The 1918 influenza A pandemic claimed more than 20 million lives worldwide in less than a year and ranks among the worst disasters in human history. In the United States alone, it is estimated that 1 in 4 people became ill during the pandemic and that 675,000 people died.

Doubt remains as to whether the 1918 influenza pandemic originated in the United States, China, or France. There is agreement that a mild wave occurred simultaneously in the United States, Europe, and Asia in March–April 1918. It is postulated that genetic changes in that virus resulted in high pathogenicity in the second wave. The second wave occurred in September–November 1918 and affected one-quarter of the world’s population; 500 million people were clinically affected during the pandemic.

The name Spanish flu came not from major outbreaks in Spain, but from high mortality among troops in France that for intelligence reasons were attributed to Spanish origins. The highest mortality from the disease occurred after the arrival of American troops in France. Indeed, General Erich Ludendorff, the Imperial German Army Chief of Staff, concluded that it was the virus, not the fresh troops, that ended the World War. A remarkable feature of the 1918 pandemic was that deaths were highest among young adults in the 20–40 year age range.

Molecular analysis of the hemagglutinin (HA), neuraminidase (NA), and nonstructural genes from formalin-treated lung samples in paraffin blocks from soldiers that died in the second wave and from lung tissue from an Inuit woman buried in the permafrost in Alaska has provided information on the probable origin of the virus (Taubenberger et al., 2001). Phylogenetic analysis of the complete HA and NA sequences supports the hypothesis that the 1918 virus was derived from avian influenza precursors and was most closely related to classical swine influenza virus. To date, however, this analysis provides no insight into the enormous pathogenicity of the virus.

The return of military personnel throughout the world coincided with the peak of the second wave. In many cities, the disease was so severe that coffins were stacked in the streets, and the impact was so profound that it depressed the average life expectancy in the United States by more than 10 years. In spring 1919, a nasty but less lethal third wave occurred, and substantial mortality also recurred in 1920 (Kilbourne et al., 1987).

The complete sequence of the 1918 virus will be resolved in the near future, and reverse genetics technology is in place to remake this virus. If we wish to understand the molecular basis of high pathogenicity, remaking the virus may be the only option. If this is done, great care must be exercised to use the highest level of biosecurity. The available sequence information on the HA would permit us to make vaccines, and the sequence of the NA indicates sensitivity to the neuraminidase inhibitors. The precursor virus(es) of the 1918 virus still exist in nature and there is nothing to prevent it or a virus of similar virulence from reemerging (Taubenberger et al., 2001).