Mixed blessing

Earlier generations understood that nature is not always benign. The farmhouse stood isolated, the surrounding plowed fields holding back the forest. At well-kept homes in the deep South, the bare, dirt yards were neatly swept and inspected often for animal — especially snake — tracks.

If we still felt that arm’s-length wariness toward nature, Lyme disease probably would not now be one of the top 10 infectious diseases, believes the scientist who holds the patent on the world’s first Lyme disease vaccine. When UCI’s Alan Barbour, who holds professorships in the School of Medicine and the School of Biological Sciences, draws a diagram of the route of transmission of the disease, as he did in his 1996 book Lyme Disease: The Cause, the Cure, the Controversy, he places humans into their most fundamental framework, as animal preyed upon by other animals.

Unlike most infectious diseases, Lyme is a problem for the rich. It tends to turn up in wooded suburbs that are full of deer, mice and people. The disease is transmitted by ticks that pick up the bacteria from the bloodstream of field mice and then pass it on to deer and humans.

Named for the upscale Connecticut suburb in which it was first diagnosed in 1975, Lyme disease had been brought forcefully to the medical community’s attention by mothers worried about their children’s aching, swollen joints. The disease has become a center of controversy among people who believe Lyme’s effects on the heart and nervous and immune systems are underestimated by the medical profession. In his book, Barbour speculates that Lyme may be the brucellosis of the nineties, a disease that for a while was thought responsible for an array of stubborn symptoms. One of Lyme’s discoverers has called the disease “a magnet for people who just don’t feel well.”

On the other hand, the numbers of people infected have placed Lyme disease in the upper ranks of infectious diseases — less than AIDS but probably more than syphilis or tuberculosis. Over the past few years, approximately 10,000 Americans per year have been diagnosed with Lyme disease, but this is a cautious count and Barbour guesses the true number of annual infections may be nearer 50,000. Antibiotic treatment exists but stirs its own controversies.

Lyme disease remains concentrated along the Atlantic seaboard from Virginia to Maine, and in the prosperous upper midwestern states of Wisconsin and Minnesota. At lower risk is the West Coast, from about Santa Barbara to British Columbia.

In 1997, 172 cases — 100 percent more than in the previous year — were reported throughout California, and in 1998, a first case was reported in Los Angeles County.

The vaccine that Barbour’s discoveries helped create went on the market in early 1999. Reaction and gratitude have been immediate. In Minnesota, a Lyme disease hot spot, a newspaper columnist wrote that a statue of Barbour should be erected at the state capitol, right next to that of Leif Ericson.

Barbour himself has mixed feelings about his creation of the vaccine, both pride and worry. “What I’d hope to see is that it will be beneficial for people who really need it,” he said. “I’d hate to see it being used under circumstances where it was primarily because of marketing that someone ended up taking it.”

Advertisements for the vaccine have appeared in national magazines and on television. In common with many other physicians, Barbour is troubled by the advertising of prescription medicines directly to an unwary public. All medicines have side-effects, he points out. Could the vaccine trigger arthritis in people who already have a genetic predisposition? He sees the possibility. Other researchers have wondered whether the vaccine might simply suppress the bull’s-eye rash and deprive victims of that valuable warning sign. Even the U.S. Food and Drug Administration committee that approved the vaccine in December 1998 issued a number of warnings against its misuse.

Marketed under the trade name LYMErix by Philadelphia pharmaceutical giant SmithKline Beecham Biologicals, the vaccine is designed to be given as three shots over a year’s time, but not to anyone younger than 17 (young people actually are more at risk, but clinical trials on them haven’t been completed). FDA clearance to sell a second Lyme vaccine also has been sought by a French pharmaceutical company, Pasteur Merieux Connaught. Either company, or both, will pay royalties to the patent-holders, Barbour and the Swedish colleague in whose lab the Lyme-causing bacteria was DNA-sequenced.

Though he’s ambivalent about the uses of the vaccine, Barbour is very proud of the research that produced it. At a time when some bacteria have grown resistant to antibiotics and new treatments must be found, he sees exciting possibilities in the way this vaccine works. Unlike any previous vaccine, this one kills the infectious bacteria not in the human bloodstream but in the body of the tick itself. A vaccinated human, in effect, cures the tick.

The basic discoveries on which the vaccine is based were made long ago. In 1981, while studying deer ticks at the National Institutes of Health Rocky Mountain Laboratories in Montana, Barbour and a fellow researcher isolated within the tick gut the bacterium responsible for causing Lyme disease. Because the other researcher, Willy Burgdorfer, first found the organism, it bears his name: Borrelia burgdorferi.

Barbour’s great initial contribution was the discovery of a culture medium in which B. burgdorferi would grow and multiply. Once it could be reproduced, it could be studied. Barbour went on to clone the bacteria, identify a biologically vulnerable protein on its surface, and eventually work on development of the new vaccine.

He identified, too, a possible tactical advantage against ticks: they’re slow. A tick takes a day to attach its sucking mouth and another day before the bacteria it carries begin passing via the tick’s saliva into the victim’s bloodstream. On the surface of the bacteria, as it was found inside ticks, was a particular protein, termed OspA, that remained virtually identical wherever in America ticks were found. As soon as it met human blood, OspA immediately began turning into another protein, OspC, in a wide variety of strains, each with different DNA. OspA remained constant inside the tick because ticks — like other invertebrates — have no immune system; with no immune attack, the bacteria had no reason to develop defenses.

Barbour describes what happens when a Lyme-infected tick meets a vaccinated human. The tick, he says, is “almost like a little drill, a roto-rooter. It carves out a place for itself and begins to feed. After a while, it begins secreting saliva to make it easier, so that’s when the infection starts. It comes in with the saliva. But by that time, it’s no longer making OspA, it’s making OspC, so the vaccine doesn’t work once that happens. In an immunized person, the person has the antibody to OspA in their blood, and that goes into the tick at the same time as the rest of the blood, killing the bacteria. So that’s unlike any other vaccine, and in terms of the potential, that indicates it may be possible to make a vaccine against malaria in the same way.”

Malaria, rheumatoid arthritis, multiple sclerosis, ulcers, heart disease — all do have or are suspected of having a bacterial trigger. All have been mentioned by Barbour as possible beneficiaries of this new approach. But the work will be done by others; Barbour plans to continue his research on ticks, with the work partly financed by his patent royalties. Ticks carry many diseases — Rocky Mountain Spotted Fever, relapsing fever, Colorado tick fever, ehrlichiosis, tularemia, among others — and Barbour intends to remain focused here.

Should field mice be vaccinated, he wonders, the way rabies vaccine is distributed to wild animals in the South, by strewing vaccine-laden food through suburbs? Could a vaccine be created which would make ticks fall off faster, or make them itch so that people would notice them quickly? Could ticks be eradicated? Should they be?

“I don’t think anybody is going to stand up and say ‘we need ticks,'” he said. “There isn’t a big constituency for ticks. They may have some role in the big scheme of things, but to be able to reduce the number of ticks — that’s what would really be the most effective way to prevent Lyme disease.”

For more information on Lyme disease, visit the American Lyme Disease Foundation web site: www.aldf.com, or the Centers for Disease Control and Prevention:www.cdc.gov/ncidod/diseases/lyme/lymeinfo.htm