After a marathon debate over a pair of
studies that show how the avian H5N1 influenza virus could become transmissible
in mammals, and an unprecedented recommendation by a government review panel to
block publication, one of the studies was finally and fully published in the
journal Nature (May 3, 2012).
Publication
caps an epic public conversation that pitted some infectious diseases experts
against flu and public health researchers who argued that publication was not
only important, but also essential to informing influenza
surveillance and preparedness for a virus that could evolve to infect
humans and cause a global
pandemic.
"Our
study shows that relatively few amino acid mutations are sufficient for a virus
with an avian H5 hemagglutinin to acquire the ability to transmit in
mammals," says Yoshihiro Kawaoka, a University of Wisconsin-Madison flu
researcher whose study of H5N1 virus transmissibility was at the center of the
debate. "This study has significant public health benefits and contributes
to our understanding of this important pathogen.
By
identifying mutations that facilitate transmission among mammals, those whose
job it is to monitor viruses circulating in nature can look for these mutations
so measures can be taken to effectively protect human health."
However,
Kawaoka cautions there may be other unknown mutations that also enable the
virus to transmit in mammals. It is therefore critical, he argues, to continue
research to identify additional mutations that have the same effect, and to
understand how they work.
The
study, conducted by an international team of researchers led by Kawaoka, a
UW-Madison professor of pathobiological sciences and a leading expert on
influenza, shows that some viruses now circulating in nature require just four
mutations to the hemagglutinin protein, which sits on the virus surface and
enables it to bind to host cells, to become an even greater threat to human
health.
A
subset of the mutations identified by the Wisconsin group has, in fact, already
been detected in some viruses circulating in poultry flocks in Egypt and parts
of Southeast Asia, underscoring the urgency of science-based surveillance,
Kawaoka says.
In the Nature report,
Kawaoka's group describes a laboratory-modified bird flu/human flu hybrid virus
that can become transmissible in an animal model for human infection with just
a handful of mutations.
Because
flu viruses in nature are constantly changing as they circulate and easily swap
genes with other flu viruses, the possibility of circulating H5N1 viruses
hitting the right combination of mutations and becoming a much bigger threat to
human health is greater than many experts believed, avers Kawaoka, a faculty
member in the UW-Madison School of Veterinary Medicine.
"H5N1
viruses remain a significant threat for humans as a potential pandemic flu
strain. We have found that relatively few mutations enable this virus to
transmit in mammals. These same mutations have the potential to occur in
nature," explains Kawaoka.
Since
late 2003, the H5N1 viruses have infected at least 600 humans, mostly in Asia,
and killed more than half of the people infected. But the virus, which can be
acquired through close contact with domestic fowl, does not easily transmit
from human-to-human, a phenomenon that led some scientists to believe H5N1
posed little threat as a potential agent for a global flu pandemic.
However,
research on transmission of viruses from animal reservoirs was deemed a
priority by the United States National Institute of Allergy and Infectious
Disease (NIAID) in a 2006 Blue Ribbon Panel report, as well as by the World
Health Organization (WHO) in its 2009 Public Health Research Agenda.
In
addition to demonstrating transmissibility, Kawaoka's results showed the
experimental mutant virus could be controlled by available medical
countermeasures. An H5N1 vaccine as well as oseltamivir, an antiviral drug
better known by the trade name Tamiflu, both proved effective.
The
study was conducted with scientists from the University of Tokyo, where Kawaoka
is also on the faculty, Kobe University, and Chubu University.
The flu
virus depends on an ability to enter and commandeer host cells to make new
virus particles, which go on to infect other cells and spread to other hosts.
But flu virus, which typically arises in animal reservoirs such as domestic
fowl and pigs before spreading to humans, must adapt by changing its surface
topography to match those of a new host species.
A
protein on the surface of the virus known as hemagglutinin is one of the keys
that allow the virus to access host cells. It utilizes a bulb-shaped structure
called the "globular head" to bind to host cells at the time of
infection.
The
amino acids in this portion of the hemagglutinin protein are like a combination
that opens a locked cell. Without the right combination, the virus is unable to
enter a host cell and cause infection.
But flu
viruses are masters of shape shifting, a characteristic that helps them adapt
to new animal hosts. They readily exchange genetic information and mutate to
acquire the molecular features that can make them more infectious.
Whether
or not the H5N1 viruses currently circulating in the world can easily acquire
the additional mutations needed to cause a pandemic is an open question,
according to Kawaoka: "It is hard to predict.
The
additional mutations may emerge as the virus continues to circulate."
The new
work will aid those who monitor flu and could provide a critical early warning.
"Should surveillance activities identify flu strains accumulating
additional key mutations, these emerging viruses should then be priority
candidates for vaccine development and antiviral evaluation," says
Kawaoka.
One
important upshot of the study by Kawaoka's group is the identification of the
mechanism by which the H5N1 virus transmits, a basic discovery that could aid
in the development of countermeasures, and that contributes to the store of
basic knowledge on influenza
virus transmission.
The
work will also help governments in some countries justify the significant
economic hardship imposed by the mass culling of poultry flocks when potentially
dangerous mutations are identified in circulating H5N1 viruses.
The new
study was conducted using ferrets, a widely accepted model for influenza
research because, when infected with the flu virus, they sneeze and cough,
generating small droplets that can carry the virus from one animal to another,
demonstrating transmissibility. The ferret respiratory tract also has cellular
features similar to those found in humans.
In
December 2011, a National Institutes of Health advisory panel, the National
Science Advisory Board for Biosecurity (NSABB), recommended redacting critical
information from the Kawaoka lab's report, as well as from a similar study
conducted in Holland. The unprecedented request was to withhold the
methodologies used to make the virus transmissible and to not identify the
mutations needed to make the virus transmissible in mammals.
This
month, the NSABB reversed itself, citing new information and manuscript
revisions that more explicitly state the public health rationale for the work
as well as the safety and security precautions in place in the labs in
Wisconsin and Holland.
It was
noted that the virus engineered in Kawaoka's lab was, in fact, of low
virulence. The hybrid virus was made by building the H5N1 hemagglutinin gene
into the pandemic H1N1 flu virus; the H5-H1N1 hybrid was less pathogenic than
pandemic H1N1 virus.
As is
the case for all studies of avian influenza transmissibility, the Wisconsin
H5N1 work was conducted under strictly controlled conditions with multiple
layers of safety and security precautions. Moreover, research involving agents
such as highly pathogenic influenza viruses
undergoes rigorous federal and institutional oversight including frequent and
unannounced inspections.
The
laboratories such as the one where the new work was conducted are designed to
strict specifications and operated to ensure safety.
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