|Scientists Identify Lab-Made Proteins That
Neutralize Multiple Strains of Seasonal and Pandemic Flu Viruses
Scientists have identified a small family of lab-made proteins
that neutralize a broad range of influenza A viruses, including
the H5N1 avian virus, the 1918 pandemic influenza virus and seasonal
H1N1 flu viruses. These human monoclonal antibodies, identical
infection-fighting proteins derived from the same cell lineage,
also were found to protect mice from illness caused by H5N1 and
other influenza A viruses. Because large quantities of monoclonal
antibodies can be made relatively quickly, after more testing,
these influenza-specific monoclonal antibodies potentially could
be used in combination with antiviral drugs to prevent or treat
the flu during an influenza outbreak or pandemic.
A report describing the research, supported by the National Institute
of Allergy and Infectious Diseases (NIAID) of the National Institutes
of Health as well as the Centers for Disease Control and Prevention,
appears online today in Nature Structural & Molecular Biology.
Wayne Marasco, M.D., Ph.D., associate professor of medicine at
the Dana-Farber Cancer Institute and Harvard Medical School in
Boston led the research team, which included collaborators from
the Burnham Institute for Medical Research in La Jolla, Calif.,
and the CDC in Atlanta.
"This is an elegant research finding that holds considerable
promise for further development into a medical tool to treat and
prevent seasonal as well as pandemic influenza," notes NIAID
Director Anthony S. Fauci, M.D. "In the event of an influenza
pandemic, human monoclonal antibodies could be an important adjunct
to antiviral drugs to contain the outbreak until a vaccine becomes
Using standard methods of production, initial doses of a new influenza
vaccine to fight pandemic influenza would be expected to take four
to six months to produce.
Key to their research, Dr. Marasco and his colleagues discovered
and described the atomic structure of an obscure but genetically
stable region of the influenza virus to which their monoclonal
antibodies bind. The hidden part of the influenza virus is in the
neck below the peanut-shaped head of the hemagglutinin (HA) protein.
HA and neuraminidase are the two main surface proteins on the influenza
The scientists also identified a new mechanism of antibody action
against influenza: Once the antibody binds, the virus cannot change
its shape, a step required before it can fuse with and enter the
cell it is attempting to infect.
Dr. Marasco, Jianhua Sui, M.D., Ph.D., and other Dana-Farber colleagues
began their study with avian flu viruses. They scanned tens of
billions of monoclonal antibodies produced in bacterial viruses,
or bacteriophages, and found 10 antibodies active against the four
major strains of H5N1 avian influenza viruses. Encouraged by these
findings, they collaborated with Ruben O. Donis, Ph.D., of the
CDC Influenza Division, and found that three of these monoclonal
antibodies had broader neutralization capabilities when tested
in cell cultures and in mice against representative strains of
other known influenza A viruses.
Influenza A viruses can include any one of the 16 known subtypes
of HA proteins, which fall into two groups, Group 1 and Group 2.
Their monoclonal antibodies neutralized all testable viruses containing
the 10 Group 1 HAs—which include the seasonal H1 viruses,
the H1 virus that caused the 1918 pandemic and the highly pathogenic
avian H5 subtypes—but none of the viruses containing the
six Group 2 HAs.
Simultaneously, Dr. Marasco’s group teamed up with Robert C. Liddington,
Ph.D., professor and chair of the Infectious and Inflammatory Disease
Center at Burnham, to determine the atomic structure of one of
their monoclonal antibodies bound to the H5N1 HA. Their detailed
picture shows one arm of the antibody inserted into a genetically
stable pocket in the neck of the HA protein, an interaction that
blocks the shape change required for membrane fusion and virus
entry into the cell.
When they surveyed more than 6,000 available HA genetic sequences
of the 16 HA subtypes, they found the pockets to be very similar
within each Group but to be significantly different between the
two Groups. The genetically stable pockets, they note, may be a
result of evolutionary constraints that enable virus-cell fusion.
This could also explain why they did not detect so-called escape
mutants, viruses that elude the monoclonal antibodies through genetic
"One of the most remarkable findings of our work is that
we identified a highly conserved region in the neck of the influenza
hemagglutinin protein to which humans rarely make antibodies," says
Dr. Marasco. "We believe this is because the head of the hemagglutinin
protein acts as a decoy by constantly undergoing mutation and thereby
attracting the immune system to produce antibodies against it rather
than against the pocket in the neck of the protein."
Their findings could also assist vaccine developers. Current influenza
vaccines target the constantly mutating head of the HA protein
and do not readily generate antibodies against the conserved region
in the neck.
"An important goal is to redirect the immune response of
vaccines to this invariable region of the hemagglutinin to try
to obtain durable lifelong immunity," Dr. Marasco states.
The monoclonal antibodies identified in their paper are very
well-characterized, Dr. Marasco notes, and he is optimistic about
their further clinical development. "These are fully human
monoclonal antibodies that are ready for advanced preclinical testing," he
says. He currently is arranging to use NIAID research resources
to take the next steps: first, testing the antibodies in ferrets,
the gold standard animal model for influenza, and then developing
a clinical grade version of one antibody that could enter human
clinical trials as soon as 18 months from when the development
program begins. Should the antibodies prove safe and effective
in humans, it could take several years to develop a licensed product.
Despite the availability of influenza drugs and vaccines, seasonal
influenza still kills more than 250,000 people worldwide each year.
During seasonal flu outbreaks, monoclonal antibodies could be used
to treat individuals with impaired immunity due to pre-existing
medical conditions or advanced age. In the event of an influenza
pandemic, these individuals plus others at risk—for example,
first responders and medical personnel and exposed family members
and coworkers—could also benefit from this type of therapy.
For more information on influenza see http://www3.niaid.nih.gov/topics/flu.htm and www.cdc.gov/flu.
Also visit http://www.PandemicFlu.gov for
one-stop access to U.S. Government information on avian and pandemic
NIAID conducts and supports research—at NIH, throughout
the United States, and worldwide—to study the causes of infectious
and immune-mediated diseases, and to develop better means of preventing,
diagnosing and treating these illnesses. News releases, fact sheets
and other NIAID-related materials are available on the NIAID Web
site at http://www.niaid.nih.gov.
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Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
Reference: J Sui et al. Structural and functional
bases for broad-spectrum neutralization of avian and human influenza
A viruses. Nature Structural & Molecular Biology DOI: 10.1038/nsmb.1566