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  • JAMA - The Next Influenza Pandemic

    Hat-tip, MomCares!

    Public release date: 8-May-2007

    Contact: Jason Bardi
    jbardi _at_ niaid.nih.gov
    301-402-1663
    NIH/National Institute of Allergy and Infectious Diseases

    Why predicting the next influenza pandemic is difficult and how scientists can best prepare

    NIAID media availability

    WHAT: In planning for a future influenza pandemic, most experts agree that two things are known for certain ? there will be another pandemic someday, and nobody can predict when. In a commentary in the May 9, 2007 issue of the Journal of the American Medical Association, scientists at the National Institutes of Health discuss why predicting the next pandemic is so difficult and outline steps that can be taken to better understand the behavior of the virus. Drawing upon the lessons of past pandemics, the authors analyze the significance of the highly pathogenic avian influenza strain H5N1, which has spread among bird populations and infected hundreds of humans in the last decade. In preparing for the next influenza pandemic, however, the authors argue that researchers and public health officials should not focus solely on H5N1 strains, because the next pandemic might be caused by a different influenza virus.

    Instead, research efforts should go beyond H5N1 and focus broadly on influenza viruses. This entails improving our knowledge of the basic biological and ecological means by which influenza A viruses infect birds; enhancing surveillance of infected animals and the circulation of influenza virus globally; understanding how the virus evolves and jumps from birds and other animals to humans; finding new approaches to vaccine design and vaccination; and developing new antivirals and diagnostics. Such broad activities can also help combat seasonal influenza, which is a major public health concern in the United States, accounting for an estimated 36,000 deaths and 200,000 hospitalizations each year.


    ###

    ARTICLE: ?The next influenza pandemic: can it be predicted?? by J Taubenberger, D Morens and A Fauci. JAMA DOI: 10.1001/jama.297.18.2025 (2007).

    In planning for a future influenza pandemic, most experts agree that two things are known for certain -- there will be another pandemic someday, and nobody can predict when. In a commentary in the May 9, 2007, issue of the Journal of the American Medical Association, scientists at NIH discuss why predicting the next pandemic is so difficult and outline steps that can be taken to better understand the behavior of the virus.
    ...when you have eliminated the impossible, whatever remains, however improbable, must be the truth. - Sherlock Holmes

  • #2
    Re: Why predicting the next influenza pandemic is difficult

    Anybody have access to the full article?

    ...when you have eliminated the impossible, whatever remains, however improbable, must be the truth. - Sherlock Holmes

    Comment


    • #3
      Re: Why predicting the next influenza pandemic is difficult

      Bird flu not only pandemic risk, U.S. experts warn
      Tue May 8, 2007

      By Julie Steenhuysen

      CHICAGO (Reuters) - While many health experts see the H5N1 bird flu virus as a likely cause for an influenza pandemic, another influenza virus could just as likely mutate into a global killer, U.S. health experts said on Tuesday.

      "You can not accurately predict if and when a given virus will become a pandemic virus," said Anthony Fauci, head of the U.S. National Institute of Allergy and Infectious Diseases.

      Fauci said too little is known about exactly how and when a virus will mutate. Focusing too much on one suspect -- even a very likely suspect such as H5N1 -- may be a mistake.

      "We should not ... forget the fact that historically pandemics have evolved. We should be building up the knowledge base and expanding the capabilities of making vaccines," he said in a telephone interview.

      Fauci and colleagues, writing in a commentary in the Journal of the American Medical Association, said pandemic prevention strategies must based on "expecting the unexpected and being capable of reacting accordingly."

      They recommend companies expand their research on vaccine design, develop new classes of drugs and improve tests to diagnose influenza.

      The H5N1 avian influenza virus that is now killing birds in countries from Indonesia to Nigeria rarely infects people.

      But many believe if it mutates in just the wrong way, it could start passing easily from one person to another and would sweep the globe, killing millions.

      Companies and governments are working feverishly to prepare for a pandemic by developing vaccines and stockpiling drugs to treat viruses.

      But focusing too much on just one viral suspect may leave the world vulnerable in the event that another virus causes a deadly flu pandemic.

      "The ability of these types of viruses to ultimately spread from birds to humans is a very complex process involving multiple genetic evolutions. It's a complicated issue that is very difficult to predict," Fauci said.

      ...when you have eliminated the impossible, whatever remains, however improbable, must be the truth. - Sherlock Holmes

      Comment


      • #4
        Re: Why predicting the next influenza pandemic is difficult

        Originally posted by Theresa42 View Post
        Anybody have access to the full article?

        http://jama.ama-assn.org/cgi/content...ct/297/18/2025
        why is it not available from the NIAID webpage ?
        Isn't this a public organization, paid from public (tax-) money
        for the purpose to educate and inform us ?

        Aren't they releasing press-statements to advertise
        for that article, which requires subscription to some
        journal ?

        What's the purpose ? To hinder (competing) researchers from examining
        the same issue for the benefit of the whole of mankind ?
        I'm interested in expert panflu damage estimates
        my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

        Comment


        • #5
          Re: Why predicting the next influenza pandemic is difficult

          whenever they say, that we shouldn't concentrate on H5N1 but also
          consider other flu viruses which might go pandemic, that makes me feel
          good.
          We have no evidence that other viruses are actually more dangerous than
          they were all the decades before, do we ?

          So the H5N1-threat is being put in the same box as these
          other, "normal" threats !
          I'm interested in expert panflu damage estimates
          my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

          Comment


          • #6
            Re: Why predicting the next influenza pandemic is difficult

            Originally posted by gsgs View Post
            why is it not available from the NIAID webpage ?
            Isn't this a public organization, paid from public (tax-) money
            for the purpose to educate and inform us ?

            Aren't they releasing press-statements to advertise
            for that article, which requires subscription to some
            journal ?

            What's the purpose ? To hinder (competing) researchers from examining
            the same issue for the benefit of the whole of mankind ?
            Most researchers can access JAMA.

            Comment


            • #7
              Re: Why predicting the next influenza pandemic is difficult

              The Next Influenza Pandemic

              Can It Be Predicted?
              <NOBR>Jeffery K. Taubenberger, MD, PhD</NOBR>; <NOBR>David M. Morens, MD</NOBR>; <NOBR>Anthony S. Fauci, MD</NOBR>

              JAMA. 2007;297:2025-2027.
              <TABLE cellSpacing=0 cellPadding=0 width="70%" align=center border=0><TBODY><TR><TD bgColor=#6a90aa colSpan=3></TD></TR><TR><TD bgColor=#6a90aa></TD><TD><TABLE cellSpacing=0 cellPadding=10 width="100%" border=0><TBODY><TR><TD align=middle>Since this article does not have an abstract, we have provided the first 150 words of the full text and any section headings.</TD></TR></TBODY></TABLE></TD><TD bgColor=#6a90aa></TD></TR><TR><TD bgColor=#6a90aa colSpan=3></TD></TR></TBODY></TABLE>
              <!--startindex-->Although most experts believe another influenza pandemic will<SUP> </SUP>occur, it is difficult to predict when or where it will appear<SUP> </SUP>or how severe it will be. Neither is there agreement about the<SUP> </SUP>subtype of the next pandemic influenza virus. However, the continuing<SUP> </SUP>spread of H5N1 highly pathogenic avian influenza A (HPAI) among<SUP> </SUP>poultry on several continents, associated with an increasing<SUP> </SUP>number of severe and fatal human infections, has raised the<SUP> </SUP>pandemic stakes.<SUP>1</SUP> Genetically and antigenically divergent H5N1<SUP> </SUP>HPAI strains appeared in 1997 and have been spreading globally<SUP> </SUP>since 2003.<SUP>2-3</SUP> To date, epizootics in approximately 60 countries<SUP> </SUP>have caused a reported 291 human cases with 172 deaths.<SUP>4</SUP><SUP> </SUP>
              Although overshadowed by H5N1, at least 8 other poultry epizootics<SUP> </SUP>have recently occurred, some involving human infections and,<SUP> </SUP>uncommonly, human deaths.<SUP>5</SUP> H5N1 epizootics are unique, <NOBR>. . .</NOBR> [Full Text of this Article]
              How the H5N1 Virus May Be Evolving

              <!--stopindex-->Author Affiliations: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.


              <!-- null -->RELATED ARTICLE <TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD width="100%" bgColor=#6a90aa></TD></TR></TBODY></TABLE>
              This Week in JAMA
              JAMA. 2007;297:1955.
              <NOBR>FULL TEXT </NOBR>

              Comment


              • #8
                Re: Why predicting the next influenza pandemic is difficult

                this is an issue with increased importance for the public,
                for the politicians.
                It's not a medical research issue.

                It should be easily available to the public.
                Why not use PLOS or EID or just put it on NIAID-webpage
                or allow FT to post and discuss it ?
                I'm interested in expert panflu damage estimates
                my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

                Comment


                • #9
                  Re: Why predicting the next influenza pandemic is difficult

                  The Next Influenza Pandemic

                  Can It Be Predicted?
                  <NOBR>Jeffery K. Taubenberger, MD, PhD</NOBR>; <NOBR>David M. Morens, MD</NOBR>; <NOBR>Anthony S. Fauci, MD</NOBR>

                  JAMA. 2007;297:2025-2027.
                  <!--startindex-->Although most experts believe another influenza pandemic will<SUP> </SUP>occur, it is difficult to predict when or where it will appear<SUP> </SUP>or how severe it will be. Neither is there agreement about the<SUP> </SUP>subtype of the next pandemic influenza virus. However, the continuing<SUP> </SUP>spread of H5N1 highly pathogenic avian influenza A (HPAI) among<SUP> </SUP>poultry on several continents, associated with an increasing<SUP> </SUP>number of severe and fatal human infections, has raised the<SUP> </SUP>pandemic stakes.<SUP>1</SUP> Genetically and antigenically divergent H5N1<SUP> </SUP>HPAI strains appeared in 1997 and have been spreading globally<SUP> </SUP>since 2003.<SUP>2-3</SUP> To date, epizootics in approximately 60 countries<SUP> </SUP>have caused a reported 291 human cases with 172 deaths.<SUP>4</SUP><SUP> </SUP>
                  Although overshadowed by H5N1, at least 8 other poultry epizootics<SUP> </SUP>have recently occurred, some involving human infections and,<SUP> </SUP>uncommonly, human deaths.<SUP>5</SUP> H5N1 epizootics are unique, however,<SUP> </SUP>in causing mortality in wild birds, occasional infections in<SUP> </SUP>mammals, severe human infections, and in rare instances possible<SUP> </SUP>human-to-human transmission.<SUP>6</SUP><SUP> </SUP>
                  Do these unique features predict an impending H5N1 pandemic?<SUP> </SUP>Despite significant research, fundamental questions about how<SUP> </SUP>influenza A viruses switch hosts from wild birds and adapt to<SUP> </SUP>domesticated poultry, pigs or horses, and subsequently to humans,<SUP> </SUP>remain unanswered, especially those regarding the changes that<SUP> </SUP>allow human-to-human transmissibility.<SUP>7</SUP> Given the potential<SUP> </SUP>for high morbidity and mortality, an approximation of the risk<SUP> </SUP>that H5N1 viruses will adapt to efficient human-to-human transmission<SUP> </SUP>would be extremely helpful for pandemic preparedness planning;<SUP> </SUP>despite the apparent inevitability of influenza pandemics, data<SUP> </SUP>accumulated over the past decade do not necessarily indicate<SUP> </SUP>pandemic emergence of H5N1.<SUP> </SUP>
                  How the H5N1 Virus May Be Evolving <TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD width="100%" bgColor=#6a90aa></TD><TD></TD></TR></TBODY></TABLE>
                  H5N1 viruses are evolving rapidly; however, the direction of<SUP> </SUP>their evolution, driven by incompletely understood selection<SUP> </SUP>pressures, is unclear. Although current H5N1 HPAI viruses are<SUP> </SUP>descendants of the 1997 epizootic virus, significant genetic<SUP> </SUP>and antigenic evolution has since occurred, involving drift<SUP> </SUP>in the H5 hemagglutinin (HA), mutations in other genes, and<SUP> </SUP>reassortment with other avian influenza viruses.<SUP>5</SUP> It is not<SUP> </SUP>yet clear which of these changes is associated with lethality<SUP> </SUP>in wild birds or with pathogenicity and transmissibility in<SUP> </SUP>poultry and other species. Asymptomatic endemic H5N1 HPAI circulation<SUP> </SUP>in domestic ducks maintains a pool of pathogenic viruses to<SUP> </SUP>which poultry are continually exposed,<SUP>8</SUP> suggesting that the<SUP> </SUP>current H5N1 situation will likely persist.<SUP> </SUP>
                  There are limited data indicating whether any H5N1 influenza<SUP> </SUP>strain is evolving in the direction of human adaptation. Some<SUP> </SUP>H5N1 viruses exhibit a change in the polymerase protein complex<SUP> </SUP>PB2 that has been associated with increased H5N1 virulence in<SUP> </SUP>mice and ferrets, and adaptation of other avian influenza viruses<SUP> </SUP>to humans.<SUP>9-12</SUP> It remains unclear, however, whether this or<SUP> </SUP>any other mutation is associated only with increased mammalian<SUP> </SUP>virulence or provides an independent evolutionary advantage<SUP> </SUP>in birds.<SUP> </SUP>
                  The pathogenicity of influenza viruses for their different hosts<SUP> </SUP>is related to complex viral and host factors and remains to<SUP> </SUP>be fully characterized. Experimental animal data with both the<SUP> </SUP>H5N1 viruses and the 1918 influenza viruses suggest that virulence<SUP> </SUP>is polygenic and depends on a complementary relationship among<SUP> </SUP>viral gene segments.<SUP>13-14</SUP> In mammals, H5N1 viruses exhibit variable<SUP> </SUP>pathogenicity depending on the H5N1 strain and host. HPAI viruses<SUP> </SUP>are pathogenic in poultry principally because of a polybasic<SUP> </SUP>amino acid insertional mutation in the HA cleavage site, conferring<SUP> </SUP>an ability to replicate systemically. The role of systemic viral<SUP> </SUP>replication in humans or experimental mammals remains unclear<SUP> </SUP>and most likely also varies with viruses and hosts.<SUP>15</SUP><SUP> </SUP>
                  Biological barriers to viral fitness based on gene segment combination<SUP> </SUP>are not well understood; however, pathogenicity, host adaptation,<SUP> </SUP>and host-to-host transmissibility are likely independent properties<SUP> </SUP>associated with different, and possibly competing, mutational<SUP> </SUP>changes. Pandemic viruses of comparatively low (eg, 1968 [H3N2]<SUP> </SUP>influenza pandemic), intermediate (eg, 1889 [data suggest a<SUP> </SUP>possible H3N8] and 1957 [H2N2] influenza pandemics), and high<SUP> </SUP>(eg, 1918 [H1N1] influenza pandemic) pathogenicity have all<SUP> </SUP>adapted to humans and exhibited efficient transmissibility.<SUP> </SUP>
                  To cause a pandemic, an avian virus would have to at least adapt<SUP> </SUP>to human HA receptors and acquire human transmissibility. History<SUP> </SUP>suggests that this may be a difficult challenge for influenza<SUP> </SUP>viruses. Despite human and mammalian exposures to countless<SUP> </SUP>avian viruses over many decades, the last 2 pandemics have resulted<SUP> </SUP>from reassortment of preexisting human-adapted viruses containing<SUP> </SUP>imported genes derived from avian influenza viruses, not from<SUP> </SUP>de novo adaptation of avian viruses to humans. When genes from<SUP> </SUP>a 1997 H5N1 virus were experimentally reassorted in various<SUP> </SUP>combinations with those from a human H3N2 virus, none were efficiently<SUP> </SUP>transmitted between ferrets,<SUP>16</SUP> raising questions about whether<SUP> </SUP>H5N1 viruses may be inherently limited in their potential to<SUP> </SUP>adapt to, and be transmitted between, humans.<SUP> </SUP>

                  Can the H5N1 Virus Become Adapted to and Transmissible Between Humans? <TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD width="100%" bgColor=#6a90aa></TD></TR></TBODY></TABLE>
                  Mutational changes associated with binding of influenza viruses<SUP> </SUP>to receptors on different hosts are complex.<SUP>17</SUP> Adaptation of<SUP> </SUP>the viral HA receptor-binding site from a form optimized for<SUP> </SUP>binding the avian receptor to a form efficiently binding the<SUP> </SUP>human receptor seems to require some loss of specificity for<SUP> </SUP>2,3-linked sialic acids in favor of increased specificity for<SUP> </SUP>2,6-linked sialic acids.<SUP>17</SUP> Experiments suggest that only 2 mutations<SUP> </SUP>in the receptor-binding site convert the H1, H2, and H3 HAs<SUP> </SUP>of the past 3 influenza pandemic viruses from an avian to a<SUP> </SUP>human receptor-binding pattern. Several mutations have been<SUP> </SUP>reported to enhance H5 binding to the human form of the receptor;<SUP> </SUP>however, none has been reported to induce a complete switch<SUP> </SUP>in specificity. While it is possible that additional unknown<SUP> </SUP>mutations could result in a complete switch, there is no evidence<SUP> </SUP>that this has occurred after 11 years of H5N1 exposure to at<SUP> </SUP>least thousands of humans, nor is there evidence that it has<SUP> </SUP>occurred after human exposure to other H5 subtype viruses over<SUP> </SUP>many decades. HA receptor-binding changes during host adaptation<SUP> </SUP>differ from subtype to subtype, and H5 viruses may well face<SUP> </SUP>unappreciated biological barriers in achieving human receptor<SUP> </SUP>binding efficiency.<SUP> </SUP>
                  Although the current number and severity of clinical H5N1 cases<SUP> </SUP>make the ongoing situation highly unusual, H5N1 viruses are<SUP> </SUP>not unique among avian influenza viruses in their ability to<SUP> </SUP>cause human infections and even limited human transmission.<SUP> </SUP>For example, since the mid 1990s, strains of H9N2 avian influenza<SUP> </SUP>viruses have become widely enzootic in poultry and have caused<SUP> </SUP>a small number of human cases. Some H9N2 viruses have even acquired<SUP> </SUP>enhanced specificity for the human form of the HA receptor.<SUP>5</SUP><SUP> </SUP>In 2003, an H7N7 HPAI virus caused a poultry epizootic in the<SUP> </SUP>Netherlands and spread regionally. Before the epizootic was<SUP> </SUP>contained, at least 86 poultry workers and 3 contacts had become<SUP> </SUP>infected and developed conjunctivitis with or without an influenza-like<SUP> </SUP>illness; there was 1 fatality.<SUP>18</SUP> Similarly, 2 persons developed<SUP> </SUP>influenza conjunctivitis during a 2004 H7N3 HPAI outbreak in<SUP> </SUP>Canada.<SUP>19</SUP><SUP> </SUP>
                  Several case clusters of H5N1 infections have been reported.<SUP>6</SUP><SUP> </SUP>While epidemiologic information has been sparse, limited person-to-person<SUP> </SUP>transmission of H5N1 has been suggested in a few instances,<SUP> </SUP>usually involving family members. It is unknown whether this<SUP> </SUP>represents infection associated with particularly intimate or<SUP> </SUP>prolonged contact or shared but unidentified host factors affecting<SUP> </SUP>either infection risk or virus transmissibility. Separating<SUP> </SUP>host susceptibility factors from shared exposures or prolonged<SUP> </SUP>contact is difficult but crucially important in assessing viral<SUP> </SUP>evolution toward human adaptation. Also important will be comprehensive<SUP> </SUP>serologic surveys to assess population experience with H5 and<SUP> </SUP>other influenza subtypes in places where exposure to domestic<SUP> </SUP>poultry or wild birds is common.<SUP> </SUP>

                  What Has Been Learned From Past Pandemics <TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD width="100%" bgColor=#6a90aa></TD></TR></TBODY></TABLE>
                  Data suggest that the 1918 virus was avian-like prior to human<SUP> </SUP>adaptation,<SUP>11, 20</SUP> after which it eventually reassorted with<SUP> </SUP>a different avian virus to acquire 3 new genes and caused the<SUP> </SUP>1957 H2N2 pandemic. A second reassortment, adding 2 additional<SUP> </SUP>avian genes, caused the 1968 H3N2 pandemic.<SUP>21-22</SUP><SUP> </SUP>
                  Serologic and epidemiologic data suggest that the 1889 pandemic<SUP> </SUP>virus was of an H3 subtype (conceivably with an N8 gene), and<SUP> </SUP>that the 1847 pandemic virus could have been of either the H1<SUP> </SUP>subtype, neuramindase (NA [N1]) subtype, or both.<SUP>7</SUP> It may thus<SUP> </SUP>be likely that viruses causing 5 pandemics during a 175-year<SUP> </SUP>span have been limited to only a few of the known avian HA and<SUP> </SUP>NA subtypes (H1, H2, H3; N1, N2, and possibly N8). Since 16<SUP> </SUP>HA subtypes and 9 NA subtypes have been found in avian influenza<SUP> </SUP>viruses, to which humans have been exposed to varying degrees,<SUP> </SUP>a question arises as to whether unappreciated biological barriers<SUP> </SUP>may restrict other subtypes from incorporation into transmissible<SUP> </SUP>human viruses. Moreover, since only H5 and H7 viruses have been<SUP> </SUP>shown to acquire the HA cleavage site mutation that makes them<SUP> </SUP>highly pathogenic to poultry, the last 3 pandemic viruses, containing<SUP> </SUP>avian-like HA genes of H1, H2, and H3 subtypes were not HPAI<SUP> </SUP>viruses like H5N1. Furthermore, there is no evidence that a<SUP> </SUP>human pandemic or even an epidemic has been caused by any previous<SUP> </SUP>HPAI virus reported in poultry for more than 125 years. None<SUP> </SUP>of the last 4 pandemics is known to have been temporally associated<SUP> </SUP>with a poultry or wild bird epizootic, leaving no historical<SUP> </SUP>data to support the possibility that poultry are capable of<SUP> </SUP>serving as intermediate hosts in pandemic development.<SUP> </SUP>

                  The Next Pandemic <TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD width="100%" bgColor=#6a90aa></TD></TR></TBODY></TABLE>
                  It is currently impossible to predict the emergence of a future<SUP> </SUP>pandemic other than to strongly suspect that one will eventually<SUP> </SUP>occur, or to predict when or where a future pandemic will occur,<SUP> </SUP>what subtype it will be, and what degree of morbidity and mortality<SUP> </SUP>it will produce. Even though concern over the emergence of an<SUP> </SUP>H5N1 pandemic is clearly warranted, if for no other reason than<SUP> </SUP>its current high case-fatality rate, experts must also anticipate<SUP> </SUP>and plan for many other possibilities for pandemic emergence.<SUP> </SUP>
                  Since 1977, H1N1 and H3N2 viruses have both circulated globally<SUP> </SUP>to produce seasonal epidemics, causing approximately 36 000<SUP> </SUP>US deaths annually.<SUP>23</SUP> Evolution has occurred not only by gradual<SUP> </SUP>antigenic drift but also by intra-clade reassortment to import<SUP> </SUP>new HAs to which there is lesser population immunity, simultaneously<SUP> </SUP>creating novel constellations of gene segments.<SUP>7</SUP> It is unclear<SUP> </SUP>whether such continuing co-circulation, coupled with the increasing<SUP> </SUP>use of influenza vaccines, will increase or decrease pandemic<SUP> </SUP>risk or influence the subtype of the next pandemic virus.<SUP> </SUP>
                  If only H1, H2, or H3 viruses have pandemic potential, the question<SUP> </SUP>arises whether such co-circulation limits the next pandemic<SUP> </SUP>to only H2 viruses in the near future. The majority of the world's<SUP> </SUP>population (younger than 40 years) has no protective immunity<SUP> </SUP>to H2 subtype influenza viruses that circulated between 1957<SUP> </SUP>and 1968. Isolates of H2N2 viruses from this era are still maintained<SUP> </SUP>in virology laboratory freezers throughout the world, while<SUP> </SUP>circulating human H3N2 viruses presumably remain susceptible<SUP> </SUP>to avian H2 importation by reassortment; this suggests obvious<SUP> </SUP>potential sources of future pandemics. H9N2 viruses, some with<SUP> </SUP>the ability to bind to human receptors and capable of causing<SUP> </SUP>human disease, are another potential source.<SUP> </SUP>
                  The past decade has demonstrated the difficulty of containing<SUP> </SUP>HPAI outbreaks given high-intensity poultry production and international<SUP> </SUP>shipping of poultry. H5N1 viruses are likely to remain indefinitely<SUP> </SUP>enzootic in domestic birds in many countries, posing agricultural<SUP> </SUP>and economic challenges while providing opportunities for H5N1<SUP> </SUP>viruses to acquire?if such acquisition is possible?either<SUP> </SUP>efficient human-to-human transmissibility or better adaptation<SUP> </SUP>to poultry and wild birds, the chief spill-over hosts. The use<SUP> </SUP>of antiviral drugs in agricultural settings has made many H5N1<SUP> </SUP>viruses resistant to adamantanes, while there has also been<SUP> </SUP>evidence for H5N1 resistance to neuraminidase inhibitors.<SUP>24</SUP><SUP> </SUP>The evolution of H5N1 into antigenically distinct clades, probably<SUP> </SUP>driven in part by the use of poultry vaccines, greatly complicates<SUP> </SUP>the situation and makes it more difficult to predict where H5N1<SUP> </SUP>evolution is going, what to expect next, and how to plan for<SUP> </SUP>it.<SUP>25</SUP><SUP> </SUP>

                  Conclusions <TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD width="100%" bgColor=#6a90aa></TD></TR></TBODY></TABLE>
                  To improve the ability to predict influenza pandemics, it is<SUP> </SUP>necessary to increase knowledge of the basic biology and ecology<SUP> </SUP>underlying host-switching events. The genetic changes that are<SUP> </SUP>needed to convert an influenza virus from one that has adapted<SUP> </SUP>to the enteric tract of wild waterfowl into a respiratory virus<SUP> </SUP>of horses, pigs, or humans are not fully understood. Enhanced<SUP> </SUP>surveillance and prospective study at the human-animal interface<SUP> </SUP>are crucial for understanding viral movement and evolution in<SUP> </SUP>an extraordinarily complex ecosystem. The H5N1 panzootic is<SUP> </SUP>a potent reminder of the constant and constantly changing risk<SUP> </SUP>posed by influenza A viruses. It is unknown whether H5N1 viruses<SUP> </SUP>will be able to adapt to humans and cause efficient person-to-person<SUP> </SUP>transmission; however, preparation for future influenza pandemics<SUP> </SUP>caused by H5N1 and any number of other viral possibilities is<SUP> </SUP>important.<SUP> </SUP>
                  Thus, it is essential that while carefully monitoring current<SUP> </SUP>and identifiable risks, pandemic prevention strategies must<SUP> </SUP>also be based on expecting the unexpected and being capable<SUP> </SUP>of reacting accordingly. In addition to enhanced surveillance,<SUP> </SUP>it will be important to expand research on vaccine design, accelerated<SUP> </SUP>development of new classes of antiviral drugs, and improved<SUP> </SUP>diagnostics. These efforts will be of immediate benefit in the<SUP> </SUP>control of seasonal influenza and will simultaneously help to<SUP> </SUP>preemptively prepare for the next pandemic.<SUP> </SUP>
                  <!-- null -->
                  AUTHOR INFORMATION <TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD width="100%" bgColor=#6a90aa></TD></TR></TBODY></TABLE>
                  Corresponding Author: David M. Morens, MD, Bldg 31, Room 7A-10,<SUP> </SUP>31 Center Dr, MSC 2520, National Institutes of Health, Bethesda,<SUP> </SUP>MD 20892-2520 (dmorens@niaid.nih.gov<SCRIPT type=text/javascript><!-- var u = "dmorens", d = "niaid.nih.gov"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></SCRIPT> ).<SUP> </SUP>
                  Financial Disclosures: None reported.<SUP> </SUP>
                  <!--stopindex--><!--null-->Author Affiliations: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
                  REFERENCES <TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD width="100%" bgColor=#6a90aa></TD></TR></TBODY></TABLE>
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Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature. 2007;445:319-323.<!-- HIGHWIRE ID="297:18:2025:14" --> FULL TEXT | PUBMED <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD></TD></TR></TBODY></TABLE><!-- null -->15. Maines TR, Lu XH, Erb SM, et al. Avian influenza (H5N1) viruses isolated from humans in Asia in 2004 exhibit increased virulence in mammals. J Virol. 2005;79:11788-11800.<!-- HIGHWIRE ID="297:18:2025:15" --> <NOBR>FREE FULL TEXT</NOBR> <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD></TD></TR></TBODY></TABLE><!-- null -->16. Maines TR, Chen LM, Matsuoka Y, et al. Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model. Proc Natl Acad Sci U S A. 2006;103:12121-12126.<!-- HIGHWIRE ID="297:18:2025:16" --> <NOBR>FREE FULL TEXT</NOBR> <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD></TD></TR></TBODY></TABLE><!-- null -->17. Taubenberger JK. Influenza hemagglutinin attachment to target cells: "birds do it, we do it." Future Virol. doi:10.2217/17460794.1.4.415. 2006;1:415-418.<!-- HIGHWIRE ID="297:18:2025:17" --> FULL TEXT <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD></TD></TR></TBODY></TABLE><!-- null -->18. Fouchier RA, Schneeberger PM, Rozendaal FW, et al. Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci U S A. 2004;101:1356-1361.<!-- HIGHWIRE ID="297:18:2025:18" --> <NOBR>FREE FULL TEXT</NOBR> <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD></TD></TR></TBODY></TABLE><!-- null -->19. Tweed SA, Skowronski DM, David ST, et al. Human illness from avian influenza H7N3, British Columbia. Emerg Infect Dis. 2004;10:2196-2199.<!-- HIGHWIRE ID="297:18:2025:19" --> ISI | PUBMED <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD></TD></TR></TBODY></TABLE><!-- null -->20. Reid AH, Taubenberger JK, Fanning TG. Evidence of an absence: the genetic origins of the 1918 pandemic influenza virus. Nat Rev Microbiol. 2004;2:909-914.<!-- HIGHWIRE ID="297:18:2025:20" --> FULL TEXT | ISI | PUBMED <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD></TD></TR></TBODY></TABLE><!-- null -->21. Scholtissek C, Rohde W, von Hoyningen V, Rott R. On the origin of the human influenza virus subtypes H2N2 and H3N2. Virology. 1978;87:13-20.<!-- HIGHWIRE ID="297:18:2025:21" --> FULL TEXT | ISI | PUBMED <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD></TD></TR></TBODY></TABLE><!-- null -->22. Kawaoka Y, Krauss S, Webster RG. Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics. J Virol. 1989;63:4603-4608.<!-- HIGHWIRE ID="297:18:2025:22" --> <NOBR>FREE FULL TEXT</NOBR> <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD></TD></TR></TBODY></TABLE><!-- null -->23. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179-186.<!-- HIGHWIRE ID="297:18:2025:23" --> <NOBR>FREE FULL TEXT</NOBR> <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD></TD></TR></TBODY></TABLE><!-- null -->24. Le QM, Kiso M, Someya K, et al. Avian flu: isolation of drug-resistant H5N1 virus. Nature. 2005;437:1108.<!-- HIGHWIRE ID="297:18:2025:24" --> FULL TEXT | PUBMED <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD></TD></TR></TBODY></TABLE><!-- null -->25. Webster RG, Govorkova EA. H5N1 influenza?continuing evolution and spread. N Engl J Med. 2006;355:2174-2177.<!-- HIGHWIRE ID="297:18:2025:25" --> FREE FULL TEXT <!-- /HIGHWIRE -->

                  Comment


                  • #10
                    Re: Why predicting the next influenza pandemic is difficult

                    thanks.
                    I printed it and will examine it.


                    > ...an approximation of the risk that H5N1 viruses will adapt
                    > to efficient human-to-human transmission would be
                    > extremely helpful for pandemic preparedness planning...
                    I'm interested in expert panflu damage estimates
                    my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

                    Comment


                    • #11
                      Re: Why predicting the next influenza pandemic is difficult

                      The Next Influenza Pandemic
                      ---------------------------
                      a better title would have been: "what we don't know"

                      excert:
                      -------

                      difficult to predict
                      neither is there agreement
                      remain unanswered
                      do not necessarily indicate
                      incompletely understood
                      is unclear
                      it is not yet clear
                      limited data
                      it remains unclear
                      remains to be fully characterized
                      remains unclear
                      are not well understood
                      unknown
                      no evidence
                      nor is there evidence
                      it is unknown
                      a question arises
                      there is no evidence
                      no historical data
                      currently impossible to predict
                      it is unclear
                      increase or decrease
                      question arises
                      are not fully understood
                      it is unknown
                      expecting the unexpected


                      a classical Taubenberger.
                      I'm interested in expert panflu damage estimates
                      my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

                      Comment


                      • #12
                        Re: Why predicting the next influenza pandemic is difficult

                        OK, here some passages,comments about the not unknown parts:

                        >most experts believe another influenza pandemic will occur

                        >current H5N1 HPAI viruses are descendants
                        >of the 1997 epizootic virus

                        I assume they mean in HA, considering HA alone.
                        But do they all have the same ancestor ? There was also
                        H5N1 in Hubei 1997 and probably elsewhere.

                        >the current H5N1 situation will likely persist.

                        >To cause a pandemic,
                        >an avian virus would have to at least adapt to human HA receptors
                        >and acquire human transmissibility.

                        many here are afraid it can happen without that - or at least
                        not both conditions are necessary. None of these had happened
                        already - yet we were concerned about Turkey,Karo,China,Egypt,
                        Indonesia. In theory it could adapt to bird receptors and bird
                        transmissibility or swine or other mammal and then jump to
                        humans as it is and cause a pandemic without further human adaption.
                        Why not ? Wasn't 1918 almost entirely avian ?

                        >History suggests that this
                        >may be a difficult challenge for influenza viruses. Despite human
                        >and mammalian exposures to countless avian viruses over many decades,
                        > the last 2 pandemics have resulted from reassortment of preexisting
                        >human-adapted viruses containing imported genes derived from avian
                        >influenza viruses, not from de novo adaptation of avian viruses
                        >to humans.

                        that's 2 from 3. We can also just look at normal virus mutations.
                        Currently most H5N1-changes seem to happen by mutations
                        fewer by reassortment. Some years back it was different.
                        Both can happen. Almost equal chances,50%, I guesstimate

                        >When genes from a 1997 H5N1 virus were experimentally
                        >reassorted in various combinations with those from a human H3N2
                        >virus, none were efficiently transmitted between ferrets, raising
                        >questions about whether H5N1 viruses may be inherently limited
                        >in their potential to adapt to, and be transmitted between, humans.

                        this has nothing to do with adaption to human HA-receptors.
                        HA isn't changed by reassortment.

                        >Experiments suggest that only 2 mutations in the
                        >receptor-binding site convert the H1, H2, and H3 HAs of the past
                        >3 influenza pandemic viruses from an avian to a human receptor-
                        >binding pattern.

                        so that looks easy to achieve. Remains (at least) the human transmissiability.

                        >Data suggest
                        >that the 1918 virus was avian-like prior to human adaptation,
                        >Serologic and epidemiologic data
                        >suggest that the 1889 pandemic virus was of an H3 subtype (conceivably
                        >with an N8 gene), and that the 1847 pandemic virus could have
                        >been of either the H1 subtype, neuramindase (NA [N1]) subtype,
                        > or both.


                        >It is currently impossible to predict the emergence of a future
                        >pandemic other than to strongly suspect that one will eventually
                        >occur, or to predict when or where a future pandemic will occur,
                        > what subtype it will be, and what degree of morbidity and mortality
                        >it will produce.

                        this is strange, since we can actually observe the opposite.
                        Actuaries, insurance companies, mortality bond traders,
                        worldbank, global economical forum, risk-analysts, etc.
                        are actually _doing_ the impossible.

                        Unfortunately without much help from the medical,microbiological,
                        virological experts who claim that it's impossible.

                        >Even though concern over the emergence of an
                        >H5N1 pandemic is clearly warranted,

                        this concern arose despite all the uncertainety

                        >if for no other reason than
                        >its current high case-fatality rate,

                        no. Other viruses have higher CFR but no history of related
                        viruses going pandemic, so there is no concern.

                        >experts must also anticipate
                        >and plan for many other possibilities for pandemic emergence.
                        >
                        >Since 1977, H1N1 and H3N2 viruses have both circulated globally
                        >to produce seasonal epidemics, causing approximately 36000 US
                        >deaths annually.

                        many (most?) of these 36000 deaths are old people, sick with other diseases
                        and probably dying anyway soon.
                        Influenza isn't even diagnosed as disease in those but just concluded
                        from seasonal mortality data.
                        H5N1 hits the younger people, their lives should be worth more.

                        >human H3N2 viruses presumably remain susceptible to avian H2 importation
                        >by reassortment;
                        >this suggests obvious potential sources of future
                        >pandemics. H9N2 viruses, some with the ability to bind to human
                        >receptors and capable of causing human disease, are another potential
                        >source.

                        but spread of H9N2 in the last years was much less spectacular
                        than that of H5N1

                        > H5N1 viruses are likely to remain indefinitely
                        >enzootic in domestic birds in many countries,

                        why didn't it happen earlier ? It should have persisted then, but hasn't.

                        >The use
                        >of antiviral drugs in agricultural settings has made many H5N1
                        >viruses resistant to adamantanes,
                        >while there has also been evidence
                        >for H5N1 resistance to neuraminidase inhibitors.

                        ...in agricultural settings ?

                        >The evolution
                        >of H5N1 into antigenically distinct clades, probably driven in
                        >part by the use of poultry vaccines, greatly complicates the situation
                        >and makes it more difficult to predict where H5N1 evolution is
                        >going, what to expect next, and how to plan for it.25

                        that should make it easier to predict, since we know the strain
                        of the vaccine


                        >Conclusions
                        >
                        >To improve the ability to predict influenza pandemics,
                        >it is necessary to increase knowledge of the basic biology and ecology
                        >underlying host-switching events.

                        this one is clearly and obviously just wrong.
                        That ability can also be increased by just observing historical data
                        and in fact that's the typical source for insurance predictions.

                        >preparation for future influenza pandemics
                        >caused by H5N1 and any number of other viral possibilities is
                        >important.

                        so, H5N1 is no more dangerous than any other "viral possibility" ?

                        >Thus, it is essential that while carefully monitoring
                        >current and identifiable risks, pandemic prevention strategies
                        >must also be based on expecting the unexpected and being capable
                        >of reacting accordingly.

                        ?? expecting the unexpected ? check the logic !
                        Do the "impossible" , make a prediction ;-)

                        >In addition to enhanced surveillance,
                        > it will be important to expand research on vaccine design, accelerated
                        >development of new classes of antiviral drugs, and improved diagnostics.
                        > These efforts will be of immediate benefit in the control of
                        >seasonal influenza and will simultaneously help to preemptively
                        >prepare for the next pandemic.

                        with the importance in this order ??
                        I'm interested in expert panflu damage estimates
                        my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

                        Comment


                        • #13
                          Re: Why predicting the next influenza pandemic is difficult

                          "Serologic and epidemiologic data
                          >suggest that the 1889 pandemic virus was of an H3 subtype (conceivably
                          >with an N8 gene), and that the 1847 pandemic virus could have
                          >been of either the H1 subtype, neuramindase (NA [N1]) subtype,
                          > or both."

                          does someone know, how they do to know it ?

                          thanks gsgs
                          Last edited by Anne; May 11, 2007, 01:36 AM.

                          Comment


                          • #14
                            Re: Why predicting the next influenza pandemic is difficult

                            Originally posted by Anne View Post
                            "Serologic and epidemiologic data
                            >suggest that the 1889 pandemic virus was of an H3 subtype (conceivably
                            >with an N8 gene), and that the 1847 pandemic virus could have
                            >been of either the H1 subtype, neuramindase (NA [N1]) subtype,
                            > or both."

                            does someone know, how they do to know it ?

                            thinks gsgs
                            serology

                            Comment


                            • #15
                              Re: Why predicting the next influenza pandemic is difficult

                              Originally posted by niman View Post
                              serology
                              of what substance or creatures?

                              .
                              "The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation

                              Comment

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