A lifelong flu shot moves closer

A universal flu shot is one of immunology’s great quests. Each year scientists race to work out which flu strains will tear around the globe, then make a vaccine to protect against them. If they’re wrong, thousands of people could die. Why can’t the flu be more like measles, which is quashed for life after two childhood jabs?

Nicholas Heaton and colleagues at the Mount Sinai Hospital in New York have tweaked the measles genome to work out why the virus is so much easier to vanquish by vaccination than the flu. Their high-speed gene mutation technique, published in Cell Reports, could take us a step closer to a one-size-fits-all flu shot.

“What’s cool about this study is they were able to quickly mimic in the lab what happens naturally,” says Melina Georgousakis, a University of Sydney public health researcher who used to design vaccines.

Viruses infect living cells in order to replicate. To gain access to a cell they use spiky protein “keys” on their surface to unlock their target and inject it with their genetic material. Once the viral genes are in, they commandeer the cell to start replicating and building new viruses. These eventually bust out and the cycle begins anew – potentially making you quite sick in the process.

The flu’s key is a mushroom-shaped protein called influenza haemagglutinin. The lock is a small sugar on the host cell called sialic acid. Sialic acid hangs off many different types of proteins all over the cell membrane. Once haemagglutinin latches on it acts like a grappling hook, pulling the virus close before springing open the host cell’s membrane so that the virus and its target fuse and the viral genes pour inside.

Measles uses a slightly different technique. It needs two keys to open a larger, more complicated protein lock. The first key is the measles version of haemagglutinin, which latches on to its intended host. The second key, a fusion protein, allows the viral particle to fuse its membrane to the host.

To see how flexible the measles keys were, Heaton’s team genetically “bent” parts of them using a high-speed experimental technique called insertional mutagenesis, which inserts bits of DNA throughout the virus’ genetic code. They then measured how well the mutated viruses infected cells in a petri dish.

They found that if either of the measles virus keys is bent, even a little, access is denied. Any change to the genes coding for measles haemagglutinin and fusion proteins rendered the virus virtually useless at infecting cells.

The flu virus on the other hand only needs one key, which happens to open many locks quite easily even if it gets bent or broken. The measles vaccine trains the body to produce antibodies that recognise the virus’s keys. As the virus can’t change the shape of the key to dodge the antibody, the  measles vaccine bestows lifelong immunity. But the flu jab is an annual affair.

Flu haemagglutinin comes in at least 18 different subtypes. Each is a bit like a mushroom with the same “stalk” but distinguished by a different “head” – vaccines target the head. An added complication is that another flu protein called neuraminidase also comes in multiple subtypes. Flu viruses are named for the type of haemagglutinin and neuraminidase they have. Avian flu, for example, is H5N1. “The predominant antibody response is against the haemogglutinin,” says Nicole La Gruta, an immunologist at the University of Melbourne. “But to really cover your bases it’s best to target both haemagglutinin and neuraminidase, rather than just one.”

It can take up to six months to make a vaccine that targets a new haemagglutinin and neuraminidase combination, so scientists must try to predict which strain of the virus will spread well in advance of each flu season. And La Gruta points out that the insertional mutagenesis technique isn’t limited to flu research – it could be used to identify vaccine targets in new viruses too.

So if measles is not a particularly adaptable virus, how has it lasted for thousands of years? “That’s the million dollar question,” Heaton laughs. “We don’t really know.”  The contagiousness of the disease might be a factor. Even though measles is a one-off infection, it spreads more easily than the flu – a patient with measles typically infects around 18 others, while someone with the flu usually only passes it on to two people.

In the quest for a universal flu jab some scientists – including Heaton’s mentor Peter Palese – are targeting the “stalk” part of the haemagglutinin protein which is common to all subtypes, rather than only its mutable “head”. Using the same insertional mutagenesis technique, Heaton’s team has already shown that if the stalk is bent out of shape the virus is denied entry to the cell.

But the immune system doesn’t see the stalk – only the head – so “the goal is to make it visible”, Heaton says. “Then you could make flu act like measles.”

And the yearly flu jab could finally be a thing of the past.