By Karen Hopkin

Often misdiagnosed, Lyme disease gained scientific prominence as two teams raced to introduce vaccines.

The bite goes unnoticed. The bug is so small and unremarkable, about the size of a poppy seed, it is not detected as it hitches a ride on a player rummaging in the rough for an errant shot. It can happen in Rhode Island, or Minnesota, or along the coast in Oregon. Wherever it is, however it occurs, that cursory look in tall grass can spell trouble.

That's because a growing portion of the U.S. has been identified as being rife with the species of tick that carry Lyme disease, the most common tick-borne disease in the world. Throughout the spring and summer, these ticks lie in wait for some unsuspecting mammal to provide them with a nourishing meal of fresh blood. And if you insist on invading their territory in search of a stray ball, that mammal could be you.

Outdoor enthusiasts such as hikers and campers take precautions to avoid becoming a tick's next meal, tucking trouser cuffs into socks and wearing long-sleeved shirts. But many golfers eschew such practices because they are ignorant of the dangers of Lyme disease or, in the case of the pants-in-socks look, think it appears silly. What golfers don't know or practice might not kill them, but one search in the wrong place for a stray ball could mean contracting a potentially debilitating disease.

Scientists trained in a broad range of disciplines, from parasite biology to pediatric medicine, have been quick to respond to Lyme disease. Researchers did not even know what caused Lyme until 1982, yet one vaccine was approved for general use late last year and approval of a second appears imminent. Lyme has floundered for many years as a misdiagnosed disease — there have been nearly 130,000 cases reported by health officials, but unconfirmed estimates suggest three times that many people or more may have been infected but misdiagnosed.

"I can remember a time when a vaccine for Lyme disease was considered ridiculous," says Alan Barbour, one of the discoverers of the infecting bacterium. Adds David Dennis of the Centers for Disease Control and Prevention in Colorado, "It was a remarkable effort on the part of the manufacturers and scientists."

While the vaccines are being hailed as a solid step in the prevention of Lyme disease, many questions remain. It is not known how long their protection will last or whether the inoculations themselves can cause side effects, such as arthritis. The vaccines are not 100 percent effective and cannot yet be administered to children, and those 15 and under are infected in nearly a quarter of all reported Lyme disease cases.

But if nothing else, the marketing efforts of this race between two Pennsylvania-based pharmaceutical firms, SmithKline Beecham Biologicals and Pasteur Merieux Connaught, to be first with a Lyme vaccine are helping dispel myths about the disease. And the story of how scientists and manufacturers brought these products to market makes for an interesting case study.

A vaccine makes economic sense when it comes to Lyme, which in complicated cases can keep infected individuals unable for months to carry on a productive life with symptoms of arthritis, heart inflammation, nerve and brain disorders, and general fatigue. The bacterium that causes Lyme can precipitate such a wide range of symptoms by provoking the body's immune system to overreact, wreaking havoc in the nervous system, heart and joints. A 1998 study conducted by MEDTAP International in Bethesda, Md., estimated the cost of treating Lyme in the U.S. at more than $2.5 billion over a five-year period. In the June issue of Emerging Infectious Diseases, Dennis and his CDC colleagues estimate that if a vaccine costs $100 per year, vaccinating high-risk individuals will result in a savings of almost $3,500 for each case prevented.

Lyme disease, or the fear of contracting it, has affected people's lives in unexpected ways, says Connaught investigator John Zahradnik. It's not just golfers who have left stray shots in the bushes. Gardeners are afraid to work their vegetable patches; people are getting rid of pets they fear might bring ticks into the house; some even pack up and move to another state, says Zahradnik.

"This is a big problem," says the CDC's Dennis. "And frankly, we've been able to do almost nothing to stop the disease at its source — eliminating or preventing the spread of ticks."

The bearer of all this woe is Borrelia burgdorferi, a bacterium that infects deer ticks. Barbour, one of the bacterium's discoverers, was working with Willy Burgdorfer at the Rocky Mountain Laboratories of the National Institutes of Health when the organism was isolated. The researchers were studying Rocky Mountain spotted fever, a disease also transmitted by ticks. They had been crushing up ticks and using a microscope to search the smears for suspicious microbes when they detected corkscrew-shaped bacterium that were similar in appearance to the bacterium that causes syphilis. Burgdorfer and Barbour, an infectious disease man who figured out how to grow B. burgdorferi in the lab, then discovered that blood taken from patients with Lyme showed signs of having been previously exposed to this bug. They had located the bacterium that caused Lyme.

Prior to that discovery, researchers Allen Steere and Stephen Malawista of Yale University had spent years painstakingly proving that Lyme was in fact caused by an infectious agent. They didn't have a lot of study patients, Malawista says, so it took four summers during the 1970s just to show that patients who were treated with antibiotics got better faster and tended not to develop complications, such as heart problems or neurological symptoms.

By 1983 Barbour, then at the University of Texas Health Science Center in San Antonio, had identified several unique proteins carried on the surface of B. burgdorferi and in 1985 had cloned their genes. Researchers soon realized that these surface proteins would be ideal candidates for vaccines. They're plentiful and B. burgdorferi is covered with them, so antibodies raised against these proteins should be able to attach themselves to, and destroy, the bacterium.

Researchers at Yale set out to test that theory. Clinical immunologist Fred Kantor, molecular biologist Richard Flavell and Flavell's then-postdoctoral fellow, Erol Fikrig, made preparations of surface proteins. They used those surface proteins to vaccinate a strain of mouse generated by Yale veterinarian Steve Barthold.

When infected with B. burgdorferi, these mice showed the same type of heart and joint problems as seen in humans with Lyme. The researchers found that mice that had been vaccinated with OspA — the most abundant protein on the surface of the Lyme bug when it's still inside the tick — were protected from the infection of B. burgdorferi. Their results appeared in the prestigious research journal Science in 1990.

That's where parasite expert Sam Telford of the Harvard Medical School comes in. He read the Yale study and thought it bogus. Fikrig and his colleagues had infected the mice by injecting the Lyme bug with a syringe. "But infection is a much more complex process than that," says Telford, who has spent the better part of 15 summers literally beating the bushes for ticks. He stressed that tick saliva contains pharmacologically active compounds that may hamper the immune response and allow the bacteria to slip unnoticed into their hosts.

"We said publicly that if they infected mice the natural way, through a tick bite, the vaccine would fail miserably," says Telford, who didn't hesitate to appreciate the Yale-Harvard rivalry. So they set up a collaboration. Telford packed up his ticks in 1991 and drove down to Yale to stick them on Fikrig's mice. Each mouse received five to eight ticks, which were allowed to feed until sated. When the ticks dropped off, Fikrig collected them and mailed them back to Telford in Boston.

Lo and behold, the results were the same: The vaccinated mice were protected from infection. That's when Telford made a startling discovery. He was checking the ticks that fell off the mice to make sure they'd actually been infected. By Telford's reckoning, more than 90 percent of his ticks harbored the Lyme bacterium, but he could find the microbe in less than half the ticks that came back from Yale. What had happened? "I had this feeling I'd screwed up," he recalls.

When Telford backtracked to figure out which ticks came off which mice, he discovered that the parasites that had fed on immunized mice "had somehow been miraculously cleared of infection," says Telford. That meant that the vaccine was killing the spirochetes while still inside the ticks. This mechanism is unlike that of any other vaccine, says Barbour, as it "prevents an infection from ever being started."

The researchers published their results in the June 1992 issue of the Proceedings of the National Academy of Sciences. Encouraged by those results, SmithKline Beecham (SKB) and Pasteur Merieux Connaught (PMC) recruited researchers to conduct clinical trials of the OspA vaccine. SKB got the jump, recruiting Telford, his colleague Andy Spielman and investigators at hospitals in Lyme endemic areas of Massachusetts and Rhode Island to conduct a phase II clinical trial to assess the proper dosage and evaluate the safety of the vaccine. Since Lyme is transmitted in spring, Telford says they had to race during the winter to get everything in place for a trial in 1993. While Telford scrambled, phase I trials in Europe showed that the vaccine caused no obvious side effects when given to a few dozen people. Meanwhile, back in the U.S., it was difficult finding volunteers.

"Nobody wanted to be a guinea pig," says Telford. "I thought we'd have to block the doors to keep them out, but it was like pulling teeth." He went so far as to post flyers in liquor stores; physicians even registered themselves. It took four months to recruit about 300 people, but the results were worth the effort. The vaccine appeared to be safe, and the researchers could even see hints that it was effective at preventing infection.

With the help of Steere, then at Tufts University School of Medicine, and Fikrig and his Yale colleagues, SKB swiftly moved into the large-scale phase III clinical trial needed to prove that the vaccine was effective. Once people knew the vaccine was not harmful, recruiting was a breeze, says David Krause, who as the vice president of clinical development at SKB had worked on a number of vaccines, including a hepatitis vaccine and diphtheria-pertussis-tetanus vaccine for kids. "We signed up 11,000 people in eight weeks," says Krause, an avid golfer who describes himself as a 6 handicap masquerading as a 20. "We could not stop enrollment."

It was at this point that researchers for both teams began to see growing public support. "People can feel that they're part of the solution when they get involved in a study like this one," says Leonard Sigal, director of the Lyme disease center at the University of Medicine and Dentistry of New Jersey's Robert Wood Johnson Medical School in New Brunswick. As lead investigator for the Connaught study, Sigal recruited about 1,400 people in New Jersey for the Connaught trial by contacting local health departments and literally taking the show on the road by packing into a van and driving around to get the word out. "It's not exactly Lewis and Clark," Sigal said of working on vaccines, "but it's satisfying to be able to pursue something that will be good for patients."

Sigal was a fellow at Yale working with Steere and Malawista around the time B. burgdorferi was discovered. The researchers were looking at the role that specialized white blood cells, called T cells, play in revving up the immune system or calming it down. "It's the yin and yang of biological systems," says Sigal. Although inflammation usually helps fight an infection, if the immune response spirals out of control, says Malawista, "it can make you miserable instead of making you better."

Which is important because in the case of Lyme, it's an overzealous immune response that really gives you the disease, not the B. burgdorferi. "The organism itself is pretty unaggressive," says Malawista, a rheumatologist who also participated in Connaught's 10,000-person phase III clinical trial of its OspA-based vaccine. "Most of what makes you sick is your response to a bug that really isn't doing much — other than stimulating your immune system."

That was a concern for the investigators who were designing the trials. They wondered if people who had previously had Lyme should be barred from study, as they might be susceptible to immune reaction when exposed to OspA. But that was not a problem, at least in Connaught's phase II trials, says Zahradnik.

Both teams published the results of their phase III clinical trials in the July 23, 1998, issue of the New England Journal of Medicine. SKB received FDA approval for its vaccine in December 1998, and Connaught is still working with the FDA to secure approval for its vaccine, which should come later this year.

Of course, just because there is a vaccine, officials warn, not everyone should rush out to be inoculated. The decision on who should be vaccinated is made, in large part, by the Advisory Committee on Immunization Practices (ACIP), appointed by the CDC. As coordinator of the CDC's Lyme disease program, David Dennis and colleague Ned Hayes did the "legwork" for the working group of vaccine and Lyme experts that advised the ACIP. In February, the committee passed recommendations that physicians take into consideration where a person lives and how much time he or she is likely to spend in tick-infested areas.

Even in Connecticut, considered the epicenter of Lyme, there are areas in which one would be at low risk for encountering an infected tick. Physicians need to determine the local incidence of Lyme, says Dennis, who spent 14 years living in remote areas in Africa and Asia, investigating infectious diseases transmitted not only by ticks, but by fleas, lice and mosquitoes. "You should talk to your health-care provider and get better educated before you decide," he says.

Even with the vaccine, an individual may not be fully protected until the second year. In medical shorthand the current vaccine administration schedule is called "0-1-12" — the second vaccination is given one month after the first, and a third is given one year later. The SKB vaccine, which received FDA approval in December and is now being marketed under the name Lymerix, offers 50 percent protection in the first year and 76 percent in the second. The Connaught preparation, ImmuLyme, which awaits FDA approval, offers 70 percent protection in the first year and 90 percent in the second. That 70 percent is "equivalent to the protection afforded by annual flu vaccines," notes Zahradnik.

SKB is working on testing more condensed administration schedules, such as 0-1-6 and 0-1-2, says Dennis Parenti, a rheumatologist who joined the company three years ago. The studies have been completed and Krause says SKB will be applying to the FDA for approval.

The vaccines have not yet been fully tested on children. Lymerix is recommended only for those from 15 to 70 years of age. SKB began a study of its vaccine in 4,000 children down to age 4 last spring. According to Parenti, earlier tests on children from ages 5 to 15 showed that the vaccine is safe for kids. Successful tests on children will be important because kids who spend the bulk of their summers running around outside are more susceptible to Lyme than adults. In fact, Lyme was discovered in more than three dozen children who showed up in Connecticut clinics in the mid-1970s with serious cases of what was thought to be juvenile rheumatoid arthritis.

Conducting clinical trials on kids is difficult, notes Connaught's Zahradnik, an expert in infectious diseases who has been developing vaccines from hepatitis to herpes for 20 years. One problem: Kids between 4 and 19 are not all alike, and they have different risks; teens are not exposed to ticks at the mall, he says. So to do a similar large-scale clinical trial in children, investigators would need to recruit more than 10,000 kids to show that the vaccine is effective at preventing Lyme in youngsters.

Other questions remain, including the duration of the vaccine's protection and the need for booster shots. In addition, researchers may still search for alternative formulations that rely on proteins other than OspA, says Malawista. "It would be crazy not to," he says, because they might find something that works even better than current vaccines.

Even if they do not take part in the next discoveries, the researchers who have brought the Lyme vaccine this far have recorded the medical equivalent of a golfer's major championship victory. It has been a totally unexpected turn in the lives of some, such as Telford, who grew up in the tropics and always figured that he'd return there to study some hot zone-type bugs. "If you'd told me that I would wind up doing a doctorate in tick biology," he laughs, "I'd have said you were bananas."

Even if an individual gets the vaccine, care must be taken to avoid being bitten. These parasites carry other diseases, such as ehrlichiosis and malaria-like babesiosis, and the vaccine does not prevent those infections. Vaccinated individuals should continue to check for ticks. "You shouldn't let ticks lunch on you," says Zahradnik, whose wild neckties amuse his colleagues but probably do little to deter ticks. "It's hard to imagine someone saying, 'Oh, there are ticks on me ... ah, it's okay, I got a vaccine,' " he says.

Golf played a central role in one study of ehrlichiosis, a sometimes fatal, flu-like disease that's also carried by the same ticks that cause Lyme, says Dennis. Doctors studying an outbreak of one type of ehrlichiosis in a retirement community in Tennessee found that people with the highest handicap indexes were most at risk for contracting ehrlichiosis. The better golfers didn't get bitten by ticks. And golfers who were less likely to retrieve wayward shots were also less likely to get the disease.

"Improve your game and stay on the fairway," says Parenti, a self-described bad golfer. If you hit one into extremely tall rough, he says, "just leave it."

Hitting those shots far out of play can be a hazard to your score. Going in to the brush to retrieve them, without taking the proper precautions, can be a hazard to your health.