In Brief
A century ago, the flu killed millions. Today, during a particularly bad flu season, we're still not rid of our viral enemy. In the future, maybe the flu will truly be a thing of the past.

 1918: The War We Lost

In 1918, the United States fought two wars. One it lost, and one it won.

You may have learned about World War I in history class, or even from your relatives. As a member of the Allied Forces, the United States defeated the Central Powers — a victory touted by history books, movies, and novels.

The second war, however, had a more elusive opponent. It descended perniciously, quietly claiming lives while armies concerned themselves with foxholes and mustard gas. In the first six months, this enemy killed 25 million people worldwide.

Ultimately, between 50 and 100 million lives — five percent of the world’s population at the time — would be lost as a result of the conflict.

This second enemy was, of course, the flu virus. By the time Americans realized that the country was under siege, it was too late to stop it. The flu made its way through the U.S., Europe, and Asia with terrifying speed; people who had been well in the morning dropped dead in the street by dinner time. Families that had already lost sons, fathers, and brothers to the war abroad dwindled as the virus attacked them, affecting the remaining young and healthy. In just one year, the average life expectancy for an American dropped by 12 years.

Over the century that followed, Americans would face three more pandemic flus, but none of them like the one in 1918. The 1957 pandemic flu killed roughly 1.1 million people worldwide; another in 1968 wiped out about another million globally. Most recently, the 2009 H1N1 pandemic flu killed between 151,700 and 575,400 people worldwide, according to estimates from the Centers for Disease Control and Prevention (CDC).

Today, a century after the 1918 pandemic, we know much more about the virus — how it spreads, how it kills. We now have influenza vaccines — unheard of in 1918 — that provide us with (albeit limited) protection. And sophisticated tracking mechanisms help us predict which flu viruses we might encounter in a given year.

We have not, however, completely vanquished the flu. In this particularly bad flu season in the U.S., we need little reminder that the virus is hardy and evolves rapidly. The flu that ravaged humanity in 1918 is not the same strain making headlines in 2018. Likewise, if another global pandemic flu is inevitable, we can’t assume the virus will be one we’ve seen before.

Today, our relationship with the flu has shifted from an adversarial, bellicose one, to one of competition; we are running a race, no longer fighting a war. To survive another century, or another season, public health experts will need stay one step ahead, armed with an artillery provided by science and a war plan drafted from the history of the battle we lost.

Image Credit: State Library of Queensland/Illustration by Victor Tangermann

Why (and How) the Flu Still Kills

A high fever, fluid in the lungs, crushing fatigue, and body aches — if you’ve ever come down with influenza, it likely needs no introduction. It’s often easy to distinguish the full-blown flu from the common cold because the flu’s symptoms tend to come on suddenly and with an intensity that makes it hard to deny.

When a person is infected by any pathogen — a virus or bacteria — they usually won’t know it until that pathogen has started damaging cells. That kicks the immune system into gear, making you start to feel sick. The fever, aches, and mucus all too familiar to flu-sufferers aren’t from the virus itself, but rather are the side effects of the body’s attempt to vanquish it.

Even though our immune systems respond rapidly and with such force, they aren’t always successful in stopping the microbes wreaking havoc on the body’s cells. While most of us who get the flu just stay home and rest, the flu makes some people seriously ill — they have to be hospitalized. Some even die as a result of complications from the flu.

(The flu doesn’t directly cause death. Instead, the virus can induce an infection like pneumonia, or exacerbate an underlying condition. But oddly enough, it’s usually the body’s too-aggressive immune response to the flu that ultimately kills people).

A flu virus spreads when a healthy person ingests or inhales virus-infected droplets flung into the air by a sick person’s cough, sneeze, or mere breath. The CDC does not know exactly how many people get the flu each year. The agency doesn’t know how many people die from it either. People who come down with the flu don’t always seek medical attention. Even when they do, doctors don’t always test for it.

Those caveats make the data on this year’s flu season more striking: as of the first week of February, the number of flu cases in the United States was the highest since the 2009 pandemic. The most people have been hospitalized at this stage in the flu season since the CDC started tracking, in 2005. Both numbers are still climbing.

When we talk about the flu, we aren’t talking about a single virus. There are four types of influenza viruses — but only two of them cause serious illness in humans, Catherine Beauchemin, an associate professor of virophysics at Ryerson University in Toronto, explained to Futurism. You might remember hearing about H1N1 (the flu type that hit us in 2009) and H3N2 (the type of flu causing problems this year) — those Hs and Ns stand for hemagglutinin and neuraminidase, proteins found on virus’ surfaces that help either enter cells (H) or separate from cells to go infect another cell (N). The numbers identify groups of strains with similar Hs and Ns.

The flu mutates remarkably quickly, changing dramatically to dodge our antibodies in the span of a flu season or two. That means it can infect people who previously contracted it.

That’s why we get flu shots every year. Even though researchers have a sophisticated global tracking system to anticipate which strain might affect a region in a given year, there’s still a surprising amount of guesswork involved.

Flu seasons typically occur during the colder months, when people are more likely to congregate indoors. Because the flu season is opposite in Australia, the CDC’s Epidemiology and Prevention Branch in the Influenza Division can track that country’s flu season about six months before flu season arrives in North America. As travelers move the virus from Australia to Europe, Asia, and the U.S., public health experts can anticipate which strain will likely be the one to make people sick in the northern hemisphere that year.

The system, and the vaccine made from it, is far from perfect though. “The issue is that the recommendations have to be made some six months before the vaccine is actually used,” Richard Webby, Director of the WHO Collaborating Center for Studies on the Ecology of Influenza in Animals and a member of the Department of Infectious Disease at St. Jude Children’s Research Hospital, told Futurism. Researchers need that time to analyze data from Australia’s flu season, then manufacture and distribute the vaccines.

For a virus that evolves so quickly, that lead time can also be problematic. “There have been instances where the viruses have changed between when the recommendations have been made and when the vaccine has been administered, leading to suboptimal performance.” Webby added. For example, the latest data on this year’s flu vaccine shows it’s around 17 percent effective, though that may change before the flu season ends.

This year’s flu virus, H3N2, isn’t like other strains that have circulated in recent years. It binds to cells differently, and seems to be mutating more rapidly, making it difficult to study and create a vaccine against. The strain also doesn’t grow well in eggs, where bacteria are most commonly grown before being put into vaccines.

“We don’t have a flu vaccine problem so much as we have an H3N2 vaccine problem,” Ed Belongia, a vaccine researcher and director of the Center for Clinical Epidemiology and Population Health at Wisconsin’s Marshfield Clinic, recently told STAT News.

Although we can identify and classify them, track them, and create vaccines to defend against them, the viruses continue to evade us, evolving faster than we can keep up — sickening or killing people in the process.

Image Credit: CDC/Illustration by Victor Tangermann

Fighting the Flu of the Future

In 1918, many of the treatments we have today for secondary infections like pneumonia or strep throat either didn’t exist or were not yet widely available. That partially explains why the epidemic killed so many.

Today, the antiviral Tamiflu can quell symptoms within the first 48 hours of their onset, or even prevent them in the first place. But it’s pricey (a five-day course costs $100 minimum) and comes with risks, especially for children and teens, who are more likely to experience serious psychological side effects and “seizures, confusion, or abnormal behavior early during their illness,” according to the CDC.

In 1918, many people felt that the flu descended upon their community out of nowhere. Today, we can at the very least see the flu coming so our doctors and emergency rooms can be prepared — even if we don’t have weapons powerful enough to completely stop it yet.

One elegant solution is to gather data from smart devices sick people usually use to track the spread of the flu. Smart thermometer company Kinsa does just that. Over the past six years, the device’s 1 million users gather real-time data to track infectious disease with the help of “smart thermometers” and a smartphone app. Though it may seem counter-intuitive that a relatively small number of users could track how many people have the flu and where, the flu-tracking data over the past two years has lined up with CDC data — and the app is gathering it much more quickly than public health agencies are able. Nationally, the number of people with the flu is 39 percent higher than it was at this time last year, according to Kinsa’s most recent report.

Some are thinking bigger than treating or tracking the flu. The holy grail for flu treatment would be a vaccine that doesn’t change from year to year depending on the annual strain. If everyone could just get the vaccine once to protect us from all strains of flu for our entire lives, hundreds of thousands of lives could be saved every year.

We’re talking, of course, about a universal flu vaccine.

A team of researchers out of UCLA is genetically-engineering flu viruses that could become candidates for a universal vaccine. The researchers engineered flu cells to stimulate a bigger, more targeted immune response than the real-life strains. So far, the team has only developed the potential vaccine in the lab; the researchers hope to test two strains in animal models before moving into human trials.

Pharma company BiondVax Pharmaceuticals recently completed Phase 3 clinical trials for its universal vaccine candidate, which incorporates synthetic compounds. It has already received a patent in India. This type of vaccine targets specific areas on the surface of a flu virus that determine the phase and severity of the immune response. Being able to “ramp up” or “tamp down” different aspects of that process in animal models has convinced researchers that the vaccine could be useful in preventing other infectious disease beyond the flu, such as HIV and malaria.

FluGen, a startup out of the University of Wisconsin-Madison, is also working with a genetically-mutated form of the virus to make a universal vaccine. According to FluGen’s website, the company’s genetically-altered  viruses have had a gene deleted so that they “can infect cells, express the entire spectrum of influenza RNA and proteins, yet cannot produce any infectious virus particles.”

But to get there, the researchers encountered substantial controversy. You have to break a few eggs to make an omelet; to create a vaccine against mutating flu viruses, you’ll have to mutate a few flu viruses. Researchers worked to avoid creating some kind of super-virus. When the researchers mutated the H1N1 virus from the 2009 pandemic, and when they recreated the 1918 pandemic flu, the global scientific community called their methods and safety into question.

Other researchers, like those on a team at Georgia State University, are harnessing nanoparticles to facilitate a universal vaccine. Most vaccines target the outside surface of a virus’s protein, which varies across different viruses. But if nanoparticles could target further down, on a part of the protein called the stalk, a vaccine could have broader efficacy. In experiments detailed in a study published in Nature Communications in January 2018, mice inoculated with nanoparticles containing the protein to elicit an immune system response were completely immune to four different strains of the flu, including this year’s H3N2. They will need to conduct more animal studies — first in ferrets, as their respiratory systems are quite similar to those of humans — before testing the vaccine on humans.

There are other logistical hurdles to a universal vaccine. There’s little financial incentive for pharmaceutical companies to develop vaccines, much less universal ones only administered once in a person’s life. Distribution of vaccines can be challenging and shortages are not uncommon. Plus, people just love to find reasons why they shouldn’t get the jab.

But these challenges are not insurmountable. A universal vaccine could be possible within a generation. How well it works, well, that’s another question.

As 1918 came to a close, the editors of the Journal of the American Medical Association published its final edition for the year. The editors reflected on what could be learned from the two wars humanity fought that year, then turned their attention to the future.

“Medical science for four and one-half years devoted itself to putting men on the firing line and keeping them there,” they wrote. “Now, it must turn with its whole might to combating the greatest enemy of all — infectious disease.” In another century, perhaps the flu of today — the damage it causes, the lives lost to it — will seem equally distant, perhaps even innocuous.