Common weak point in flu virus strains could lead to universal flu
6 March 2009
Two recent studies have found a common Achilles’ heel in a wide range
of seasonal and pandemic influenza A virus strains.
Researchers at The Scripps Research Institute in La Jolla,
California, have found an infection-fighting human protein, or human
antibody, that neutralizes various influenza A virus subtypes by
attaching to these viruses in the same place.
The study provides data about the antibody attachment site that are
similar to the findings of another research group
led by Dr Wayne Marasco, associate professor of medicine at the
Dana-Farber Cancer Institute and Harvard Medical School in Boston. This
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.
This common attachment site provides a constant region of the flu
virus for scientists to target in an effort to develop a so-called
universal flu vaccine. Such a vaccine would overcome the annual struggle
to make the seasonal flu vaccine match next year’s circulating flu
strains and might help blunt emerging pandemic influenza viruses as
The Scripps research team, led by Dr Ian A Wilson, in collaboration
with researchers at the biopharmaceutical company Crucell Holland (The
Netherlands), discovered the potent antibody during a systematic
examination of blood samples taken from healthy individuals who
previously had been vaccinated with the ordinary seasonal flu vaccine.
The results have been published in the journal Science .
Using sophisticated screening technologies, the team isolated
antibodies that recognize flu viruses to which the average person has
never been exposed, such as H5N1 avian flu viruses.
Through this process, the scientists found one antibody called CR6261
that had broad neutralizing capabilities. Subsequently, they found
several antibodies similar to CR6261 in other donors as well. With the
help of a robotic crystallization laboratory, the Scripps team quickly
determined the detailed three-dimensional structures of this antibody
when bound to the H1 virus that caused the 1918 pandemic flu as well as
to an H5 virus with pandemic potential.
CR6261 bound to a relatively hidden part in the stem below the
mushroom-shaped head of the hemagglutinin protein, one of two major
surface proteins found on the flu virus.
In the second study , 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 virus.
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.
Ribbon diagram of the influenza virus H5
hemagglutinin (HA) surface protein bound by
the F10 monoclonal antibody (red). The two
chains of H5 are HA1 (yellow) and HA2 (blue).
(Credit: William Hwang and Jianhu Su, Dana-Farber Cancer Institute)
Dr Marasco, Jianhua Sui, MD, PhD, 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,
PhD, of the US Centers for Disease Control (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, PhD, 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 mutation.
“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
“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.
Emergency planning still required
Dr Jean Challiner, Medical Director of Clinical Solutions, a UK
supplier of clinical decision-support systems, says that it is still
essential to maintain disease-outbreak response systems: “It is of
course welcome news indeed that new treatments are being developed to
protect the population from the devastating consequences Pandemic
Influenza would currently have. However, development of effective
antiviral medicine alone is not the only requirement to both prepare for
and manage the consequences of an outbreak, and we must not become
oblivious to the threats posed by other diseases, such as SARS — for
which there is no specific treatment or vaccine available.
“The outbreak of any pandemic can be manageable if effective measures
are taken to prepare for outbreaks in advance — and the development of
antiviral medication, although crucial, only makes up part of this.
Offering the public access to healthcare professionals who can carry out
an appropriate assessment and offer up-to-date advice and information,
will reduce public anxiety, support effective use and distribution of
medicines available, and help contain the outbreak so minimising risk.
"Having the right tools to support healthcare professionals involved, as
well as the ability to collect and analyse information gathered, is an
essential part of forward planning — and this is where technology can
lend a hand.
“In an emergency situation traditional access to healthcare is not
always an option. Technology can deliver web and telephony-based support
for assessment, direction of care, advice, guidance and, where
appropriate, authorisation of antiviral medicine treatment without the
need for people to leave their homes.
"Technology can also be used in a command centre environment to help
monitor the situation in real-time with the facility to rapidly change
and update the instructions available on websites and for call operators
who are communicating with the public.
“The onset of Pandemic Influenza is well overdue and we cannot be
sure when the next pandemic will strike. For that reason it is essential
that we are prepared as a nation to effectively manage a pandemic threat
through provision of systems which will give the general public easy
access to consistent assessment processes and advice — so ensuring the
most effective implementation of immunisation and treatment regimes and
maximising the benefit that new medicines can provide.”
1. DC Ekiert et al. Antibody recognition of a highly conserved
influenza virus epitope. Science. DOI 10.1126/science.1171491
2. 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 (2009).
The Dana-Faber Cancer Institute website has
an animation of human monoclonal antibodies and the flu virus.
For more information on influenza see the
US National Institute of
Allergy and Infectious Diseases's (NIAID) flu portal
and the Centers for Disease Control's
Also visit www.PandemicFlu.gov
for a one-stop access to US Government information on avian and pandemic
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