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One of the most successful pathogens ever, the influenza virus
is easily spread and potentially deadly. Waves of pandemics arise
when the virus mutates the hemagglutinin (H) protein in its outer
coat, producing new strains that bypass the immunity to previous
versions. Currently, vaccines must be given every year and tailored
to the prevailing H strain to be effective. For a long time, the
goal of a common flu vaccine, a one-time shot that would silence
all strains, has been elusive.
Wayne Marasco, MD, PhD, and Jianhua Sui, MD, PhD, a fellow in
his laboratory in the Department of Cancer Immunology and AIDS, are bringing that goal closer to reality.
In recent work, Marasco's lab screened a library of 27 billion
different antibodies, developed previously in his laboratory, with
the hemagglutinin protein from the highly pathogenic avian
influenza virus or "bird flu." He found ten antibodies that
potently inhibited infection in mice. Unlike most previously
isolated antibodies, the new ones did not block the attachment of
the virus to the cell, but instead stopped its internalization.
Even more surprising, the antibodies blocked the infectivity of
other influenza variants that have a different hemagglutinin
subtype, including the 1918 pandemic flu virus.
Cross-reactivity between different hemagglutinin subtypes was a
very unusual finding. To understand how that could happen, Marasco
turned to Robert Liddington, PhD, a crystallographer at the Burnham
Institute for Medical Research. When he analyzed the crystal
structure of the antibody-hemagglutinin complex, Liddington found
that the antibody bound to an unusual, and usually hidden, region
of the hemagglutinin protein. Knowing the exact spot recognized by
the antibodies, the researchers then compared that to other
hemagglutinin proteins whose sequences were available in public
databases. "That was the moment we realized that this was a highly
conserved region present in all influenza A viruses," Marasco says.
"For the next several months, we worked closely with the Centers
for Disease Control (CDC) to prove that what looked like a broadly
cross-reactive antibody in silico was confirmed by bio logical
Marasco's work, published in February 2009, was especially
timely with the news of the H1N1 (swine) flu breaking shortly
after. In April, he was on vacation when he got a phone call from
the CDC. "It was about the new outbreak," he said. "It [the H1N1
virus] happened to be of the same class that our antibodies
recognize. Can you imagine? How often in one's research career does
something like that happen, a new pandemic emerging on the heels of
a major therapeutic advance in the field?"
While it is still too early to say definitely that Marasco's
antibodies provide protection against the new H1N1 pandemic strain
in vivo (those experiments are underway), they do block infection
in tissue culture studies. Meanwhile, Dana-Farber is in the process
of licensing the finding to a major pharmaceutical company, and the
NIH is supporting Marasco's lab to develop the antibodies and wants
to stockpile them in case of a pandemic outbreak.
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