Issue: January 2018
January 22, 2018
6 min read

100 years after 1918 pandemic, flu still top ID threat

Issue: January 2018
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On a graph, the downward trend of infectious disease-related deaths over the first half of the 20th century is interrupted by a large spike. The line rises and falls sharply to mark the immense toll of the 1918 influenza pandemic.

Striking near the end of World War I, the pandemic killed at least 50 million people between late 1918 and early 1919 — more than the war itself — and infected an estimated one-third of the world’s population.

Peter Palese

The pathogen responsible for the pandemic, an avian influenza A(H1N1) virus, could kill with speed. Unusual for influenza, the 1918 strain killed large numbers of young, otherwise healthy adults. Stories of victims being upright and active one day and dead the next were common. In the United States, where military camps were decimated by the illness, the death toll from the pandemic caused the average life expectancy to drop by more than a decade in just 1 year.

“There are examples of people who were drinking beer in a bar and the next day they were blue,” Peter Palese, PhD, professor and chair of the department of microbiology in the Icahn School of Medicine at Mount Sinai in New York, said in an interview.

A century later, despite the scientific advances that have made us more prepared for infectious disease threats, experts still fear the deadly power of influenza and consistently rate it as the disease likeliest to cause a pandemic.

“It’s always No. 1 because it’s always out there,” Anthony S. Fauci, MD, director of the NIH’s National Institute of Allergy and Infectious Diseases, said in an interview.

‘Spanish influenza’

The 1918 virus is commonly called “Spanish influenza,” a result of neutral Spain’s free wartime press reporting widely on the pandemic while censorship precluded other countries from doing the same. But the virus almost certainly did not originate in Spain. It may have come from China, or from birds in North America, according to researchers.

The virus, which has since been reconstructed by Palese and others, was well-equipped for a pandemic. It was highly virulent, easily transmitted and overwhelmed a global population that was largely unprotected against it — “a real winner,” Palese said. He thinks people born before 1889 may have been exposed to a similar virus, giving them some immunity against the 1918 strain. This — or a severe immunological response — would explain why it was so disproportionately deadly among young, healthy adults.


The virus killed quickly by decimating epithelial cells in the lungs. However, most patients died more slowly of bacterial pneumonia, which took root in their respiratory system and thrived during the viral infection, Palese said.

Sneeze screens protect sailors against the spread of influenza in a crowded sleeping area at the Naval Training Station in San Francisco.

Source: Naval History and Heritage Command

Many of these deaths would have been prevented today by vaccines, antivirals or antibiotics, underscoring how much better prepared the world is to face an influenza pandemic. That a virus caused influenza was not even known until 1933.

“I think we should be worried, we should be cognizant of a new pandemic strain, but it is not the same as it was in 1918,” Palese said.

The ‘chasing game’

In other ways, an influenza pandemic is more difficult to stop today, and potentially costlier to manage. Global connectivity — Hong Kong to New York in about 15 hours — allows pathogens to spread more widely and at a quicker pace, experts said.

Moreover, according to Michael T. Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, a large-scale influenza pandemic can disrupt the supply of essential generic drugs, which are often manufactured in countries like India and China.

“One of the things that makes pandemics of influenza more consequential today than ever is the fact that we’ve become so dependent on global trade for essential products of life,” Osterholm said. “The collateral damage in the next pandemic could be substantially more than what’s actually caused by influenza itself if we have a major shortage of these life-saving drugs.”

Results of a modeling study published recently in PLoS Computational Biology showed that an influenza pandemic is more likely to occur in the spring or summer than during the height of a seasonal influenza season. Still, the unpredictability of influenza concerns experts. In 2005, they worried about a pandemic of H5N1 that never came.

Michael T. Osterholm

“We made a vaccine. We stockpiled it. Nothing happened,” Fauci said.

Four years later, Fauci said experts had fixed their eyes on China when the first influenza pandemic in 41 years — and the third since 1918 — emerged on the border between Mexico and California instead. The H1N1 strain that struck in 2009 was relatively mild compared with the 1918 virus, but it killed as many as 18,300 people in the U.S. The lesson, experts said, is that it is difficult to know when an influenza pandemic will strike, where it will come from and what it will look like.


“If you’ve seen one influenza pandemic, you’ve seen one influenza pandemic,” Osterholm said.

Influenza’s staying power depends on its ability to mutate. Seasonal vaccines target the globular head of hemagglutinin surface proteins that bind the virus to human cells. But vaccine compositions must be updated frequently to account for changes in the hemagglutinin of circulating strains.

The specter of pandemic influenza is one reason Palese and other researchers have been working to develop a “universal” influenza vaccine — one that would target a different part of the virus and protect against both seasonal and pandemic strains for years, if not decades.

The seasonal influenza vaccine, which protects against three or four strains, is not particularly effective compared with vaccines against other diseases like measles and polio, according to Fauci.

“In a good year, it’s no better than 60% effective, and in a bad year, it’s 10%,” he said.

A sign counts the number of dead at the Naval Aircraft Factory in Philadelphia and warns that spitting spreads influenza.

Source: Naval History and Heritage Command

Worse, when influenza pandemics strike, making a vaccine against the new strain takes a long time. A new vaccine to combat the 2009 pandemic took 6 months to develop — stretching from April, when cases were first reported, to October, after the pandemic had already peaked.

“We’re playing this chasing game,” Fauci said. “A universal vaccine is going to be the only solution to this because when you get an inkling of a pandemic coming, even if you rush, it’s still going to take months to get a vaccine. We should put every effort — and we are — into developing a universal flu vaccine.”

In the meantime, Fauci said improvements to the platforms of vaccine development are needed to cut down on the time it takes to make a new vaccine, from 6 months to around 2 or 3 months.

“If we can do that, we wouldn’t have gotten into the trouble that we got into in 2009,” he said.

What’s next?

Since 2013, China has experienced five epidemics of H7N9, a worrisome avian influenza virus that kills 40% of infected patients who are hospitalized, although the actual mortality rate is surely lower, Osterholm said. The fifth epidemic has been by far the largest and most widespread.

Although human cases of H7N9 have risen over time, almost all the infections so far have spread from poultry, not people. The virus has not evolved to be easily transmitted by humans, and experts are not sure it ever will be. But if that evolutionary tweak does occur, the virus could be difficult to contain.


Responding to H7N9 is complicated in several ways. In 2017, health agencies were forced to make new vaccines after evidence emerged that H7N9 had split into two strains, making the old stockpiles useless. In the U.S., trials of a new candidate vaccine began near the end of 2017, Fauci said.

Anthony S. Fauci

Because most cases have been acquired through close contact with poultry, especially chickens, it is also important to protect birds against H7N9. China began to vaccinate poultry against the virus last summer, but Osterholm called it “wishful thinking” that this could be done comprehensively.

“Just to supply the needs of Shanghai, about 100 million chickens are born each month,” Osterholm said. “On average, it’s about 35 days from the time a chicken is hatched until it’s on the plate. That’s just one city.”

According to the CDC, H7N9 is the influenza strain that is likeliest to cause a pandemic, but the designation is based on a tool that was developed by the agency and outside experts to evaluate risks, not predict them. No one knows for sure if H7N9 will cause a pandemic.

“Pandemics are completely unpredictable,” Fauci said. “We may be focusing on H7N9 and a pandemic will arrive that will have nothing to do with any of these viruses.” – by Gerard Gallagher

Editor’s note: For more information on the pandemic potential of influenza A(H7N9), click here.

Disclosures: Fauci, Osterholm and Palese report no relevant financial disclosures.