ON JUNE 29th 1918 Martín Salazar, Spain’s inspector-general of health, stood up in front of the Royal Academy of Medicine in Madrid. He declared, not without embarrassment, that the disease which was ravaging his country was to be found nowhere else in Europe.

In fact, that was not true. The illness in question, influenza, had been sowing misery in France and Britain for weeks, and in America for longer, but Salazar did not know this because the governments of those countries, a group then at war with Germany and its allies, had made strenuous efforts to suppress such potentially morale-damaging news. Spain, by contrast, was neutral, and the press had freely reported on the epidemic since the first cases had appeared in the capital in May. Before the summer was out, the disease Spaniards knew as the “Naples Soldier”—after a tune from a popular operetta—had been dubbed the “Spanish illness” abroad, and that, somewhat unfairly, was the name which stuck.

Spanish flu was probably the worst catastrophe of the 20th century. The current estimate is that it killed at least 50m people and perhaps as many as 100m. At minimum, therefore, it ended the lives of three times as many as died in the first world war (in the region of 17m). It was probably also more lethal than the second world war (60m), and may well have outstripped the effects of both wars put together. The death toll was so high partly because Spanish flu was truly pandemic (some 500m people, more than a quarter of those then alive, are believed to have been infected), and partly because of its high mortality rate (5-10%, compared with 0.1% for subsequent influenza epidemics).

Understanding what happened is therefore important. Two questions in particular need answering. One is: what made this outbreak of influenza so much more lethal than both previous and subsequent ones? The other is: given that knowledge, what defences need to be put in place to nip any similar outbreak in the bud?

Origin of a species

The first cases of the 1918 flu to be recorded officially as such were at Camp Funston, a military base in Kansas, on March 4th 1918. That morning, Albert Gitchell, a mess cook, reported sick. By lunchtime the camp infirmary was dealing with dozens of similar incidents. The highly contagious nature of the Camp Funston outbreak suggests, however, that Gitchell was not the real “patient zero”. An emerging flu strain tends not to infect people very well at first. Researchers hunting for the individual Gitchell caught it from have therefore scoured records for an earlier, more localised outbreak of respiratory disease that quickly petered out.

At the moment, there are three theories as to where the 1918 flu first manifested itself. John Oxford, a British virologist, has long argued that it was in a British army camp at Étaples on the northern French coast, not far from the Western Front. Here, an outbreak of “purulent bronchitis”, characterised by a dusky blue hue to the face, was reported as early as 1916. Such blue faces were also characteristic of fatal cases of Spanish flu.

In 2004 John Barry, an American journalist, put forward a rival theory. He claimed that a small but severe outbreak of flu-like disease in Haskell County, Kansas, in January 1918, could have seeded the later one at Camp Funston. The camp’s catchment area for recruits included Haskell.

In 2013 a third hypothesis joined these two—or rather was revived, since it was fleetingly popular in the years immediately following the pandemic. According to Mark Humphries, a historian at Wilfrid Laurier University in Waterloo, Ontario, the 1918 flu began in Shanxi province, China, where an epidemic of severe respiratory disease in December 1917 had doctors squabbling over its identity. Some thought it was pneumonic plague, a respiratory variant of bubonic plague to which China was distressingly prone. Others suspected a form of influenza.

Since they could not agree, and since it was also difficult to explain how the flu might have travelled from that remote and poorly connected region to the rest of the world, the theory fell by the wayside. Dr Humphries gave it new life when he pointed out that China, though neutral in the war until 1917, nevertheless played a role earlier than this date by providing Allied forces with a body of workers—the Chinese Labour Corps—who were recruited from provinces, including Shanxi, and shipped via Canada to Europe.

Dr Humphries’s hypothesis is weakened by work published the year following his proposal, by Michael Worobey, an evolutionary anthropologist at the University of Arizona, Tucson. Dr Worobey suggests that the 1918 human flu virus was genetically related to a virus circulating in North American birds at the time. The truth, though, is unlikely to be known unless and until a comparison can be made between the genetic sequence of the 1918 virus (which was determined in 2005, by Jeffery Taubenberger and Ann Reid of the Armed Forces Institute of Pathology in Washington, DC) and the sequences of each of the putative ancestors, of which, at the moment, no known samples exist.

The Blue Death

Whatever its origin, once Spanish flu got going it spread rapidly. It traversed the world in three waves, of which the second—that of the northern-hemisphere autumn of 1918—was the most severe. For that reason, the autumn of 2018 is marked by many as the epidemic’s centenary.

That second wave was preceded by a milder one in the spring of 1918 and succeeded by a final wave, intermediate in severity between the other two, in the early months of 1919. The disease lingered on, though, until at least March 1920, with cases being reported that month in Peru and Japan. Indeed, Dennis Shanks, an epidemiologist at the Australian Army Malaria Institute, in Queensland, recently reported that the epidemic continued on some Pacific islands for another year, with cases still being reported in New Caledonia as late as July 1921.

In the mind of Paul Ewald, an evolutionary biologist at the University of Louisville, in Kentucky, the 1918 virus’s global reach and its particular virulence were shaped by a common factor. Both were a consequence of the trench warfare of the Western Front.

Its virulence, in Dr Ewald’s view, was a result of the abnormal evolutionary environment that the trenches provided. Normally, natural selection causes a virus that is transmitted directly from host to host to moderate its virulence. The longer the host stays alive, the more new hosts that initial victim is likely to come into contact with. Less virulent strains are thus favoured, and so spread. Observation shows that such drops in virulence do, indeed, happen in most influenza epidemics.

Dr Ewald, however, suggests that the war forced the 1918 virus down a different evolutionary path. The large numbers of young men packed into trenches in eastern France for days or weeks on end were, first of all, living cheek by jowl, making contagion easy, and, second, quite likely to die of causes other than influenza before they could pass it on. In these circumstances the strategy favoured by selection would be to breed rapidly in a new host’s body, shedding lots of virus particles as this happens, even if that risks killing a host—for the host may soon be unavailable anyway.

Historians confirm that the virus did indeed race through the trenches, killing as it went. Those soldiers who survived then took it home with them when they went on leave. This process was exacerbated by the demobilisation which followed the armistice of November 1918 that ended the fighting, with American, Australian, Canadian and New Zealand troops returning home, and also soldiers from the European combatants’ colonies in Africa and Asia.

Most of those who fell ill from Spanish flu experienced nothing more than the symptoms of ordinary flu—a sore throat, fever and a headache. The unlucky, however, began to have difficulty breathing. Their faces took on a mahogany hue and they bled from their noses and mouths. Mahogany deepened to blue, an effect doctors dubbed “heliotrope cyanosis”, and before long their entire bodies turned black.

The actual cause of death in most cases was pneumonia brought on by opportunistic bacteria. This made diagnosis complicated—for in 1918 the concept of a “virus” was a newish one. Most of the world’s doctors therefore thought they were dealing with a bacterial infection. The 1918 influenza thus appears in historical records under a kaleidoscope of labels ranging from the common cold to pneumonic plague. That is one reason why estimating the death toll accurately is hard.

At the molecular level, the explanation for the virulence of the Spanish flu remains unknown. But there are clues. Shortly after Dr Taubenberger and Dr Reid had worked out its genetic sequence, a group led by Terrence Tumpey, a virologist at the Centres for Disease Control and Prevention in Atlanta, Georgia, reconstructed the virus by feeding its genes to cultured human kidney cells in a dish, and forcing them to churn out viral particles in the way that human lung cells do during the normal process of infection. This reconstructed virus is now being studied at high-security biocontainment facilities in America.

One of 500m

One promising line of inquiry is the 1918 strain’s version of haemagglutinin, a surface protein that helps the virus break into a target cell (see article). When this is swapped into a strain of virus normally almost harmless to mice, it makes that strain deadly.

Such work is controversial. Some critics point to possible military applications. Those working in the area, such as Dr Tumpey, prefer to emphasise its potential help to the job of creating better flu vaccines.

Never again?

The glittering prize of such work would be a universal vaccine—something that protects recipients against all possible versions of the virus. One approach to creating such a vaccine exploits the observation that, although the convoluted head of the haemagglutinin molecule (which is the target of most existing vaccines), is highly variable in its composition, the stem that anchors it to the rest of the virus is not. A vaccine aimed at the stem might thus be universally effective.

Vaccines which employ this principle are already in clinical trials. But even if they do work, they might not be as universal as their supporters hope. Sceptics point to a phenomenon called imprinting, that might cause a “universal” vaccine’s efficacy to vary between individuals who have had different histories of exposure to flu.

Imprinting is the name given to the observation that an immune system mounts its most effective response to the first flu strain it ever encounters. A memory of this first response is retained by the system and subsequent responses are therefore likely to be poor matches for new and different strains, whether caught from someone else or introduced by inoculation as vaccines. To the extent that haemagglutinin’s molecular stems really are the same in different strains, the effects of imprinting should be diminished. But they may not be abolished entirely.

Imprinting probably shaped the 1918 pandemic. One of its surprises was that people in their twenties and thirties were particularly vulnerable, while the elderly—normally a high-risk group for flu—were actually more likely to survive than they had been in flu seasons throughout the previous decade. The first flu virus that most of those who were young adults in 1918 were exposed to as children was the one that caused the pandemic of the 1890s. This belonged to viral subtype H3N8 (subtypes are named after particular versions of haemagglutinin and a second surface protein, neuraminidase, that they contain), and was thus a different beast from the H1N1 strain with which they were confronted in 1918, so imprinting would have harmed their response.

By contrast, there is evidence that those who were elderly in 1918 had often been exposed when young to viruses circulating earlier in the 19th century which contained H1 or N1. In their cases, imprinting would have helped their resistance mechanisms.

Understanding imprinting could assist efforts to predict who will come off worst in a future pandemic, and to build a better universal vaccine. The imprinting story is unlikely to be simple, though. For example, there seems to be cross-reactivity between some subtypes of influenza, meaning that exposure to one offers protection against another. America’s National Institute of Allergy and Infectious Diseases is planning a large study of imprinting in infants, to explore these effects.

The better vaccines promised by this sort of research are one arm of an effective response to a new pandemic. The other is early detection. The world has, thankfully, moved on from the point where a high-ranking health official can stand up four months into a flu pandemic and be ignorant of the situation in countries beyond his own. But the ability of a virus to spread around the world has increased hugely.

Troops demobilised after the first world war went home by railway and ship. Now, passenger airliners mean that a virus in one part of the planet could cross to that place’s antipodes in a day. Moreover, though humanity at large is not as crowded together as were the troops in the trenches, the world’s population has quadrupled since 1918. About half of it now lives in cities, with a proximity between neighbours unknown to the far more rural world of a century ago. Monitoring systems are much better than they were in 1918, so the chances are that a threatening influenza outbreak would be picked up quickly. But the conditions needed for a pandemic to happen do exist. As with liberty, so with health: the price of retaining it is eternal vigilance.