A “universal” flu vaccine could bring one of the world’s longest pandemics to an end.

By Matthew Hutson

n 2009, global health officials started tracking a new kind of flu. It appeared first in Mexico, in March, and quickly infected thousands. Influenza tends to kill the very young and the very old, but this flu was different. It seemed to be severely affecting otherwise healthy young adults.

American epidemiologists soon learned of cases in California, Texas, and Kansas. By the end of April, the virus had reached a high school in Queens, where a few kids, returning from a trip to Mexico, had infected a third of the student body. The Mexican government closed its schools and banned large gatherings, and the U.S. considered doing the same. “It was a very scary situation,” Richard Besser, who was then the acting director of the Centers for Disease Control and Prevention, told me. Early estimates suggested that the “swine flu,” as the new strain became known, killed as many as fourteen per cent of those it infected—a case fatality rate more than two hundred times higher than typical seasonal flu. The virus soon spread to more than a hundred and fifty countries, and the Obama Administration considered delaying the start of school until after Thanksgiving, when a second wave could be under way. Manufacturers worried about vaccine supplies. Like most flu vaccines, the one for the swine flu was grown in chicken eggs. “Even if you yell at them, they don’t grow faster,” Tom Frieden, who replaced Besser as the director of the C.D.C., said, at a press conference.

In the end, the world got lucky. The early stats were misleading: although swine flu was extremely contagious, it wasn’t especially deadly. Sometimes the reverse is true. Avian flu, which spread across the world during the winter of 2005-06, is not particularly transmissible but is highly lethal, killing more than half of those it infects. Each flu virus has its own epidemiological profile, determined by its genetic makeup, and flu genes shift every year. Howard Markel, a physician and historian of epidemics who, in the early two-thousands, helped invent the concept of “flattening the curve,” compared influenza’s swappable genetic components to “two wheels of fortune.” A double whammy—ease of spread combined with lethality—could make covid-19, or even the 1918 flu, which killed between forty million and a hundred million people, look like a twenty-four-hour bug.

After the swine flu’s relatively harmless nature became apparent, many people asked if the alarm it provoked had been warranted. A Swiss survey found that trust in institutions had decreased. Some scientists and officials accused the World Health Organization of stirring up a “faked” pandemic to justify its budget. But most drew the opposite conclusion from the experience. Trying to prepare for a deadly flu pandemic had left them more alarmed. “There was just a sense of overwhelming relief,” Besser said. “If this had been like 1918, we sure weren’t ready.”

In truth, we’re never fully ready for the flu. We know it’s coming, like the first fall leaf, and yet three times in the past century—in 1918, 1957, and 1968—it has flattened us, killing a million or more each time. Even in ordinary years, the disease infects a billion people around the world, killing hundreds of thousands; one study estimated that it costs the United States economy close to a hundred billion dollars annually. Our primary weapon against the virus, the flu vaccine, is woefully inadequate. Over the last decade and a half in the United States, flu vaccines have prevented illness only forty per cent of the time; in particularly bad years, when vaccines were less fine-tuned to the strains that were circulating, they were only ten-per-cent protective. Today, the coronavirus pandemic is rightfully the object of our most strenuous efforts. And yet, as the infectious-disease specialists David Morens, Jeffrey Taubenberger, and Anthony Fauci wrote, in a 2009 article in The New England Journal of Medicine, that “we are living in a pandemic era that began around 1918,” when the flu used shipping networks to traverse the world. Since the 1918 pandemic, this century-long, multi-wave pandemic has killed roughly the same number of people.

We’ve controlled a vast number of diseases with vaccination—chicken pox, diphtheria, measles, mumps, polio, rabies, rubella, smallpox, tetanus, typhoid, whooping cough, yellow fever—and, to some degree, we’ve added covid-19 to the list. But the pathogens behind those diseases tend to be relatively static compared with the flu, which returns each year in a vexingly different form. For decades, scientists have dreamed of what some call a “universal” flu vaccine—one that could target many strains of the virus. A universal vaccine would save countless lives not just this year but every year; as those numbers add up, it would become one of the greatest medical breakthroughs in history. Until recently, it’s been beyond the reach of molecular biology. But new technologies are extending our abilities, and researchers are learning how to see through the flu’s disguises. Without knowing it, we’re living on the cusp of a remarkable scientific achievement. One of the world’s longest pandemics could soon be coming to an end.

What we call “the flu” is really plural. Every season, several strains circulate. When it’s summer in one hemisphere, flu infections surge in the other. Virologists at the W.H.O. investigate the viruses and share what they learn with pharmaceutical companies; pharmaceutical researchers then often develop quadrivalent vaccines, which target four separate strains simultaneously. It’s the shotgun approach.

It takes more than six months to design, test, and manufacture a season’s worth of flu vaccine. In that time, a lot can change. Out in the world, strains mutate, jostling for dominance; prevalent varieties fade away, and sleepers come to the fore. Arnold Monto, an epidemiologist at the University of Michigan who has advised the Food and Drug Administration on flu-vaccine targeting, told me that choosing strains to target requires “science and a little bit of art.” The selected flu viruses mutate further as a result of vaccine manufacturing. By the time a needle reaches your arm, there’s a good chance that the vaccine might be off target or obsolete.

Each strain of the flu can be seen as plural, too. Morrens, Taubenberger, and Fauci explain that “it is helpful to think of influenza viruses not as distinct entities but as eight-member ‘gene teams.’ ” A flu virus, they write, “must sometimes trade away one or more team members to make way for new gene ‘players’ with unique skills.”

The surface of a virus is covered by a forest of proteins; as the virus’s genes change, the proteins change along with them. From a vaccine perspective, two proteins are of preëminent importance. The first, hemagglutinin (HA), helps the virus break into cells; the second, neuraminidase (NA), helps it break out of them. The cryptic code names given to flu viruses—H1N1, H3N2, and so on—reflect the dozens of numbered variations in which these proteins come. The variations themselves mutate when the virus reproduces, making vaccine targeting even more difficult: flu vaccines focus on the more vulnerable HA proteins, and must be tailored to fit the newest version of the virus.

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