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http://www.nytimes.com/2003/05/20/science/20TICK.html?tntemail0
May 20, 2003
Looking for a Vaccine to Defang the Lyme Tick...
By JAMES GORMAN
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."
Copyright 2003 The New York Times Company
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