamsters injected with the vaccine were more likely to get arthritis.

"I want people to be aware; they should know of the potential [to cause arthritis]. Right now, there's a lack of choice," said Dr. Charlene DeMarco, an emerging-diseases specialist in Egg Harbor, N.J., who has served as a consultant in the class action suit. DeMarco believes people who carry a gene that may predispose them to an autoimmune response should be warned before getting the vaccine.

The vaccine works by stimulating the immune system to produce antibodies to a protein found on the outer surface of the bacterium B. burgdorferi, which causes Lyme disease.

But the lead researcher for the SmithKline vaccine, Dr. Allan Steere of New England Medical Center in Boston, knew -- and indeed published the fact six months before the vaccine was approved -- that a part of that outer-surface protein, called OspA, has the potential of inducing a "cross-reaction" with a human protein (hLFA-1) in about 20- 30 percent of the population (those people who have the HLA-DR4 gene). Cross-reacting means that in these people, the body's immune system could attack the human protein, thinking it was part of an invading bacterium. Some experts think it is this part of the bacterium that induces so-called Lyme arthritis, which resembles rheumatoid arthritis.

Steere's study, published in the journal Science in July, 1998, was a test tube study, not proof it could occur in humans. But it has added fuel to concern about the possibility. In it, three groups of four to seven hamsters each were given different doses of a Lyme vaccine suspended in aluminum hydroxide. The vaccine was not LYMErix but was very similar to it. Seven others were injected with a commercially available canine version of the vaccine. A group of nonvaccinated hamsters and a group injected with just aluminum hydroxide were comparison groups. All were then infected with the Lyme bacteria. All the vaccinated hamsters developed "severe destructive Lyme arthritis;" in some groups 100 percent of the vaccinated hamsters were afflicted. By comparison, none of the unvaccinated hamsters developed higher than normal levels of arthritis typical of hamsters with Lyme disease.

The study, published last month in the journal Infection and Immunity, has caused a stir among Lyme experts. In fact, Schell initially refused to discuss the article, saying it was "too political." But he and his colleagues state unequivocally in the study:

"Recently the Food and Drug Administration approved the use of OspA for vaccination of humans despite indirect evidence and concerns that OspA is associated with arthritis. In this study, we present direct evidence that vaccination ... can induce severe destructive arthritis in hamsters after challenge with the Lyme borreliosis spirochete." Schell says his study does not prove the vaccine can induce arthritis in people, but "it raises the flag, and I am concerned."

While Schell was reluctant to discuss his findings, others were quick to assail them. Dr. Neal Halsey, director of Johns Hopkins University's Institute of Vaccine Safety, questioned the study's relevance, saying that hamsters are prone to develop arthritis and that the vaccine used was not LYMErix.

Schell countered that hamsters are not particularly prone to arthritis. "There's no evidence of that in the literature," he said. And he said he avoided using LYMErix in the study "for political reasons." His own formulation was different by "one amino acid."

But Halsey and others said that animal studies are not as significant as the results of clinical trials in humans. Halsey was head of the data monitoring and safety board for the SmithKline vaccine trials. In that trial of 10,936 people begun in 1995, most side effects were minor, and only about 1 percent of those vaccinated and 1 percent of those in the placebo group developed arthritis, Halsey said. A trial of 10,305 of a similar vaccine made by Pasteur Merieux Connaught of Swiftwater, Pa. -- never brought for FDA approval -- showed similar results.

"No way would I have gone on to the pediatric studies if I had seen anything in the study to show there were worries," he said.

Members of the FDA's advisory panel also said the data they saw showed no pattern of serious side effects in the clinical trial vaccine. "The advisory panel was aware of the theoretical risk of this vaccine causing autoimmunity. A careful evaluation of study patients did not reveal any problems, but the panel recommended the vaccine be monitored post-approval to see if anything occurred as greater numbers were vaccinated," said panel member Raymond Dattwyler, director of the Lyme disease research center at the State University of New York at Stony Brook.

"Regarding cross-reactivity, we were all very aware, and we looked at it very carefully," said Kathyrn Edwards, a vaccinologist at Vanderbilt University in Nashville and a panel member. "I think we take the very best data we can; we think about it very seriously ... No one has a crystal ball."

Dr. Leonard Sigal, chief investigator for the Connaught vaccine trial, said there were no untoward side effects in his study. "Cross- reactivity wasn't seen in the Connaught trial under very controlled conditions."

But there were signs that some participants felt they were having bad reactions. Before the vaccine was approved, at least four lawsuits were filed by people who had participated in the vaccine trials -- highly unusual since participants sign informed consents. Three were filed against Connaught; the other was filed against SmithKline. In two of the Connaught suits and the SmithKline case, the participants said they had had debilitating arthritic-like problems. One case was settled for an undisclosed amount, another dropped and two are pending, said Maurer, the lawyer in those suits.

And others who have experience with the vaccine since its approval are sure it has done them more harm than good, regardless of the clinical studies. An East Northport woman who did not want to be identified decided to have her son, 16, get the vaccine after the repeated urging of his doctor. He had been diagnosed with Lyme disease in January, 1998. Now she thinks it has made his knee swell, sidelining the promising track star at a time when colleges are looking to offer athletic scholarships.

"Had I known then what I know now, I never would have let him have it," the mother said.

-- Andre Weltman (aweltman@state.pa.us), April 09, 2001.

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