Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

  1. Michael Worobeya,1,
  2. Guan-Zhu Hana, and
  3. Andrew Rambautb,c,d
  1. 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)


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.


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.

1918 Flu Pandemic That Killed 50 Million Originated in China, Historians Say

Chinese laborers transported across Canada thought to be source.

1918 Influenza: the Mother of All Pandemics

Jeffery Taubenberger*Comments to Author  and David M. Morens†
Author affiliations: *Armed Forces Institute of Pathology, Rockville, Maryland, USA; †National Institutes of Health, Bethesda, Maryland, USA

Suggested citation for this article


The “Spanish” influenza pandemic of 1918–1919, which caused ≈50 million deaths worldwide, remains an ominous warning to public health. Many questions about its origins, its unusual epidemiologic features, and the basis of its pathogenicity remain unanswered. The public health implications of the pandemic therefore remain in doubt even as we now grapple with the feared emergence of a pandemic caused by H5N1 or other virus. However, new information about the 1918 virus is emerging, for example, sequencing of the entire genome from archival autopsy tissues. But, the viral genome alone is unlikely to provide answers to some critical questions. Understanding the 1918 pandemic and its implications for future pandemics requires careful experimentation and in-depth historical analysis.

J Transl Med. 2004; 2: 3.
Published online 2004 Jan 20. doi:  10.1186/1479-5876-2-3
PMCID: PMC340389

The site of origin of the 1918 influenza pandemic and its public health implications

Villager’s remains lead to 1918 flu breakthrough

Ned Rozell
Article Number:
November 20, 2014

About arnulfo

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