Re: Man Made H5N1 - Super Version
Palese opinion:
http://www.pnas.org/content/early/2012/01/24/1121297109.full.pdf
doesn't make much sense to me.
"fear needs to be put to rest"
I wonder whether he has some interest in the data-release, i.e. whether he wants to
work on the issue.
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www.pnas.org/cgi/doi/10.1073/pnas.1121297109 PNAS Early Edition
H5N1 influenza viruses: Facts, not fear
Peter Palese (a,b,1) and Taia T. Wang (a)
Departments of (a) Microbiology and (b) Medicine,
Mount Sinai School of Medicine, New York, NY 10029
Author contributions: P.P. and T.T.W. wrote the paper.
The authors declare no conflict of interest.
(1) To whom correspondence should be addressed. E-mail:
peter.palese@mssm.edu
*Details of the manuscripts have already been disclosed to many in the field
of influenza virology; for example, one of us (P.P.) was sent one of the
manuscripts in September 2011 as a courtesy and to elicit comments.
>The ongoing controversy
>over publication of two studies involving the transmission in
>ferrets of H5N1 (H5) subtype influenza viruses and the recommendations
>of the National Science Advisory Board for Biosecurity to redact
>key details in the manuscripts call for an examination of relevant
>scientific facts. In addition, there are calls in the media to
>destroy the viruses, curtail future research in this area, and
>protect the public from such “frightening” research efforts. Fear
>needs to be put to rest with solid science and not speculation.
>avian influenza | moratorium | World Health Organization |
>case fatality rate | National Science Advisory Board for Biosecurity
Facts
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What Are the Studies About?
>The two studies
>discussed here are by Ron Fouchier at Erasmus Medical Center in
>Rotterdam and Yoshihiro Kawaoka at the University of Wisconsin
>(not yet published by Science and Nature, respectively) . Both
>senior authors are experienced virologists who have worked for
>years with highly pathogenic avian influenza viruses. Their respective
>studies differ in many ways, but both were designed to answer
>one question of whether H5 influenza viruses can achieve sustainable
>aerosol transmission in ferrets. The studies use the age-old method
>of virus adaptation by repeated passage in cells or in naive animal
>hosts. H5 viruses (WT or with specific mutations introduced that
>are known to confer tropism to mammalian tissue) were passaged
>in ferrets, a well established animal model for the study of influenza
>transmission (1–5) . Ultimately, both studies determined that,
> indeed, H5 viruses could acquire aerosol transmissibility while
>maintaining virulence in ferrets. * The experiments demonstrate
>the important finding that aerosol transmission between ferrets
>can be determined by a relatively small number of mutations that
>do not significantly change virus virulence. Thus, the need for
>continued surveillance efforts around H5 viruses is clearly reinforced
>by these works, as is the importance of continuing to develop
>H5 vaccines and therapeutics (6) .
How Relevant Are These Studies for Humans?
>The ferret system is an important model for the study
>of influenza transmission, virulence, and immunity (7–11) . Generally,
> the ferret model provides a more accurate reflection of how influenza
>viruses affect humans compared with the mouse model (another common
>system) (12) . Ferrets are quite susceptible to infection with
>influenza viruses. However, it is not clear that all virus strains
>that replicate in and transmit between ferrets necessarily do
>so in humans (13, 14) . Ferrets are also more likely than humans
>to have disseminated, multiorgan influenza disease including neurologic
>sequelae resulting from virus replication in the brain (15–18).
>Thus, the mutations identified in the studies by Fouchier and
>Kawaoka could cause the viruses to be more transmissible between
>humans, but this is simply unknowable from the available data.
> The viruses may well be more adapted to ferrets, but not more
>adapted to other mammals; one cannot directly extrapolate from
>the data to make predictions about humans. In fact, passage of
>viruses in a different host is the most frequently used strategy
>to reduce viral virulence in humans. Many live, attenuated virus
>vaccines have been generated by that approach, including those
>for poliovirus and yellow fever virus. Further experiments in
>other mammalian systems would enhance our understanding of the
>potential for the H5 viruses to transmit between nonferret mammals
>and/or cause disease in these systems (19–21) . It is known that
>H5 viruses have been circulating in poultry for at least 50 years
>(probably much longer) and that they cause natural infection and
>even transmit between some mammals such as pigs, dogs, and cats
>(21–24) (Figs. 1 and 2) . Despite regular human contact with animal
>reservoirs and the virus’ propensity to mutate, strains able to
>cause sustained disease in humans have not emerged. In fact, in
>humans, only influenza viruses of the subtypes H1, H2, and H3
>have circulated during the past 100 years, suggesting that other
>subtypes may not easily become significant human pathogens.
Why Is it Important to Have the Full Data Published?
>With respect
>to the specific papers by Fouchier and Kawaoka, it would be important
>for other scientists to replicate portions of these works to test
>new vaccines/therapeutic agents and for continued studies on the
>molecular aspects of influenza transmission, a topic that is extremely
>important yet relatively poorly understood (25–27) . From a broader
>perspective, publishing relevant methods and data related to important
>experimental findings is fundamental to progress in science. Enabling
>others to repeat published data makes it possible to expand on
>what is known; the cycle of publication followed by experimental
>replication and advancement has resulted in the majority of our
>scientific and medical achievements. With specific reference to
>influenza viruses, the free flow of data has enabled the timely
>development of vaccines and other medications for seasonal and
>pandemic disease, and has, without question, saved millions of
>lives.
Fear
-----
>With the understanding that all parties involved have
>worthy intentions, it is difficult to ignore some of the incongruities
>that overshadow discussions related to H5 viruses and the publication
>of these two manuscripts. Examination of the topics discussed
>below may relieve some of the fear that is fueling the current
>debate.
Is the Case Fatality Rate for Human H5 Infections Truly Greater than 50% ?
>At the heart of this controversy is the notion
>that the case fatality rate for human H5 infections is in the
>range of 50% to 80% . This rate is derived from the list of H5
>cases that have been “confirmed” under World Health Organization
>(WHO) guidelines; the list tallies 573 cases in 15 countries
>(as of December 15, 2011) , with nearly 60% of total cases resulting
>in death (28) . The frequency and certainty with which this staggering
>fatality rate is reported is troubling when one considers how
>the numbers are generated; in order for a case to be confirmed
>by WHO, a person must have an acute, febrile respiratory illness
>(temperature >38C/100.3F) with known H5 exposure in the 7
>days preceding symptom onset and have molecular confirmation of
>H5 infection by a WHO-approved laboratory (e.g. , virus isolation,
> PCR, serology) (29) . This definition does not allow for asymptomatic
>infections and essentially requires that a person actively seek
>medical help at a hospital that is
>equipped to draw samples and ship them to an approved laboratory.
>Given that rural populations in developing countries are most
>commonly affected by H5 viruses, it seems unlikely that even a
>small fraction of the total number of infected cases has been
>accounted for under the WHO surveillance system. Also, the fatal
>cases that have been reported are most likely caused by mega-doses
>of H5 virus inhaled by the patients, who are living in very close
>contact with infected poultry. Transmission involving small doses
>of virus (as observed under regular aerosol transmission conditions)
> may not result in overt disease. Of the 10 largest studies of
>which we are aware (N=500) (30-39) , which document seroevidence
>in humans for H5 infections, two studies report no seropositivity
>and the other eight report rates ranging from 0.2% to 5.6% ; the
>studies are mostly conducted in rural areas where H5 in fections
>have been previously documented (30-39) . Even if only a low percentage
>of the rural population is asymptomatically/ subclinically infected,
> the case fatality rate that is offered by the WHO—and that is
>driving this controversy—is likely orders of magnitude too high.
> This suggests that more work should be done to determine an accurate
>case fatality rate for H5 infections, which takes into account
>mild and asymptomatic cases.
Why These Papers, Why Now?
>The type of work performed in the studies under evaluation is quite common
>in virology becauseitisausefulwaytostudymolecular determinants
>of virus adaptation, pathogenesis, and transmission. The reasoning
>behind the selection by the National Science Advisory Board for
>Biosecurity of these specific papers for redaction/censorship
>seems somewhat arbitrary relative to what has previously been
>published in the field of influenza. In 2005, the complete sequences
>for the 1918 pandemic influenza virus were published in Nature
>and methods describing the rescue of the 1918 virus were published
>in Science (40, 41) . In 2006, both Science and Nature published
>reports of specific mutations that enable the H5 viral hemagglutinin
>to bind human, rather than avian, tissues (42, 43) . In 2012,
>a report from the Centers for Disease Control and Prevention that
>bears striking resemblance, in principle, to the works by
>Fouchier and Kawaoka was already published in Virology;
>it describes mutations in an H5N1 virus that confer airborne transmissibility
>between ferrets (44) . Studies have also been published recently
>that describe mutations enabling other potential pandemic strains
>to transmit between ferrets (45, 46) or that make currently circulating
>virus strains more virulent (47) . These are a small fraction
>of studies published during the past decade that could have been
>considered controversial (some were controversial at the time,
> but all were published in full) . We know from studies like these
>that, for example, the 2009 pandemic vaccine protects against
>the 1918 pandemic virus and thus the 1918 strain is not a pandemic
>threat at this time (48) , nor would it be of any advantage for
>a bioterrorist to lay his/her hands on it. Other striking examples
>of achievements based on the free exchange of potentially controversial
>information are the elimination of SARS corona virus in only 6
>months and the fact that the dangers of HIV have been dramatically
>reduced by the development of effective antiviral treatments.
>None of this would have been possible without the uncensored exchange
>of scientific data.
Could the Data from These Two Papers Realistically
Be Used to Generate an H5N1 Biologic Weapon?
>The answer is simply no.
>It would be unrealistic to assume that these ferret viruses
>could be successfully used against humans. Even if the viruses
>were transmissible between humans and were to cause disease in
>humans, viable vaccine candidates for H5 viruses do exist and
>available influenza medications have good activity against H5
>strains (49, 50) . Additionally, safely generating a stock of
>highly virulent influenza virus based on raw sequence information
>would require (i) access to a sophisticated laboratory setting,
> (ii) proficiency in relevant concepts of molecular biology, and
>(iii) experience with laboratory methods related to influenza
>viruses (e.g. , rescue by reverse genetics, growth and harvesting
>of the virus, storage) . In contrast to the expertise and resources
>that would be required to use nucleic acid sequences for virus
>production, passing a virus in animals (or humans) to adapt it
>to a mammalian host would require no training or data, and could
>likely be done very quickly. Still, this approach is extremely
>unlikely to be successful. As mentioned earlier, passing viruses
>in animals typically results in attenuation of the disease phenotype
>and, perhaps most importantly, this experiment has been and is
>going on every day in a natural setting. So far, of the likely
>millions of mammals that have hosted H5 viruses,
>none of the strains that have emerged are real human pathogens.
> It would be very difficult for a bioterrorist to come up with
>a human virus strain that is transmissible and still highly
>virulent. Under natural conditions, however, there is virtually
>unlimited allowance for generation of capable viruses, the opportunities
>for infection of humans are plentiful, and the evolutionary pressures
>of selection are great. If anyone could do it, Nature could.
