A century ago, as the First World War drew to an end, Spanish influenza brought terror to an already shell-shocked world. Industrialised warfare had caused the loss of many young lives and there must have been a sense that things couldn't get any worse. And yet they did: a virus unlike any other in recent memory unleashed itself onto a weakened and highly mobile population, causing more than 50 million additional deaths.

Now is a good time to reflect on this tragic episode and to apply knowledge gained from a century of progress to understand how it happened and to consider whether it could happen again. What do we know about the 1918 virus, where it came from and why the outbreak it caused was so devastating? Was the severity of the pandemic attributable to the susceptibility of the human population after 4 years of wartime stress, to other factors (such as co-infecting bacteria), or was the particular virus that emerged endowed with an unusual highly pathogenic phenotype?

Research into the 1918 virus was reinvigorated in 1997 by the elucidation of its sequence , pieced together from fragments amplified from histological sections of lungs of soldiers who died of the disease. This enabled the reconstitution of the virus from synthetic complementary DNAs, and studies in animal models revealed a pathogenicity higher than that seen after experimental infection with any modern day seasonal influenza viruses. These advances coincided with the emergence of a new highly pathogenic virus (avian influenza A H5N1), that crossed over into people exposed to infected poultry in 1997, and again in 2003, sparking great concern that it might initiate a new pandemic. Then, the 2009 H1N1 swine flu pandemic struck, triggering a wave of genomic and immunological research that described the human response to influenza at a level not possible during previous outbreaks and defined clear risk factors for serious disease.

Influenza pandemics arise when a virus with novel antigenicity acquires the ability to transmit between people. These viruses originate from animal reservoirs, typically birds or pigs. For human-to-human transmission to be maintained, the major surface antigen (viral haemagglutinin, HA) has to be able to bind to receptors in the human airway and to be chemically stable enough to survive between human hosts in airborne droplets.

series of autopsy cases of soldiers who died from influenza in 1918 reveal this evolutionary process; the viral sequences obtained from the lungs of victims who died in May 1918 (before the pandemic really took off), show an HA that binds avian-like receptors and confers poor airborne transmissibility between ferrets. However, by autumn 1918, the autopsy material reveals that the virus had mutated in ways that enhanced its ability to bind human airway receptors, presumably gaining transmissibility. Similar studies of the 2009 H1N1 pandemic virus also showed the transition from a first wave virus only just adapted enough to sustain transmission, to a third wave virus that had potentiated its adaptation to its new host.

Controversy still surrounds the nature of the direct ancestors of the 1918 virus, with some people believing it to be derived directly from an avian precursor. It is pertinent that host responses in non-human primates infected with the reconstituted 1918 virus share some similarities with responses in animals infected with the zoonotic avian influenza virus H5N1, such as early cytokine dysregulation. Several viral genes drive the lethal phenotype of the 1918 strain in animal models, including HA and the viral RNA-dependent RNA polymerase. The 1918 virus polymerase had enhanced its activity in human cells by a single amino acid mutation that confers avian to human adaption to an essential species-specific host cofactor. Like unruly teenagers, viruses that are crudely adapted to new hosts often wreak havoc, triggering pathological innate immune responses—eg, by replicating inappropriately in myeloid cells. In the years that followed 1918, the pandemic virus transformed into seasonal influenza and accumulated mutations that calmed its behaviour. Acquisition of a less pathogenic phenotype during host adaptation might increase virus transmission by enhancing exposures from pre-symptomatic or asymptomatic individuals.

Copyright © 2018 National Library of Medicine/Science Photo Library

Copyright © 2018 National Museum of Health and Medicine/Science Photo Library

Although the 1918 influenza virus is especially virulent in cells and experimental animal models, a strong body of evidence implicates other pathogens in the extreme loss of life of the pandemic: most of the human victims were co-infected with bacteria such as Streptococcus pneumoniae, Strep. pyogenes or Staphylococcus aureus. Mice co-infected with 1918 influenza virus and Strep. pneumoniae show enhanced disease characterised by a neutrophil-driven transcriptomic signature and histological evidence of coagulation and pulmonary thrombosis reminiscent of autopsy slides from human 1918 cases.

Tantalisingly, the most severe cases of pandemic H1N1 in 2010–11 were associated with a bacterial transcriptomic signature , even when bacterial co-infection was not confirmed. Whether the damage that results from severe influenza paves the way for bacteria normally carried in the nasopharynx to descend to the lung and trigger the neutrophil response, or whether the virus itself triggers this immunopathological pathway is not yet clear, but the implications for future plans and treatment strategies for pandemic preparedness are important.

As in every influenza outbreak, the very young and very old were badly affected by the Spanish influenza pandemic, but in 1918 an exceptional number of influenza-related deaths occurred in relatively young healthy adults between 15–30 years of age, giving rise to the so-called W-shaped mortality curve. Just as in 2009, and in the H1N1 mini-pandemic of 1977, people older than a certain age who had been infected in early life with a virus of similar antigenicity were likely to have either maintained sufficiently high levels of antibody or retained immunological memory that was quickly activated to protect them from infection or disease. An influenza virus of the same H1 subtype as 1918 that might have circulated before 1889 might explain the relative protection of individuals older than 30 years compared with those in their 20s in 1918.

Indeed, the concept that previous immunological experience of influenza shapes the outcome of subsequent infections is increasingly being used to explain observations about influenza in modern times; the first influenza infection an individual experiences appears to establish the response to subsequent infections. This concept has been termed original antigenic sin. It is now thought that the ‘sin’ extends to viruses with HAs that lie in the same phylogenetic group. People who have previously been infected with H1 subtype viruses are less likely to be zoonotically affected by H5 avian influenza viruses, whereas if the first influenza was H3, then a level of protection against H7 infection is observed.

Conversely, a strong immunological imprint can render certain age groups more vulnerable to a related but drifted virus: in the 2013–14 influenza season, people in their 50s were particularly vulnerable to an antigenically drifted version of the H1N1 pandemic virus because their imprinted immune system preferred to respond to the original 2009 strain that was antigenically similar to an H1 virus they had experienced as children.

The left-sided dip of the W is more difficult to account for. Why were children aged 5–15 less likely than 25-year-olds to succumb to infection in 1918? An attractive hypothesis is that a different quality of the maturing paediatric immune response was less likely to trigger the immunopathological pathways that paved the way for viral damage and subsequent bacterial descent to the lung. One study of childhood response to influenza infection found a qualitative difference related to age, but further studies are required to thoroughly understand this so-called honeymoon period.

Understanding the exceptional impact of the 1918 influenza pandemic, including the immunological explanations for the atypical age-related sensitivity to virus infection, might have important implications for dealing with future influenza pandemics: at a time when the world is calling for new approaches to influenza vaccination, we are embarking on novel vaccination strategies that induce quite different arms of the immune response to those engaged by traditional vaccines or natural immune responses. It is important that we consider the possible immunological ramifications of these innovations on the outcome of infection by contemporary and future influenza viruses.

Copyright © 2018 NARA/Science Photo Library