Good Riddance

This Universal Jab Will Make the Flu a Horrible, Distant Memory

A flu vaccine once seemed impossible. Not anymore.

You’re crazy if you think you should forgo your flu shot this season—or any season: The World Health Organization (WHO) estimates annual deaths from flu-related complications range from 250,000 to 500,000. And a quick glance at the numbers from the century’s more gruesome pandemics—like the 1918-1919 Spanish flu that killed somewhere between 50 to 100 million people—illustrate the havoc an exceptionally vicious strain of the virus could wreak.

But, you’re also crazy to think that getting a flu shot will make you impervious to infection. According to the Centers for Disease Control and Prevention, only 42 percent of those inoculated last year actually experienced immunity from flu infection. The year before, 48 percent. The year before that? A paltry 19 percent.

“It has been very clear that in the broad realm of vaccines, influenza vaccines are far from perfect,” Dr. Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases (NIAID) under the National Institutes of Health, said. “The efficacy of the seasonal vaccine is variable and never really is as effective as the vaccines we have for smallpox, measles, polio, and things like that.”

So why can’t we just end the flu once and for all?

Well, the influenza virus is blessed with the right evolutionary traits to edge out a simple vaccine fix. Strains of the flu are notorious for how rapidly they mutate. The virus’ genes are encoded not by DNA, but by RNA. That means the flu can replicate itself within host cells without proofreading mechanisms that would correct mistakes. “Every single influenza that’s made has, say, between 1 and 10 mutations within its genome,” Dr. Jeffrey Taubenberger, an influenza researcher at NIAID, said. “Basically, the viruses live in this kind of enormous pool where every kind of possible mutation already exists, at a low rate.”

Every season another round of strains torches through the globe and infects people, eventually waning as that exposure (plus vaccination) bestows people with immunity. Another set of strains have mutations that escape pre-existing immunity, and they gear up to do the same thing their predecessors tried last season: Try to take over the world. Or something.

The flu vaccine is always comprised of three-to-four broad strains that WHO predicts will cause the most infections. This vaccine is reformulated annually to match the minute mutations in the strain’s structures. When you get a flu shot, you’re technically covered for just a few specific strains (although there’s some degree of potential cross-protection against other strains).

Imperfections are myriad. Doctors might miscalculate which strains will be most virulent. Maybe the strains mutated after the vaccine is manufactured. Prior experience with influenza can drastically affect what type of response a vaccine can elicit. Regardless, making a seasonal vaccine is fraught with pitfalls.

There’s also the looming threat of a particularly vicious strain like Spanish Flu rearing its head and creating a global health crisis. The flu doesn’t just affect humans—it’s a virus that can also affect pigs, dogs, horses, and especially birds, which are capable of migrating large distances. Sometimes, the animal virus mutates in a way that it can infect humans. These often create false alarms, (like H5N1 and H7N9, better known by the moniker “bird flu”) that don’t spread as fluidly with humans. But every so often, there’s a case like Spanish flu or H1N1 (“swine flu”) that spreads like wildfire, leading to a pandemic. Because of how swift the mutation rate is for the influenza virus, a highly transmissible, highly lethal strain is entirely possible.

The key to solving both problems hinges on developing a universal vaccine for the flu, providing immunity to all strains of the virus through a single dose, seasonal and pandemic-causing alike. But after nearly a century’s worth of work, there’s no one-jab-for-life treatment. Will we ever get one?

Fauci has made it a core mission of NIAID to develop such a shot. “I’m totally convinced and committed to the fact that we need a universal flu vaccine,” he said. “There really is a strong intention and effort to figure out how to address in the next coming years the best approach towards a universal flu vaccine.” The way to go about such a treatment, however, isn’t agreed upon.

Conventional flu vaccines create an immune response against a surface protein called hemagglutinin (the “H” in the viral HXNX nomenclature). “You can visualize hemagglutinin as a tree, with a large head canopy of branches of leaves sticking out from a long stem or trunk,” says Taubenberger. The heads are what the host normally interfaces with to create immune response, because like in a forest, the stems are shrouded under sprawling canopies at the top. That top also happens to be the part that mutates insanely quickly.

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But it’s the stem which could be key to a universal flu vaccine. That’s because it’s more conserved from mutations over time, remaining the same from strain to strain. Though the stem isn’t readily accessible to the immune system, there are groups trying to devise a method for getting the immune system to respond to it anyway. Fauci noted that “if you want a universal flu vaccine that will be good this year, and the next year, and the year after, that would be a good place to target.”

Dr. Ian Wilson, a researcher at the Scripps Research Institute in La Jolla, California, and his colleagues working with a Dutch group from Janssen Pharmaceuticals developed a “headless mini-hemagglutinin” which ostensibly “forces the immune system to react to these stems, without the distraction of the heads, because they’ve been chopped off.” The team successfully elicited immune responses against multiple flu strains in tests on mice and primates, and have since been underway in trying to replicate the same success for humans.

Taubenberger and his team, however, chose an unorthodox approach. They’ve created what he calls a “cocktail vaccine” that possesses particles which look like bird flu hemagglutinin on the surface, but don’t have any genes inside of them. “They can’t infect you and replicate and cause infection. It’s like a dummy.

“When you inject that as a squirt up the nose of animals, they are not infected with anything but they do develop antibodies against the hemagglutinin head and stem.” In those animal subjects, there is nearly 100 percent protection against any strain of flu. That understandably excites Taubenberger, who hopes to transition into Phase I clinical trials on humans in about a year.

And that’s the last obstacle. The British are already ahead of the U.S. with human testing, with the U.K.’s National Health Service is recruiting 500 patients aged 65 or older to take part in a new clinical trial to test an experimental flu vaccine. The new treatment administers both the seasonal vaccine (as a way to elicit an antibody response) as well as a new vaccine that primes the immune system’s T cells against more permanent “core proteins” from all “influenza A” type viruses. Since vaccines generally work less effectively in the elderly, the hope is that a vaccine like this would jumpstart an immune response against the flu more effectively than just the singular seasonal vaccine.

The implications of all of this work extends beyond just combating the flu. “Whenever you learn something about one vaccine and the immune response,” says Fauci, “in one way or another it can help you in the broad field of vaccinology. That’s a given.” But Fauci emphasizes that influenza’s ability to mutate puts it on a different platform than other viruses. The measles vaccine, first introduced in 1963, is 98 percent effective, because it protects against the same measles humans have dealt with for several decades. There is obviously no such luck with the flu.

Still, that doesn’t mitigate what an astounding accomplishment it would be to find a cure to the flu, and put a dent into the 1 billion cases which occur around the world every year. Imagine just getting one shot to keep the flu away for the rest of your life. Beats the hell out of scheduling an appointment every fall and setting for an efficacy that averages to less than .500.