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PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

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  • PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

    Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

    Michael Worobeya,1,
    Guan-Zhu Hana, and
    Andrew Rambautb,c,d

    Author Affiliations

    Edited by Neil M. Ferguson, Imperial College London, London, United Kingdom, and accepted by the Editorial Board April 8, 2014 (received for review December 30, 2013)


    Significance

    The origin of the 1918 pandemic influenza A virus (IAV) and the reasons for its unusual severity are two of the foremost biomedical mysteries of the past century. We infer that the virus arose via reassortment between a preexisting human H1 IAV lineage and an avian virus. Phylogenetic, seroarcheological, and epidemiological evidence indicates those born earlier or later than ∼1880?1900 would have had some protection against the 1918 H1N1 virus, whereas many young adults born from ∼1880?1900 may have lacked such protection because of childhood exposure to an antigenically distinct H3N8 virus. Our findings suggest that better understanding of how initial exposure shapes lifetime immunity may enhance the prediction and control of future IAV pandemics and seasonal epidemics.
    Abstract

    The source, timing, and geographical origin of the 1918?1920 pandemic influenza A virus have remained tenaciously obscure for nearly a century, as have the reasons for its unusual severity among young adults. Here, we reconstruct the origins of the pandemic virus and the classic swine influenza and (postpandemic) seasonal H1N1 lineages using a host-specific molecular clock approach that is demonstrably more accurate than previous methods. Our results suggest that the 1918 pandemic virus originated shortly before 1918 when a human H1 virus, which we infer emerged before ∼1907, acquired avian N1 neuraminidase and internal protein genes. We find that the resulting pandemic virus jumped directly to swine but was likely displaced in humans by ∼1922 by a reassortant with an antigenically distinct H1 HA. Hence, although the swine lineage was a direct descendent of the pandemic virus, the post-1918 seasonal H1N1 lineage evidently was not, at least for HA. These findings help resolve several seemingly disparate observations from 20th century influenza epidemiology, seroarcheology, and immunology. The phylogenetic results, combined with these other lines of evidence, suggest that the high mortality in 1918 among adults aged ∼20 to ∼40 y may have been due primarily to their childhood exposure to a doubly heterosubtypic putative H3N8 virus, which we estimate circulated from ∼1889?1900. All other age groups (except immunologically naive infants) were likely partially protected by childhood exposure to N1 and/or H1-related antigens. Similar processes may underlie age-specific mortality differences between seasonal H1N1 vs. H3N2 and human H5N1 vs. H7N9 infections.


    Attached Files
    Last edited by Giuseppe; April 29, 2014, 02:34 AM. Reason: Full PDF document added

  • #2
    Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

    The interesting part of the discussion section of the above paper in relation to current epizootic derived H5N1 & H7N9 human infections, suggests that:

    -- those 'primed' during childhood with type 1 HA viruses (such as H1 & H2 subtypes) are likely more susceptible to complications when infected with novel H7N9 avian influenza viruses;

    -- those 'primed' during childhood with type 2 HA viruses (such as H3N2) are likely more susceptible to complications when infected with novel H5N1 avian influenza viruses.

    This suggests also targeted control measures and preventative use of some vaccines which may enhance heterotypic protection toward H5 or H7 AIVs.

    For individual born during prevalent circulation of type 1 HA viruses (before H1 was replaced by H3 subtypes, and after H1 re-emerged in 1977 and in 2009), the infection with H5N1 may be less pathogenic, as observed in age-related morbidity and mortality in affected regions.

    For individual born during prevalent circulation of type 2 HA viruses (after 1968), the infection with H7N9 may be less pathogenic as seen in age-related morbidity and mortality in China (65+ years old).

    Comment


    • #3
      Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

      why would childhood infection provide better priming
      than adulthood infection ?
      I didn't see that theory before.
      I'm interested in expert panflu damage estimates
      my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

      Comment


      • #4
        Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

        The original antigenic sin theory

        Comment


        • #5
          Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

          OK, I saw that theory before. But it doesn't make sense to me.
          If that effect were so significant it should be possible to demonstrate
          it in another controlled setting.


          and we give trivalent vax to the children

          it was worst in 1918 in remote populations

          excess deaths in 1918 decline almost linearly with age,
          with childhood OAS I'd expect another curve (leveling off)

          in a seasonal or pandemic wave people (and animals) are protected
          for some months from other flus
          I'm interested in expert panflu damage estimates
          my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

          Comment


          • #6
            Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

            > Even if most or all 20-to 40-y-olds in 1918 had already been exposed to the putative H1
            > virus circulating between ∼1900 and 1918, we speculate that their
            > initial exposure to an H3 virus

            ... at age 0-22

            > might nevertheless have interfered
            > with their immune responses to the 1918 HA

            but not to the 1900-1917 HA ?
            and then suddenly it gave so strong protection since 1920 ?


            and there was clear protection in wave 2 in 1918 in those infected
            (even asymptomatic) in wave 1
            I'm interested in expert panflu damage estimates
            my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

            Comment


            • #7
              Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

              Originally posted by gsgs View Post
              why would childhood infection provide better priming
              than adulthood infection ?
              I didn't see that theory before.
              May be also the A.D.E. (Antigen-dependent enhancement)? I've seen earlier suggestions about ADE and possible skewed age-related morbidity and mortality toward old adults in China.

              Through ADE, an individual primed with a mismatched strain in relation to current one, would develop a stronger Abs response toward the former (ie: primed w/ H1--> when H7 infected--> +++H1 Abs, instead of a mounting specific Abs response toward H7).

              -- primed H1---> +++Abs vs H5 ---> ---Abs vs H7
              -- primed H3---> +++Abs vs H7 ---> ---Abs vs H5

              Comment


              • #8
                Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

                In addition, it would be useful to draw a graphic function of H1 / H7 peak incidence in Chinese affected regions.

                Comment


                • #9
                  Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

                  antibody response was quite good in 1918, see how the deathrate
                  went down in 1919,1920,1921

                  they argue that a new HA came in ~1922, probably a less virulent one.
                  If they think H1 circulated since 1901 it could just have been the re-emerged
                  old H1 (how did it survive the pandemic - maybe in animals

                  Although 1929 was still quite bad after 11 years of circulation
                  I'm interested in expert panflu damage estimates
                  my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

                  Comment


                  • #10
                    Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

                    that A.D.E. was it ever observed in humans on a large scale ?

                    we have H3 and H1 since 1977, they should have noticed it

                    and mice,ferrets in labs ?



                    only 2 pubmed hits for "Antigen-dependent enhancement"
                    and only 20 google hits
                    none about influenza
                    I'm interested in expert panflu damage estimates
                    my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

                    Comment


                    • #11
                      Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

                      such hypothesizing papers should be discussed.
                      In the magazines, blogs, webpages,conferences,journals.

                      But that is not supported by the current scientific system.
                      It's unwanted by the authors, reviewers, those who fund it.

                      PNAS doesn't allow commenting, such as PLOS.
                      When you send email to the authors, they don't like it,
                      won't correct errors, discuss it - it's not good for them
                      if possible problems become public.
                      We saw many examples for that meanwhile, even here at FT.

                      I see this as a followup to the Smith et. al. paper
                      their reference 9.) discussed here:

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

                      Comment


                      • #12
                        Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

                        a more severe outcome in children or young adults "primed" as children with seasonal H3N2
                        has never been observed, afaik. Not in 1977 nor in 2009 nor in all those years of
                        cocirculating H1 and H3 since 1977.
                        Nor was it demonstrated in mice,ferrets in the labs afaik.

                        And if that negative priming effect "works" with natural infection, shouldn't it also
                        work with vaccine ? After all the know antigenic changes that are observed in
                        vaccinated and exposed people are the same.
                        Shouldn't that have given a discussion whether trivalent vaccine is suitable ?
                        The anti-vax people would have jumped on it.

                        I'm not happy that they always write "20-40" year old and "born in 1880-1900"
                        when there are clear and substantial differences in that group.
                        The peak excess mortality happened at age ~28 and then almost linearly
                        declined until age ~40 where the decline started to become less steep
                        but still continued until age at least 80. If that steepness reduction hadn't happened
                        at age ~40, all the reduction would have been exhausted at age ~45 and there had been
                        no more room for decline above that age.

                        We have the effect that H1 just isn't as deadly in the elderly as H3
                        observed after 1977 with seasonal H3,H1 and 2009 pandemic H1
                        just this season.
                        It became worse for the elderly in the later years, 1929 , Liverpool 1951, though.
                        Attached Files
                        I'm interested in expert panflu damage estimates
                        my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

                        Comment


                        • #13
                          Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

                          Shouldn't that have given a discussion whether trivalent vaccine is suitable ?
                          There is a quad out now with two B strains, but I don't think triggering original antigenic sin is driven by strain count in a vaccine. I thought it was more complex than that - along the lines of a certain divergence from the vaccine or previous infecting live virus by the circulating virus.

                          A CDC article tetano posted in 2012:

                          http://www.flutrackers.com/forum/sho...d.php?p=436322
                          Historical records and findings from laboratory animal studies suggest that persons who were exposed to influenza once before 1918 (e.g., A/H3Nx 1890 pandemic strain) were likely to have dysregulated, pathologic cellular immune responses to infections with the A/H1N1 1918 pandemic strain. The immunopathologic effects transiently increased susceptibility to ultimately lethal secondary bacterial pneumonia. The extreme mortality rate associated with the 1918?19 pandemic is unlikely to recur naturally. However, T-cell?mediated immunopathologic effects should be carefully monitored in developing and using universal influenza vaccines.
                          Here's a controlled study on vaccines:

                          Paradoxical response to a novel influenza virus vaccine strain: the effect of prior immunization
                          Conclusions: the decrease in serologic response to influenza vaccine among healthy, young adults who were previously vaccinated appears to be unique for this year's influenza vaccine. Further studies are required to determine the frequency and clinical significance of this phenomenon observed in younger healthy adults, and whether it is a general one. Based on its proven efficacy, influenza vaccine should continue to be given on an annual basis to high risk children and adults and to all those 65 years or older.
                          Then there are observations in pigs:
                          http://www.ars.usda.gov/research/pub..._no_115=204405
                          http://www.newscientist.com/article/...1#.U2HmTaLGDMo

                          If anyone figures out exactly how original antigenic sin works in influenza - then I'll worry about flu being used as a bioweapon.
                          _____________________________________________

                          Ask Congress to Investigate COVID Origins and Government Response to Pandemic.

                          i love myself. the quietest. simplest. most powerful. revolution ever. ---- nayyirah waheed

                          "...there’s an obvious contest that’s happening between different sectors of the colonial ruling class in this country. And they would, if they could, lump us into their beef, their struggle." ---- Omali Yeshitela, African People’s Socialist Party

                          (My posts are not intended as advice or professional assessments of any kind.)
                          Never forget Excalibur.

                          Comment


                          • #14
                            Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

                            ahh, the Shanks/Bundage theory.

                            When they say "suggests" that means that they suggest it.
                            it sounds absurd to me and I don't think that theory is widely supported.

                            I didn't see other known experts supporting it.

                            ----------------------------------------------------------------------------------
                            A: n=68, vaxed with A/Texas/36/91(H1N1),A/Nanchang/933/95(H3N2),B/Beijing/184/93
                            B: n=70, vaxed with TX,BJ only
                            A had lower postvaccination HAIs Tx:127 vs. 359, NC:31 vs. 93,BJ:140 vs. 205
                            ----------------------------------------------------------------------------------
                            I remember the 2009 Canada discussion (Skowronski) that the seasonal vax gave fewer
                            protection in 2009 than no vax
                            --------------------------------------------------------

                            Reichert et.al. OAS in p2009 ?
                            --------------------------------------------------------

                            Morens et.al. generally about OAS-phenomenon
                            ----------------------------------------

                            Skowronski et.al.
                            (B/Victoria-vax after Yamagata vax increased Yamagata antibodies
                            more than Victoria ones)
                            ----------------------------------------------------------
                            http://www.ars.usda.gov/research/publications/publications.htm?seq_no_115=204405[/URL]
                            IA1930-vax made MN2003 infection even worse (n=3) while infection with live
                            IA1930 was protective
                            ---------------------------------------------------------
                            I'm interested in expert panflu damage estimates
                            my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

                            Comment


                            • #15
                              Re: PNAS: Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

                              so the theory is : (?)
                              you are better protected in future against the strain of the
                              _first_ flu that you got in life.

                              less so for the 2nd,3rd,...


                              and that's why H3N2 is more deadly for the elderly than H1 - H3 is around only since 1968
                              I'm interested in expert panflu damage estimates
                              my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

                              Comment

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