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Science Mag Special Issue - Influenza: The State of Our Ignorance

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  • Science Mag Special Issue - Influenza: The State of Our Ignorance

    Science 21 April 2006:
    Vol. 312. no. 5772, p. 379
    DOI: 10.1126/science.312.5772.379

    Introduction to special issue

    Influenza: The State of Our Ignorance
    Caroline Ash and Leslie Roberts

    The startling spread of H5N1 across much of the globe highlights our vulnerability to the emergence of novel subtypes of influenza virus. Yet despite our fears of pandemic human disease, H5N1 is primarily a disease of birds. Olsen and colleagues (p. 384) outline the unseen network of influenza among migratory birds that spans Earth. H5N1 has engendered alarm not only because it is unusually virulent, laying waste to poultry and causing severe economic losses for farmers, but also because it can, with some difficulty, infect humans and other mammals. So far, the virus has killed more than half of the nearly 200 people known to have been infected. Kuiken and colleagues (p. 394) explore the routes through the obstacles to interspecies transmission (the host species barrier) of viruses. Their analysis focuses on which adaptations are needed to facilitate bird-to-human transfer of H5N1. Examples are provided by Shinya* and in a Brevia by van Riel et al. (p. 399). These authors show that the virus preferentially binds to cell types bearing specific surface receptors found deep in the lungs, which may partly explain its poor human-to-human transmissibility.

    The combination of ever-unfolding modes of variability (Stevens, p. 404) and symptomless transmission makes identification of the virus slow and hinders the implementation of influenza containment. As Lu outlines in his Editorial (p. 337), we urgently need faster and more robust diagnostic tests for field use (an area we will be covering shortly in our pages). Further articles in this special section describe other tools and approaches for preparedness. Smith (p. 392) summarizes the models that have been developed for tracing the rate and spread of pandemic influenza through human populations, including scenarios for the deployment of drugs and development of vaccines. We might be able to buy some time for vaccine manufacture by stockpiling antiviral drugs for immediate use, but that time may be short. Regoes and Bonhoeffer (p. 389) indicate that the generation and transmission of resistant strains could happen quickly. Unfortunately, our knowledge of influenza transmission is incomplete, and more basic data are needed to make models accurate and to give them predictive weight. Seasonal influenza statistics will provide an important insight into the transmission biology of influenza; Viboud et al. (p. 447) have used a large data set from the United States to model annual waves of infection.

    In a News story (p. 380), Kaiser explores efforts to develop broader influenza vaccines that protect against new strains and perhaps even all influenza subtypes. Antiviral drugs are also sorely needed to fight a pandemic, but oseltamivir, or Tamiflu, has been in short supply. As Enserink describes (p. 382), Roche and other companies are now ramping up production, while scientists are investigating faster and cheaper synthetic pathways that could make the drug affordable to developing countries. In an accompanying podcast, Wills interviews some of the contributing authors and journalists.

    An energetic response to H5N1 does not have to be alarmist. We can marshal existing concern about this particular strain of avian influenza to build a long-lasting international infrastructure to monitor and thwart threats from such emerging infections.

    *K. Shinya, Nature 440, 435 (2006).

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

  • #2
    A One-Size-Fits-All Flu Vaccine?

    Science 21 April 2006:
    Vol. 312. no. 5772, pp. 380 - 382
    DOI: 10.1126/science.312.5772.380

    News

    A One-Size-Fits-All Flu Vaccine?
    Jocelyn Kaiser

    The threat of avian influenza has revived efforts to develop "universal" flu vaccines that protect against all human influenza strains. Although that goal remains elusive, vaccines that protect against seasonal flu variants could be closer

    Modern medicine's main weapon against the influenza virus is woefully unsophisticated. Each year, companies have to make a new batch of flu vaccine because unlike, say, polio or chickenpox, flu strains change every year. The vaccine is grown in eggs, a process that takes up to 9 months, and people have to be vaccinated annually, which many don't bother to do. More troubling, if a pandemic strain of influenza came along, the virus could kill millions of people in the time it would take to prepare a matching vaccine.
    What scientists dream of is a vaccine that can protect against any flu strain for years or even a lifetime. This so-called universal flu vaccine is still a long way off, if it's even possible. But many labs are dusting off past projects on broad flu vaccines, spurred by new funding and fears that H5N1, the deadly avian influenza that has swept across half the world, could acquire the ability to be transmitted from human to human. Until now, "flu has never been before high enough on the radar screen" for companies in particular to follow through with a strong push for a universal vaccine, says Gary Nabel, director of the Vaccine Research Center at the U.S. National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland.

    Doing so, however, means coming up with an alternative way to stimulate immunity to the virus. The tried-and-true technique for seasonal flu uses a killed virus vaccine that works mainly by triggering antibodies to hemagglutinin (HA), the glycoprotein on the virus's surface that it uses to bind to human cells. Hemagglutinin and neuraminidase (NA), another surface glycoprotein that helps newly made viruses exit cells, give strains their names (H5N1, for example). The sequences of HA and NA mutate easily, which is why each season's flu strain--although it may be the same in subtype, such as H3N2--"drifts" slightly from the previous year's, and the annual vaccine must be tailor-made.

    To make a universal vaccine for influenza A, which includes the main seasonal flu strains and bird flu, as well as past pandemic strains, some scientists are hoping to use "conserved" flu proteins that don't mutate much year to year. (Influenza B, the other type, occurs only in humans and causes milder symptoms.) Some of the conserved protein vaccines in the works stimulate production of antibodies as do conventional flu vaccines, whereas others rouse certain immune system cells to battle the virus....

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

    Comment


    • #3
      Emergence of Drug-Resistant Influenza Virus: Population Dynamical Considerations

      Science 21 April 2006:
      Vol. 312. no. 5772, pp. 389 - 391
      DOI: 10.1126/science.1122947

      Perspective

      Emergence of Drug-Resistant Influenza Virus: Population Dynamical Considerations
      Roland R. Regoes and Sebastian Bonhoeffer*

      Given the considerable challenges to the rapid development of an effective vaccine against influenza, antiviral agents will play an important role as a first-line defense if a new pandemic occurs. The large-scale use of drugs for chemoprophylaxis and treatment will impose strong selection for the evolution of drug-resistant strains. The ensuing transmission of those strains could substantially limit the effectiveness of the drugs as a first-line defense. Summarizing recent data on the rate at which the treatment of influenza infection generates resistance de novo and on the transmission fitness of resistant virus, we discuss possible implications for the epidemiological spread of drug resistance in the context of an established population dynamic model.

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

      Comment


      • #4
        Predictability and Preparedness in Influenza Control

        Science 21 April 2006:
        Vol. 312. no. 5772, pp. 392 - 394
        DOI: 10.1126/science.1122665

        Perspective

        Predictability and Preparedness in Influenza Control
        Derek J. Smith

        The threat of pandemic human influenza looms as we survey the ongoing avian influenza pandemic and wonder if and when it will jump species. What are the risks and how can we plan? The nub of the problem lies in the inherent variability of the virus, which makes prediction difficult. However, it is not impossible; mathematical models can help determine and quantify critical parameters and thresholds in the relationships of those parameters, even if the relationships are nonlinear and obscure to simple reasoning. Mathematical models can derive estimates for the levels of drug stockpiles needed to buy time, how and when to modify vaccines, whom to target with vaccines and drugs, and when to enforce quarantine measures. Regardless, the models used for pandemic planning must be tested, and for this we must continue to gather data, not just for exceptional scenarios but also for seasonal influenza.

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

        Comment


        • #5
          Host Species Barriers to Influenza Virus Infections

          Science 21 April 2006:
          Vol. 312. no. 5772, pp. 394 - 397
          DOI: 10.1126/science.1122818

          Perspective

          Host Species Barriers to Influenza Virus Infections
          Thijs Kuiken,1* Edward C. Holmes,2 John McCauley,3 Guus F. Rimmelzwaan,1 Catherine S. Williams,2 Bryan T. Grenfell2,4

          Most emerging infectious diseases in humans originate from animal reservoirs; to contain and eradicate these diseases we need to understand how and why some pathogens become capable of crossing host species barriers. Influenza virus illustrates the interaction of factors that limit the transmission and subsequent establishment of an infection in a novel host species. Influenza species barriers can be categorized into virus-host interactions occurring within individuals and host-host interactions, either within or between species, that affect transmission between individuals. Viral evolution can help surmount species barriers, principally by affecting virus-host interactions; however, evolving the capability for sustained transmission in a new host species represents a major adaptive challenge because the number of mutations required is often large.

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

          Comment


          • #6
            Global Patterns of Influenza A Virus in Wild Birds

            Science 21 April 2006:
            Vol. 312. no. 5772, pp. 384 - 388
            DOI: 10.1126/science.1122438

            Review

            Global Patterns of Influenza A Virus in Wild Birds
            Bj?rn Olsen,1,2 Vincent J. Munster,3 Anders Wallensten,4,5 Jonas Waldenstr?m,6 Albert D. M. E. Osterhaus,3 Ron A. M. Fouchier3*

            The outbreak of highly pathogenic avian influenza of the H5N1 subtype in Asia, which has subsequently spread to Russia, the Middle East, Europe, and Africa, has put increased focus on the role of wild birds in the persistence of influenza viruses. The ecology, epidemiology, genetics, and evolution of pathogens cannot be fully understood without taking into account the ecology of their hosts. Here, we review our current knowledge on global patterns of influenza virus infections in wild birds, discuss these patterns in the context of host ecology and in particular birds' behavior, and identify some important gaps in our current knowledge.

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

            Comment


            • #7
              Early Diagnosis of Avian Influenza

              Science 21 April 2006:
              Vol. 312. no. 5772, p. 337
              DOI: 10.1126/science.1128199

              Editorial

              Early Diagnosis of Avian Influenza
              Peter S. Lu*

              The current wave of pandemic avian influenza looks likely to spread via-migrating ducks into North America by early fall of this year. Although this form of influenza A virus primarily targets wild birds and poultry, it can infect some mammals. In the few human cases that have been reported (usually only after intimate contact with domestic birds), the infection followed an unusually aggressive course and more than half of the victims have died (on 24 March 2006, the World Health Organization reported 186 human cases and 105 fatalities). The danger is that if the virus adapts sufficiently to allow serial human-to-human transmission, a global human pandemic may rapidly develop.

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

              Comment


              • #8
                Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus

                Originally published in Science Express on 16 March 2006
                Science 21 April 2006:
                Vol. 312. no. 5772, pp. 404 - 410
                DOI: 10.1126/science.1124513

                Research Articles

                Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus
                James Stevens,1* Ola Blixt,1,2 Terrence M. Tumpey,4 Jeffery K. Taubenberger,5 James C. Paulson,1,2 Ian A. Wilson1,3*

                The hemagglutinin (HA) structure at 2.9 angstrom resolution, from a highly pathogenic Vietnamese H5N1 influenza virus, is more related to the 1918 and other human H1 HAs than to a 1997 duck H5 HA. Glycan microarray analysis of this Viet04 HA reveals an avian 2-3 sialic acid receptor binding preference. Introduction of mutations that can convert H1 serotype HAs to human 2-6 receptor specificity only enhanced or reduced affinity for avian-type receptors. However, mutations that can convert avian H2 and H3 HAs to human receptor specificity, when inserted onto the Viet04 H5 HA framework, permitted binding to a natural human 2-6 glycan, which suggests a path for this H5N1 virus to gain a foothold in the human population.

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

                Comment


                • #9
                  Synchrony, Waves, and Spatial Hierarchies in the Spread of Influenza

                  Originally published in Science Express on 30 March 2006
                  Science 21 April 2006:
                  Vol. 312. no. 5772, pp. 447 - 451
                  DOI: 10.1126/science.1125237

                  Reports

                  Synchrony, Waves, and Spatial Hierarchies in the Spread of Influenza
                  C?cile Viboud,1* Ottar N. Bj?rnstad,1,2,3 David L. Smith,1 Lone Simonsen,4 Mark A. Miller,1 Bryan T. Grenfell1,3

                  Quantifying long-range dissemination of infectious diseases is a key issue in their dynamics and control. Here, we use influenza-related mortality data to analyze the between-state progression of interpandemic influenza in the United States over the past 30 years. Outbreaks show hierarchical spatial spread evidenced by higher pairwise synchrony between more populous states. Seasons with higher influenza mortality are associated with higher disease transmission and more rapid spread than are mild ones. The regional spread of infection correlates more closely with rates of movement of people to and from their workplaces (workflows) than with geographical distance. Workflows are described in turn by a gravity model, with a rapid decay of commuting up to around 100 km and a long tail of rare longer range flow. A simple epidemiological model, based on the gravity formulation, captures the observed increase of influenza spatial synchrony with transmissibility; high transmission allows influenza to spread rapidly beyond local spatial constraints.

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

                  Comment


                  • #10
                    H5N1 Virus Attachment to Lower Respiratory Tract

                    Originally published in Science Express on 23 March 2006
                    Science 21 April 2006:
                    Vol. 312. no. 5772, p. 399
                    DOI: 10.1126/science.1125548

                    Brevia

                    H5N1 Virus Attachment to Lower Respiratory Tract
                    Debby van Riel, Vincent J. Munster, Emmie de Wit, Guus F. Rimmelzwaan, Ron A. M. Fouchier, Ab D. M. E. Osterhaus, Thijs Kuiken*

                    Highly pathogenic avian influenza virus (H5N1) may cause severe lower respiratory tract (LRT) disease in humans. However, the LRT cells to which the virus attaches are unknown for both humans and other mammals. We show here that H5N1 virus attached predominantly to type II pneumocytes, alveolar macrophages, and nonciliated bronchiolar cells in the human LRT, and this pattern was most closely mirrored in cat and ferret tissues. These findings may explain, at least in part, the localization and severity of H5N1 viral pneumonia in humans. They also identify the cat and the ferret as suitable experimental animals based on this criterion.

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

                    Comment


                    • #11
                      Re: Science Mag Special Issue - Influenza: The State of Our Ignorance

                      So - theresa - now that you have all those articles digested, what do you think about them?

                      You can post faster than I can read and understand. that's after I find the time.

                      .
                      "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


                      • #12
                        Re: Science Mag Special Issue - Influenza: The State of Our Ignorance

                        Originally posted by AlaskaDenise
                        So - theresa - now that you have all those articles digested, what do you think about them?
                        Ha! :p If only I could read -- and more importantly comprehend what I read -- that quickly!

                        The only one I did peruse was "Global Patterns of Influenza A Virus in Wild Birds" -- and even that one I'd like to re-read a couple of times.

                        Delving into this issue of Science is definitely this weekend's project. That and digging in the garden....
                        ...when you have eliminated the impossible, whatever remains, however improbable, must be the truth. - Sherlock Holmes

                        Comment


                        • #13
                          Re: Science Mag Special Issue - Influenza: The State of Our Ignorance

                          Originally posted by Theresa42
                          Ha! :p If only I could read -- and more importantly comprehend what I read -- that quickly!

                          The only one I did peruse was "Global Patterns of Influenza A Virus in Wild Birds" -- and even that one I'd like to re-read a couple of times.

                          Delving into this issue of Science is definitely this weekend's project. That and digging in the garden....
                          I asked questions over at CE which I ask you to answer here, if you don't mind, as well as there. The questions are I know unanswerable, but they invite your own opinion, albeit a lay opinion. Thx, GR

                          Comment


                          • #14
                            Re: Science Mag Special Issue - Influenza: The State of Our Ignorance

                            Originally posted by GaudiaRay
                            I asked questions over at CE which I ask you to answer here, if you don't mind, as well as there. The questions are I know unanswerable, but they invite your own opinion, albeit a lay opinion. Thx, GR
                            Well, the short answer to your questions is -- I have no idea.

                            I'm guessing that what you're driving at is do I support recombination or not. As far as I'm concerned, I think the jury's still out on the mechanism(s) behind the changes that occur in viruses. While I certainly think Dr. Niman's theory seems completely plausible and possible, I actually personally don't have enough basic knowledge in biology/chemistry/genetics/etc. to form a sound opinion at this time. So, I remain an (open-minded) agnostic as far as viral evolution goes -- for now.

                            Also, please don't think that just 'cause I post an article that that means I necessarily believe in its veracity. I'm just lookin' to be informed.
                            ...when you have eliminated the impossible, whatever remains, however improbable, must be the truth. - Sherlock Holmes

                            Comment


                            • #15
                              Avian influenza: Solving another piece of the H5N1 puzzle

                              Review of the article summarized in this post (above):


                              Nature Reviews Microbiology 4, 321 (May 2006) | doi:10.1038/nrmicro1412

                              Avian influenza: Solving another piece of the H5N1 puzzle
                              Shannon Amoils

                              As the H5N1 avian influenza virus continues to sweep across the globe, its potential to emerge as a human-adapted virus remains high. One crucial determinant of the species specificity of influenza viruses is the haemagglutinin (HA) protein: viruses carrying only 3 of the 16 known avian and mammalian HA subtypes (H1, H2 and H3) have adapted to humans, but in each case, these viruses have caused major pandemics.

                              Stevens et al. now report the high-resolution crystal structure of the HA of a highly pathogenic H5N1 influenza virus (Viet04 HA). The study published in Science compares the Viet04 HA structure with an avian H5 HA structure (Sing97), and with HA structures from pandemic influenza A viruses ? the deadly 1918 human H1 virus and the 1968 human H3 virus. In addition, the authors use new microarray technology to identify mutations that could allow H5N1 to take hold in the human population.

                              The general structure of Viet04 HA is similar to other HA structures, consisting of a globular head that contains the receptor-binding domain, a vestigial esterase domain and a membrane-proximal domain. Surprisingly, although the Viet04 HA sequence shows most similarity to that of the avian Sing97 HA, structural comparisons show that Viet04 HA is most closely related to the 1918 H1 HA. The crystal structure of 1918 HA0 revealed two pH-sensitive histidine patches, one in the membrane-proximal domain and one in the vestigial esterase domain, that are thought to promote release of the fusion peptide in the endosome, contributing to pathogenicity. The histidine patch in the membrane-proximal domain is conserved in Viet 04 HA, and additional structural features in the vestigial esterase might contribute further to virulence.

                              Using glycan microarray technology, the authors showed that Viet04 HA binds preferentially to 2-3 sialic-acid glycan receptors, which typifies the binding specificity of avian influenza viruses. Although mutations in the receptor-binding domain that switch H3 HAs from avian to human specificity did not have a similar effect on Viet04 HA, the binding profile of a double mutant, Gln226Leu, Gly228Ser Viet04 HA, was markedly altered. This double mutant showed reduced affinity for 2-3 receptors, with significant binding to a natural branched 2-6 biantennary glycan. The respiratory mucins in the human upper airway contain 2-3 glycans, which are thought to filter out avian virus that enters the respiratory tract. Reduced binding to these protective mucins coupled with enhanced binding to 2-6 biantennary glycans in the lower airways is one way in which H5N1 could establish a foothold in the human host.




                              ORIGINAL RESEARCH PAPER
                              Stevens, J. et al. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 16 Mar 2006 (doi:10.1126/science.1124513)

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

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