Looking for a Vaccine to Defang the Lyme Tick
By JAMES GORMAN
Published: May 20, 2003
Dr. José Ribeiro is sequencing the ''spitome'' of the deer tick. This is a little bit like sequencing a genome, except that it has to do with saliva, specifically the saliva of the deer tick, the tiny menace that lives off deer and white-footed mice and likes to give suburban gardeners Lyme disease.
What Dr. Ribeiro and other scientists at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., are finding is that tick spit is a complex weapon, with an array of components that alleviate pain, keep blood from coagulating and subdue the host's immune system at the site of the bite. ''Tick saliva is amazing,'' said Dr. Fred S. Kantor of the Yale School of Medicine, who is also working on deciphering tick saliva.
The goal of the research is to develop a vaccine, not against the bacteria that causes Lyme, a twisty spirochete called Borrelia burgdorferi, but against the tick itself.
More than 16,000 people become infected with the Lyme disease spirochete each year, and the season starts now, when nymphs that have been inactive over the winter join adult ticks in the hunt for blood. Increasing numbers of ticks are met by increasing numbers of people outside, and infection rates begin to rise in late spring and summer. The disease is rarely fatal, but can cause neurological problems if not treated promptly. Lyme disease is here to stay, experts say, but anything that can reduce tick numbers or fight infection would save thousands of people from a potentially damaging illness.
In one sense the vaccine research is in the vanguard, since it is exposing the working of a chemical arsenal that is not well understood. In another sense, it is a rear-guard action, a purely defensive maneuver against a prolific and superbly efficient enemy. A vaccine could not take the battle to the ticks. It would take effect only when a tick began drilling for blood.
Other researchers are working on low-tech tick control solutions like feeding stations for deer and baited boxes for mice that are set up to treat the animals' fur with a pesticide that will kill the ticks. These efforts have met with some success.
Both avenues of research are necessary, said Dr. Durland Fish of the Vector Ecology Laboratory at Yale. But, he said, he sees a damaging lack of money and energy going toward tick control and research. Even more of a problem, he said, is that medical and ecological work are separate. There is an ''artificial division between environmental science and medicine,'' he said. ''These problems are identified as medical problems but they require environmental solutions.''
The vaccine research is squarely in the medical camp. It was inspired by the observation, as early as 1939, said Dr. Kantor, whose specialty is immunology, that some animals develop an immunity to ticks after successive bites.
Strong immunity has been demonstrated in rabbits, guinea pigs and humans, he said -- but not in white-footed mice, which are necessary for the life cycle of the Lyme bacterium.
He has induced immunity in guinea pigs, he said. ''We made them tick immune by repeated exposure to noninfected ticks,'' Dr. Kantor said. When they were exposed to infected ticks, the creatures fell off sooner, didn't eat as much, and didn't reproduce as well.
And, he said, the immunity ''profoundly affects transmission'' of Lyme bacteria, although the mechanism is not clear. The immunity may, he said, stop the bacteria from leaving the tick at all.
Unfortunately, subjecting humans to many bites from uninfected ticks to create immunity is neither appealing nor practical. Thus, the pursuit of a vaccine. The idea is to find which genes are active in tick saliva, make copies of these genes, and insert them in other organisms, and use those copies to produce more of the proteins the ticks use.
The work has made Dr. Kantor something of an admirer of ticks. ''This little animal,'' he said, ''has an incredible spectrum in its genome of changing anticoagulants. We found a whole family of anticoagulants, a whole family.'' The chemicals are used by the ticks to keep the blood flowing as they are feeding.
The biochemical salvos of saliva are not limited to anticoagulants. Other components allay pain, so that the host doesn't notice the drilling, and subdue various kinds of immune system defenses against the molecules in tick saliva. The saliva also contains vasodilators to keep veins and capillaries wide open.
Dr. Ribeiro and his colleagues in Bethesda are working to document the whole range of molecules the tick uses in its saliva. He is sequencing the sialome, or in the common term that he favors, the spitome. So far, he has found about 90 genes that contain information to produce various components of the saliva. And he is continuing to search.
The intriguing aspect of a vaccine against a tick, or any other vector, or carrier, of disease, he said, is that it does not need to be as narrowly aimed as a vaccine that creates an immune response to a specific disease-causing organism. A vector vaccine would simply stir up such a storm of immune response, including both defensive molecules, or antibodies, and killer cells, that the bite site would be inhospitable to pathogens.
''Instead of getting into a house where everybody is sleeping,'' he said, ''you get into a house where everybody is shooting and you get caught in the crossfire.''
The idea has been shown to be workable. In one published report, Dr. Jesus Valenzuela, a colleague of Dr. Ribeiro at the institute, described the creation of a vaccine that produces an immune reaction to sand fly saliva. Sand flies carry the parasite that causes a disease called leishmaniasis. Dr. Valenzuela used cloned genes to recreate a protein in sand fly saliva and use that in a vaccine. A result was that vaccinated mice resisted infection by the parasite when they were bitten by infected flies.
Sand fly saliva is not as complex as that of ticks, and unlike ticks, sand flies do not stay on the animals they bite for very long. But the principle of the vaccine is similar. Vaccines that respond to tick saliva would have great value because they could work against more than one disease. Deer ticks can infect humans with other diseases, in addition to Lyme, like babesiosis and human granulocytic ehrlichiosis. Victims may become infected with more than one, sometimes with all three.
Another scientist working on tick saliva is Dr. Stephen K. Wikel at the University of Connecticut Health Center in Farmington. He said the molecules in tick saliva, in addition to serving the tick, helped the disease-causing bacteria. ''It's abundantly clear,'' said Dr. Wikel, ''that these molecules in the spit are essential for successful pathogen transmission.''
Dr. Wikel and his colleagues are concentrating on the early period of tick attachment. Deer ticks don't start to draw blood until several days after they attach. During that time they prepare the bite site, like oil prospectors preparing a well for pumping out crude oil. ''There are a lot of different proteins produced early on that are not produced later on,'' Dr. Wikel said.
At the University of Rhode Island, Dr. Thomas N. Mather, the director of the Center for Vector-Borne Disease in Kingston, is also looking at what is in the saliva when the tick is first attached. Saliva is hard to collect then, so he removes the salivary glands from a creature that is, as an adult, the size of a sesame seed. ''It's always made my mother proud that I could take out salivary glands from ticks,'' he said. Dr. Mather collaborates with Dr. Ribeiro.
While the research on vaccines looks to the future, and would result in a defense that begins at the skin, a number of ways are being devised to control tick populations before they get to humans.
One method that has been shown effective is a feeding station for deer equipped with rollers that apply a pesticide to the deer fur.
Dr. Fish at Yale said his tests of this system had shown reductions in tick populations of 65 percent. He had been hoping for a greater reductions, but since Lyme infection rates are directly connected to tick density, that drop is significant, he said.
Other methods of tick control are directed at white-footed mice. Cardboard Damminix tubes have been available for years. They contain cotton impregnated with permethrin, an effective tick killer. The idea is that mice collect the cotton for their nests, and it kills the ticks.
Dr. Kirby C. Stafford III of the Connecticut Agricultural Experiment Station in New Haven has been testing bait boxes designed to attract mice. As the mice go into the box, a tick killer called Fipronil is brushed on their fur.
Laboratory prototypes, Dr. Stafford said, were very effective in reducing tick populations on Mason's Island in Mystic, Conn., reducing the tick population by 96 percent after two years. But, he said, that was a small community, and the prototype boxes required frequent visits to replenish the pesticide. A commercial product, called Maxforce, is being tested.
Research may, however, not be the most important avenue if simple reduction of Lyme disease cases is the goal. There are standard recommendations for personal protection that can help if people are wary.
Dr. Mather of the University of Rhode Island says he is convinced that the tools to reduce disease rates are there, but that awareness is lacking. In areas of very high Lyme disease rates, where in a few minutes people can collect 500 ticks in a back yard, there is still very little action and knowledge about what to do, he said.
People need to receive information at the moment they need it, he added.
With a small grant, Dr. Mather said, he planned to start working on a way to take surveillance data and deliver it to the public.
Ideally, he said, he would like to see something like a tick forecast, the equivalent of weather reports or air quality or allergy indexes. Then, people would know how to prepare for a picnic. If tick numbers were down, they might relax more. If the numbers were up, then people would be more careful about putting repellents on their clothes.
For the moment, he said, people cannot go wrong pulling their socks up over their pants. It is, he said, ''the most cost-effective thing they can do.''
Photos: Researchers are fighting ticks on two fronts, with medical research and ecological control. Shown in comparison with a nail are, from left, two nymph deer ticks, two adult deer ticks and an American dog tick. (James Occi)(pg. F6); May be accompanied by fever, chills or achiness. (LymeNet); (The New York Times; images by K. Eward/Photo Researchers [micrograph] and Darwin Dale/Photo Researchers [small tick])(pg. F1) Chart: ''From Slow Bite to Sickness'' When infected deer ticks bite humans, they can transmit a bacteria that causes Lyme disease. EARLY LOCALIZED LYME DISEASE BULLS-EYE RASH -- appears in 80 to 90 percent of cases, one to two weeks after bite. TREATMENT -- 10 days of antibiotics. DISSEMINATED LYME DISEASE Headache, neck stiffness, facial paralysis, pain or numbness in the extremities, heart block (can cause palpitations or dizziness), arthritis, difficulty with concentration or memory. TREATMENT -- Two to four weeks of antibiotics. PROBLEMS AFTER TREATMENT ARTHRITIS -- Treated with anti-inflammatory medications; in some cases, surgical removal of joint tissue. OTHER SYMPTOMS -- Fatigue, lasting muscle or joint pain, problems with concentration and memory. INFECTION -- Begins an average of 36 to 48 hours after the tick attaches itself to the skin. REMOVING TICK -- in the first 24 hours will most likely prevent infection. Use tweezers, gently. If tick is engorged, your doctor may recommend antibiotics to prevent infection; if it is not, watch for rash around the bite. Bacteria pass from the midgut by the tens of thousands... The tick inserts cutting parts (chelicerae) and its serrated hypostome into the hosts skin. ...through the salivary glands. The tick injects agents to numb the host, subdue its immune response and make blood flow; they also may aid infection. The tick begins its meal, alternating between drawing blood and injecting saliva. DESIGNED FOR DINING This electron micrograph shows a 50-fold enlargement of a deer ticks feeding apparatus, viewed from its underside. TINY PEST The deer tick actual size, about 2.5 millimeters. (Sources: Dr. Gary P. Wormser, Dr. Mark S. Klempner, Dr. Marc A. Tack, Dr. Stephen K. Wikel, Ohio State University)(pg. F1)