1910s

"The 1918 pandemic occurred in an era when viruses, as we know them today, were largely theoretical conceptualizations. Back in 1918, the extraordinarily high pandemic mortality, especially in young adults, frustrated physicians and scientists, who were unable to identify an etiological agent and thus were unable to diagnose and successfully treat the disease it caused. As virology matured as a scientific discipline, influenza A viruses were eventually isolated from pigs (1930) and from humans (1933). Serological data from the 1930s first suggested that the 1930s “classical” swine virus and the 1918 pandemic virus were closely related antigenically (23). This was later verified by viral genetic sequence analysis and by antigenic and pathogenesis studies. The subsequent pandemics, beginning with the 1957 H2N2 pandemic, revealed that new pandemic viruses could arise from previous pandemic viruses through genetic reassortment (Fig. 1). But where the 1918 virus had come from and what the basis of its severity had been remained among the most discussed medical mysteries throughout most of the 20th century. Solving that mystery was often referred to as a scientific “Holy Grail,” and few believed that it would ever be found. In 1976, historian Alfred Crosby (1931–2018) wrote that “It has been the dream of scientists working on influenza for over a half century to somehow obtain specimens of the virus of Spanish influenza, but only something as unlikely as a time capsule could provide them”."

"Remarkably, miniscule degraded viral RNA fragments recovered from just a few of the pandemic’s many millions of victims are now yielding, a century after their deaths, new insights into influenza virus biology and pathogenesis and are providing important lines of investigation into the prevention, treatment, and control of future pandemics."

"Pinpointing the origin of the 1918 pandemic virus, including discovering exactly how, where, and when it emerged to initiate sustained human-to-human pandemic transmission, will likely never be possible. Because human-adapted influenza A viruses are only moderately contagious and moderately fatal, it is the nature of influenza pandemics that many weeks, and more likely many months, must pass between the emergence of a pandemic and its detection. During this time, there would be relatively few deaths, given (relatively) low influenza case fatality, and those deaths that occurred would be difficult or impossible to recognize beneath the background of deaths from seasonal influenza and from other prevalent respiratory agents. It remains important to seek genomes of additional influenza viruses from the months and years before May 1918, when the earliest virally confirmed fatal 1918 case occurred. The hope is that new viral sequences identified from before 1918 will help to answer fundamental questions about the origin of the 1918 pandemic virus and population immunity before the pandemic, but the viral evolutionary and host adaptational sequences of events that bridge wild waterfowl gene constellations and pandemic viral genomes occur inside a “black box” that currently remains largely invisible to science. We have information about the genome of the 1918 virus at a very early stage of its emergence, but we do not yet know anything about evolutionary steps that may have occurred before it became adapted to human hosts."

"The bacteria most frequently associated with secondary infections after influenza in 1918–1919 were the pneumopathogens Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. Almost all of the tens of millions of deaths worldwide during the 1918 pandemic were associated with secondary bacterial infections, primarily with Gram-positive bacteria. Had it not been for secondary bacterial pneumonias caused by these and other pneumopathogens, the 1918 pandemic likely would have been associated with a far lower mortality. Increased susceptibility to secondary bacterial pneumonias in persons with influenza should be considered an intrinsic property of influenza virus pathogenicity, and this is likely to be the case for other pathogenic influenza viruses."

"A unique epidemiological feature of the 1918 influenza virus, related to its origin, was infection of both humans and swine. Influenza was first recognized as a clinical entity in swine in the United States in autumn 1918, concurrent with the spread of the pandemic in humans, having apparently been transmitted from humans to pigs. This host switch split the virus off into two independent viral lineages, one human and the other porcine. After 1918, the epizootic disease became widespread among herds of swine in the U.S. midwest. Epizootic viruses appeared annually thereafter, leading to Shope’s 1930 isolation of the first influenza virus, A/swine/Iowa/30, 3 years before the first human isolation of a descendant of the parent 1918 virus, A/WS/33. The two 1918 viral H1N1 lineages, one human and the other porcine, evolved and antigenically drifted at different rates until 2009. In the 2009 pandemic, the human-adapted H1N1 descendant was replaced by a different H1N1 virus that was also a 1918 viral descendant, ironically one that had been circulating enzootically in pigs. The original 1918 classical swine lineage still circulates enzootically today."