As this year’s flu season gathers steam, doctors and pharmacists have a
fresh stock of vaccines to offer their patients. The vaccines usually provide
strong protection against the virus, but only for a while. Vaccines for other
diseases typically work for years or decades. With the flu, though, next fall it will be time to get another dose. “In the history
of vaccinology, it’s the only one we update year to year,” said Gary J. Nabel,
the director of the Vaccine Research Center at the National Institute of
Allergy and Infectious Diseases.
That has been the case ever since the flu vaccine was introduced in the
1950s. But a flurry of recent studies on the virus has brought some hope for a
change. Dr. Nabel and other flu experts foresee a time when seasonal flu shots
are a thing of the past, replaced by long-lasting vaccines. “That’s the goal:
two shots when you’re young, and then boosters later in life. That’s where we’d
like to go,” Dr. Nabel said. He predicted that scientists would reach that goal
before long — “in our lifetime, for sure, unless you’re 90 years old,” he said.
Such a vaccine would be a great help in the fight against seasonal flu
outbreaks, which kill an estimated 500,000 people a year. But in a review to be published in the journal Influenza and Other Respiratory Viruses,
Sarah Gilbert of Oxford University argues that they could potentially have an
even greater benefit. Periodically, a radically new type of flu has evolved and
rapidly spread around the world. A pandemic in 1918 is estimated to have killed
50 million people. With current technology, scientists would not have a vaccine
for a new pandemic strain until the outbreak was well under way. An effective
universal flu vaccine would already be able to fight it. “Universal vaccination with
universal vaccines would put an end to the threat of global disaster that
pandemic influenza can cause,” Dr. Gilbert wrote.
Vaccines work by enhancing the protection the immune system already
provides. In the battle against the flu, two sets of immune cells do most of
the work. One set, called B cells, makes antibodies that can latch onto free-floating viruses. Burdened by these antibodies, the
viruses cannot enter cells. Once flu viruses get into cells, the body resorts
to a second line of defense. Infected cells gather some of the virus proteins
and stick them on their surface. Immune cells known as T cells crawl past, and
if their receptors latch onto the virus proteins, they recognize that the cell
is infected; the T cells then release molecules that rip open the cells and
kill them.
This defense mechanism works fairly well, allowing many people to fight
off the virus without ever feeling sick. But it also has a built-in flaw: The
immune system has to encounter a particular kind of flu virus to develop an
effective response against it. It takes time for B cells to develop
tightfitting antibodies. T cells also need time to adjust their biochemistry to
make receptors that can lock quickly onto a particular flu protein. While the
immune system educates itself, an unfamiliar flu virus can explode into
full-blown disease.
Today’s flu vaccines protect people from the virus by letting them make
antibodies in advance. The vaccine contains fragments from the tip of a protein
on the surface of the virus, called hemagglutinin. B cells that encounter the
vaccine fragments learn how to make antibodies against them. When vaccinated
people become infected, the B cells can quickly unleash their antibodies
against the viruses. Unfortunately, a traditional flu vaccine can protect
against only flu viruses with a matching hemagglutinin protein. If a virus
evolves a different shape, the antibodies cannot latch on, and it escapes
destruction.
Influenza’s relentless evolution forces scientists to reconfigure the
vaccine every year. A few months before flu season, they have to guess which
strains will be dominant. Vaccine producers then combine protein fragments from
those strains to create a new vaccine. Scientists have long wondered whether
they could escape this evolutionary cycle with a vaccine that could work
against any type of influenza. This so-called universal flu vaccine would have
to attack a part of the virus that changes little from year to year.
Dr. Gilbert and her colleagues at Oxford are trying to build a T
cell-based vaccine that could find such a target. When T cells learn to
recognize proteins from one kind of virus, the scientists have found, they can
attack many other kinds. It appears that the flu proteins that infected cells
select to put on display evolve very little.
The scientists are testing a vaccine that prepares T cells to mount a
strong attack against flu viruses. They engineered a virus that can infect
cells but cannot replicate. As a result, infected cells put proteins on
display, but people who receive the vaccine do not get sick. In a clinical trial reported this summer, the scientists found that people who received the
vaccine developed a strong response from their T cells. “We can bring them up
to much higher levels with a single injection,” said Dr. Gilbert, the lead
author of the study. Once the scientists had vaccinated 11 subjects, they
exposed them to the flu. Meanwhile, they also exposed 11 unvaccinated
volunteers. Two vaccinated people became ill, while five unvaccinated ones did.
While the Oxford researchers focus on T cell vaccines, others are
developing vaccines that can generate antibodies that are effective against
many flu viruses — or perhaps all of them. The first hint that such antibodies
exist emerged in 1993. Japanese researchers infected mice with the flu virus
H1N1. They extracted antibodies from the mice and injected them into other
mice. The animals that received the antibodies turned out to be protected
against a different kind of flu, H2N2. In hindsight, that discovery was hugely
important. But at the time no one made much of it. “By and large, people just
said, ‘This is an oddity — so what?’ ” said Ian Wilson of the Scripps
Research Institute.
Scientists did not appreciate its importance for more than 15 years,
until Dr. Wilson and other researchers began isolating the antibodies that
provided this kind of broad protection and showed how they worked. The new
antibodies turn out to attack different parts of the flu virus from the ones produced
by today’s vaccines. Today’s vaccines cause B cells to make antibodies that
clamp onto a broad region of the tip of the hemagglutinin protein. Recently,
Dr. Wilson and his colleagues discovered a new antibody with a slender tendril.
It can snake into a groove in the hemagglutinin tip.
Dr. Wilson and his colleagues found that this tend riled antibody can attach to a wide range of flu viruses. The
results hint that the groove — which flu viruses use to attach to host cells —
cannot work if its shape changes much. The antibody is also impressively
powerful, the scientists found. They infected mice with a lethal dose of the
flu and then, after three days, injected the new antibody into them. The
antibody stopped the virus so effectively that the mice recovered. The
hemagglutinin groove is not the only promising target for antibodies. Dr.
Wilson and other scientists are discovering antibodies that attack the base of
the protein. Influenza viruses can be broadly categorized into three types — A,
B and C. Until now, scientists have found only antibodies that attack different
versions of influenza A. Dr. Wilson and colleagues at Scripps and the Crucell
Vaccine Institute in the Netherlands recently found a stem-attacking antibody that blocks influenzas A and B. “The whole field is
invigorated,” Dr. Wilson said. “It’s a great time.”
Building on these discoveries, Dr. Nabel and other scientists have
recently developed vaccines that generate some of the new antibodies in humans.
Now they are trying to figure out how to get the body to make a lot of the antibodies.
“Once you have an antibody that has all the properties you desire, how do you
coax the immune system to make that?” Dr. Nabel said. “That’s the classic
problem in immunology.”
NY Times
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