Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

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.

Keywords: cohort immunity; pathogenicity; phylogeny; reassortment; virulence.

Fig. 1.

Mortality in 1918 and seroarcheological patterns. (A) Influenza and pneumonia mortality (solid line) in different age groups in the United States in 1918 (data from ref. 1), and N8 neuraminidase inhibition titers (legend at right) in sera from different age groups (data from ref. 11). Vertical bars indicate the pandemics of 1830–1833, 1847–1850, 1889–1893, and 1918–1920. (Ages/birth years are indicated below B). (B) Case-fatality ratios in 1918 (in black) (data from ref. 1) and percentages of deaths by age from pandemic-related causes in Ontario, Canada (in gray) (data from ref. 33). Also shown are percentages of sera from different age groups with HA inhibition antibody titers (SI Appendix).

Fig. 2.

Maximum clade credibility (MCC) tree of the H1 subtype of HA. (Right) Clade-specific rate distributions (in substitutions per site per year). (Left) Time window of the pandemic of 1918–1920 is shown with a gray bar, as is that of the putative pandemic around 1900. The posterior probability of each node and the 95% CIs on node dates are shown. The orange star indicates the H1 variant that evidently gave rise to postpandemic seasonal H1N1 lineage in humans. The widths of the green rectangles indicate the comparable extent of H1 genetic diversity in 1918 and 1945 (more than 10 y in each case).

Fig. 3.

Excess mortality in 1918 and the childhood exposure/cohort immunity model. (A) Age group-specific annual excess mortality due to pneumonia and influenza in 1918 (data from ref. 5). (Year of birth and age in 1918 are indicated below B.) (B) Expected cohort protection due to childhood exposure. Each segment of the 1918 H1N1 genome is shown in blue. Putative H1- and N1-like genes in the 1830, 1847, and 1900 genomes are also shown in blue, whereas putative heterosubtypic genes (H3 and N8) in the 1847, 1889, and 1900 viruses are shown in red. The human silhouettes are colored by putative childhood exposure to HA and NA antigens matched or mismatched to the 1918 H1N1 (+/+, blue; +/−, blue/red; −/−, red), whereas the newborn is colored gray, indicating no prior exposure. The pandemics of 1847, 1889 (red), 1900, and 1918 are indicated with vertical bars.