Last year’s seasonal flu vaccine was a bit of a dud: It reduced a person’s risk of needing to see a doctor for the flu by only 23 percent. That wasn’t anyone’s fault really. Vaccines take months to make, and flu viruses are constantly mutating, so making the shots takes some guesswork. But what if doctors had a universal flu vaccine—one that worked for multiple years across multiple strains? Two new studies take them a small step closer to that goal.
Today, independent teams reported in Science and Nature Medicine how they’ve tinkered with a piece of viral protein so it can teach immune systems—in this case, in mice, ferrets, and monkeys—to fight whole groups of viruses rather than just a single strain. “It’s a great first step in the road for generating a universal flu vaccine,” says Gary Nabel, who oversaw one of the studies as former head of the National Institutes of Health’s Vaccine Research Center. (Disclosure: My father works at the vaccine maker Sanofi, which has since hired both Nabel and an author on the other study. Sanofi had no role in funding these studies.)
Influenza viruses are covered in lollipop-shaped proteins called hemagglutinin, which they use to sneak into cells. Get familiar with hemagglutinin, or HA, because I’ll be talking about it a lot. The immune system produces molecules called antibodies that bind to and neutralize the head of HA, which, inconveniently for humans, mutates over and over to escape detection. The HA head varies widely across different flu viruses, but HA’s stem tends to stay the same.
In 2008, scientists discovered unusual antibodies in humans that bind to the stem of HA in many different flu strains. This was an ah-ha moment. “We could protect not only against seasonal flu from year to year but also perhaps against other influenza viruses like bird flu or new strains emerging in the human population,” says Ian Wilson, a virologist at the Scripps Research Institute who co-authored the second study with colleagues at the Crucell Vaccine Institute, now known as the Janssen Prevention Center.
All they needed was a vaccine that elicits these antibodies. The problem? As long as the HA head is there, the immune system largely ignores the stem and doesn’t make broadly neutralizing antibodies. Nabel describes it like this: If you think of a virus coated in HA as a small planet covered in trees, the most visible parts are the heads of the HA, or the leaves of the tree. To see the trunk from up above, you have to chop off the leaves. But when you chop off HA's head, the whole protein falls apart—making the stem unrecognizable to that new class of antibodies.
So the scientists got to tinkering, starting with a H1N1 or swine flu virus. The team based at the National Institutes of Health designed self-assembling HA-stem nanoparticles, basically a stripped down version of HA held together with another protein called ferritin. The other team, mostly based at Crucell Vaccine Center, replaced and added several amino acids, which are the building blocks of proteins, to stabilize a mini-HA lacking a proper head.
Both HA proteins modified from the swine flu virus could protect mice infected with, importantly, a second strain (H5N1 or avian flu) from losing weight through illness. The nanoparticles also saved four out of six ferrets from dying of avian flu. (The untreated ones all died.) The mini-HA reduced fever in five swine flu-infected monkeys and elicited antibodies that could bind to the avian flu.
To be clear, neither group has created a truly universal flu vaccine, which would have to work against the entire dizzying array of influenza viruses. The highest level of classification divides the viruses into influenza A, B, and C; A includes all the biggest troublemakers. Within influenza A are group 1 and group 2, sorted based on which HAs are expressed on the viral surface. On top of that, sixteen different HA subtypes mix and match with nine subtypes of another protein called neuraminidase to create strains such as H3N2 or H5N1.
In both of these studies, the researchers began with a group 1 strain (H1N1 or swine flu) and tested whether its stem could induce immunity against another group 1 strain (H5N1 or avian flu). But creating a vaccine that would incite immunity against both group 2 and Influenza B would probably require engineering proteins to elicit different antibodies. “To be realistic, rather than calling it universal, it’s broadening protection,” says Nagel.
Still, that would be a great achievement. The current seasonal flu vaccine confers protection against two A strains and one B strain—it’s basically three vaccines that are made separately and combined. The process is inefficient: It takes nine months and uses up millions of eggs. A vaccine that protects against all A group 1 strains, made in one batch, may not be universal but it’s still a step up.
Alternative universal flu vaccine strategies exist, too. Two leading approaches target a viral ion channel protein called M2 or an internal protein called nucleoprotein. These proteins have the advantage of being more universal across flu viruses, but they also appear to confer less protection. That may be also true of HA-stem vaccine because the stem binding site is not as exposed as the head binding site. That’s the inherent tradeoff: The more specifically a vaccine targets a strain, the more effective the vaccine is against that strain and that strain only. If the virus strain mutates, the vaccine’s useless again. It's like putting all your money on one horse versus spreading it out across the field.
In any case, the HA research is coming up against its real test. “The real issue is what will work in humans,” says Peter Palese, a microbiologist at Mount Sinai. “Mice are not men, ferrets are not humans.” Palese has worked on creating HA vaccines using a third technique, which replaces the HA heads on a virus with a “stealth” head that the immune system totally ignores. That vaccine is entering clinical trials in the next year. A handful of other modified HA vaccines, made with earlier basic techniques, are in Phase I clinical trials, too. In the meantime, though, don’t forget your seasonal flu shot.