Annually changing flu vaccines with
their hit-and-miss effectiveness may soon give way to a single, near-universal
flu vaccine, according to a new report from scientists at The Scripps Research
Institute and the Dutch biopharmaceutical company Crucell. They describe an
antibody that, in animal tests, can prevent or cure infections with a broad
variety of influenza viruses, including seasonal and potentially pandemic
strains.
The
finding, published in the journal Science Express on July 7, 2011, shows the
influenza subtypes neutralized with the new antibody include H3N2, strains of
which killed an estimated one million people in Asia in the late 1960s.
"Together
this antibody and the one we reported in 2009 have the potential to protect people
against most influenza viruses," said Ian Wilson, who is the Hansen
Professor of Structural Biology and a member of the Skaggs Institute for
Chemical Biology at Scripps Research, as well as senior author of the new paper
with Crucell's chief scientific officer Jaap Goudsmit.
Tackling
a Major Shortcoming
Wilson's
laboratory has been working with Crucell scientists since 2008 to help them
overcome the major shortcoming of current influenza vaccines: They work only
against the narrow set of flu strains that the vaccine makers predict will
dominate in a given year, so their effectiveness is temporary. In addition,
current influenza vaccines provide little or no protection against unforeseen
strains.
These
shortcomings reflect a basic flu-virus defense mechanism. The viruses come
packaged in spherical or filamentous envelopes that are studded with
mushroom-shaped hemagglutinin (HA) proteins, whose more accessible outer
structures effectively serve as decoys for a normal antibody response.
"The outer loops on the HA head seem to draw most of the antibodies, but
in a given strain these loops can mutate to evade an antibody response within
months," said Wilson. Antiviral drugs aimed at these and other viral
targets also lose effectiveness as flu virus populations evolve.
"The
major goal of this research has been to find and attack relatively unvarying
and functionally important structures on flu viruses," said Damian Ekiert,
a graduate student in the Scripps Research Kellogg School of Science and
Technology who is working in the Wilson laboratory. Ekiert and Crucell's Vice
President for Antibody Discovery Robert H. E. Friesen are co-first authors of
the Science Express report.
By
sifting through the blood of people who had been immunized with flu vaccines, Goudsmit
and his colleagues several years ago discovered an antibody that bound to one
such vulnerable structure. In mice, an injection of the antibody, CR6261, could
prevent or cure an otherwise-lethal infection by about half of flu viruses,
including H1 viruses such as H1N1, strains of which caused deadly global
pandemics in 1918 and 2009.
The
Crucell researchers approached Wilson, whose structural biology lab has
world-class expertise at characterizing antibodies and their viral targets.
Ekiert, Wilson, and their colleagues soon determined the three-dimensional
molecular structure of CR6261 and its binding site on HA, as they reported in
Science in 2009. That binding site, or "epitope," turned out to be on
HA's lower, less-accessible stalk portion. The binding of CR6261 to that region
apparently interferes with flu viruses' ability to deliver their genetic
material into host cells and start a new infection. That antibody is about to
begin tests in human volunteers.
The
Missing Piece
Crucell
researchers subsequently searched for an antibody that could neutralize some or
all of the remaining flu viruses unaffected by CR6261, and recently found one,
CR8020, that fits this description. As the team now reports in the Science
Express paper, CR8020 powerfully neutralizes a range of human-affecting flu
viruses in lab-dish tests and in mice. The affected viruses include H3 and H7,
two subtypes of great concern for human health that have already caused a
pandemic (H3) or sporadic human infections (H7).
As
with the CR6261 project, Ekiert and colleagues were able to grow crystals of
the new antibody bound to an HA protein from a deadly strain of H3N2, and........For complete article CLICK HERE
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