COVID isn’t humanity’s first pandemic rodeo. How did we make it through the Spanish flu?

What caused the 1918 “Spanish flu” to cease?

– Miranda

I get it Miranda. Sitting, as we are, in throes of a pandemic, our interest in outbreaks of bygone eras is naturally piqued. Everything’s crazy; everything changes – there’s no pandemic handbook, right?

Or is there?

The swings and roundabouts of the COVID pandemic feel new and strange, but it’s not the first time humanity has stared down a deadly viral disease. Can past pandemics offer a blueprint as to how our current mess will play out?

Learning from the past

The US Centre for Disease Control (CDC) certainly believes there’s merit to this idea.

In 2005, the CDC recreated the Spanish flu virus – safely contained within tightly controlled laboratories, of course. They hoped to sequence its genome and study its secrets in order to be better prepared for future pandemics.

The Spanish flu of 1918-19 has long stood out to virologists and epidemiologists as a stark warning that devastating viruses can spring seemingly from nowhere and wreak havoc across the globe. The Spanish flu killed as many as 50 million people worldwide over a period of approximately 18 months, with an unusually high death rate among otherwise healthy young people (15–35 year olds). Around 500 million people were infected – almost a third of the global population at the time.

It’s easy to see the merit in trying to understand the trajectory of a virus that hit hard a century ago but no longer poses any threat – perhaps we’ll see our own path out of the dark COVID woods. What was it that made the 1918 virus so deadly? Where did it come from? And where did it go?

Missing pieces of the puzzle

Today’s pandemic is mapped and documented in minute detail. We track its waves across the globe in real time, and our understanding of its internal machinery is developing rapidly. But in 1918, the study of infectious pathogens was a new field. In the wake of Spanish flu, generations of researchers and public health experts had little more than estimated death tolls and social histories with which to build a picture of the pandemic.

How could scientists understand what happened when the biggest puzzle piece, the pathogen itself, was missing?

That conundrum was initially tackled by Swedish researcher Johan Hultin in 1951. He’d heard of a mass burial site in an Alaskan village called Brevig Mission. There, the interred bodies of at least 72 Spanish flu victims lay untouched in the permafrost. Hultin – with permission from village elders – set to work excavating frozen corpses, hoping to find tissue harbouring traces of the 1918 virus.

Hutin’s efforts failed, although not for want of trying – on his flight from Alaska to research facilities at the University of Iowa he tried to keep lung samples frozen using carbon dioxide from a fire extinguisher. But the technology of the time didn’t allow him to properly prepare and analyse the samples.

In 1997, nearly a half century after his first attempt, Hultin returned to Brevig Mission to give it another shot. Armed with his wife’s garden shears and a handful of local assistants, Hultin dug the frozen burial grounds once more.

Tech advancements had allowed other researchers to partially sequence the viral genome of a lung sample from a US serviceman who died in 1918. Hultin reset his sights on obtaining the best possible tissue samples for these scientists to work with – and this time his efforts paid off.

He unearthed and preserved the perfectly frozen lungs of an Inuit woman who’d died of Spanish flu complications. Just days after the lungs reached the researchers, Hultin had the news: positive genetic material had been obtained from the frozen samples.

Resurrecting an old foe

By 1999, and largely thanks to Hultin’s samples, the entire code of the 1918 flu was sequenced, laying the foundations for the ultimate goal – reconstructing a live version of the lost virus.

The effort began in earnest in 2005.

Using a pioneering technique called reverse genetics, CDC researchers took small, circular strands of DNA called plasmids for each of the 1918 virus’s eight gene segments and inserted them into human kidney cells. The plasmids then instructed the cells to reconstruct the RNA of the complete 1918 virus. This zombie-like reanimation of the Spanish flu was then tested on mice, allowing researchers to document for the first time the mechanisms of its virulence and spread.

The results were terrifying. Four days after infection, the amount of Spanish flu virus found in the lung tissue of infected mice was 39,000 times higher than that produced by similar strains in the flu family.

By watching the virus in action, researchers were finally able to link its genetic structure with the patterns of disease it produced. Experiments showed that it was not any single component of the 1918 virus but instead, as researchers wrote at the time, “the constellation of all eight genes together” that made the Spanish flu an “exceptionally virulent virus”.

The CDC team also tested theories on the virus’s origins. After much experimentation, it was ultimately a chicken egg that held the answer. When 10-day-old fertilised eggs were inoculated with the virus, the results were lethal for the nascent chicken embryos. Paired with gene sequencing evidence suggesting a close link between the Spanish flu virus and other avian influenza viruses, this insight was enough for researchers to declare that the 1918 virus first arose in birds before making the leap to humans.

So that covers off the first two big questions about the Spanish flu – where it came from, and why it was so deadly.

But what about the biggest – how did the pandemic end?

How do pandemics end?

This first requires a little clarification.

The Spanish flu pandemic certainly ended, but the virus that kicked it off did not.

Instead, it gradually grew milder, morphing from its lethal beginnings into a much more placid sniffle.

This is a common natural progression for viruses, partly because the best evolutionary pathway optimises spread but leaves virulence primarily to random chance. This means that while there’s active selection for increased transmissibility, there’s a good chance that lethality will fade. But there is no concrete rule that dictates diminishing virulence, and there can certainly be surprising spikes along the way.

This was true of the Spanish flu, which ebbed and flowed in waves much like COVID’s peaks and troughs. While the general trajectory was towards becoming milder, the path wasn’t linear – some waves were significantly deadlier than their predecessors, just as in the current crisis, the Delta and Omicron variants have posed challenges that the first viral waves did not.

But if the Spanish flu’s overarching pattern is followed by SARS-CoV-2, as many experts believe it will be, we can expect that while we’ll never eradicate the virus, it won’t always be a major public health threat.

The scarily virulent 1918 form of Spanish flu that researchers reanimated is long gone, but its descendants still circulate as part of our seasonal flus. Some genetic aspects of the virus have been implicated in the lesser pandemics of 1957 and 1968; it’s likely that people who lived through the Spanish flu years had a degree of protection from these genetic ‘cousins’.

Here again is a lesson for current times: immunity is key. Each wave of the Spanish flu added layers of immunity to the surviving global population, until gradually the threat abated. With COVID, we know that whilst our immunity fades over a period of months following vaccination or infection, we retain an increasing ability to ward off severe disease with each exposure.

But as we wait for global immunity to build, our key public health measures remain vital in protecting us from the worst effects of the virus.

The importance of these measures was laid bare in the 1918-19 pandemic. As the flu raged a century ago, people were asked to wear masks and adopt social distancing measures, just as we are today. And, just as today, a number of anti-mask advocates opposed these impositions. But experts agree that these measures significantly dampened the death toll while immunity grew, and that they remain vital for us in the current pandemic as we wait for its severity to diminish.

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Masks were just as vital in making it through the 1918 pandemic as they are in today’s COVID crisis. Credit: Bettmann Archive.

Have we learnt our lesson?

When CDC researchers resurrected and characterised the Spanish Flu, they felt they’d taken significant steps towards safeguarding humanity against future outbreaks. They described how the 1918 virus was special – a uniquely deadly product of nature, evolution and the intermingling of people and animals. Sound familiar?

At the time, they believed their work would serve as a portent of nature’s ability to produce future pandemics and help us to begin building our defences and public health capabilities.

But were we paying enough attention?

In a summary of their work on the virus, CDC researchers noted that despite advances in medicine and public health, “a severe pandemic could still be devastating to populations globally”.

Amongst other things, they identified a global deficiency in surveillance capacity, infrastructure, and pandemic planning, and noted insufficient critical and clinical care capacity, especially in low-income countries. They bemoaned the fact that milestones established in 2005 in revised International Health Regulations (IHR) for countries to improve their response capacity for public health emergencies had only been met by a third of countries by 2016.

In a sense, the blueprint for our current pandemic was laid out for us in CDC’s study of the Spanish flu. Though the two viruses are genetically dissimilar, the lessons regarding their management were made clear years before COVID emerged.

We will inevitably make it through this pandemic, though the length of the road ahead remains unclear. But when the next outbreak occurs, will we be any better prepared than we were this time?

This much is clear: if we fail to heed the lessons of pandemics past, COVID-19 will fade from our collective memory the way that the Spanish flu did over the course of a mere century.

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