There are exceptions though. Some parts of HA are almost always the same, no matter the strain or subtype. They are hard to mutate without compromising the entire protein. But since these conserved regions are found on inaccessible parts of the protein that the immune system cannot reach, it’s hard to make antibodies against them. Hard, but not impossible.
In 1993, Japanese scientists isolated an antibody from a mouse that had been immunised against H2N2 flu. It protected against viruses from the H2 subtype, but also those from H1, H5, H6 and H9. Fifteen years later, other teams found similar “broadly neutralising antibodies” in human patients. The most exciting of these was discovered in 2011 by a group led by immunologist Antonio Lanzavecchia at the Institute for Research in Biomedicine in Bellinzona, Switzerland. Known simply as F16, it’s a super-antibody that binds to all 16 types of HA that were known at the time (the 17th was only found last year).
But F16 isn’t a vaccine in itself. You cannot mass-produce it and inject it into healthy people - their immune systems must learn to make the antibody for themselves. “The good news is that we know where to target and we know human antibodies have done it,” says Wilson. The next step is to design molecules that mimic the part of HA that F16 recognises, to stimulate the immune system into making similar antibodies. “You want it to look like what it does on the virus, but much more exposed,” says Wilson. “You want to focus the immune response on that particular area.”
Another approach might be to display natural HA molecules in a more accessible way. Gary Nabel, formerly at the US National Institute of Allergy and Infectious Diseases, did it by fusing HA molecules to ferritin, a protein that naturally assembles into spheres. Twenty-four of these fused proteins will spontaneously merge into a ferritin ball with eight HA spikes protruding from it. These spikes are far more accessible than they would be on a real flu virus, where some 450 HA molecules are crowded together alongside other proteins. For this reason, the ferritin particles raise 10 to 40 times more antibodies against flu than licensed vaccines, including ones that recognise the HA stem and protect against many strains.
Meanwhile, other scientists are trying to create universal flu vaccines by tapping into a different branch of the immune system. During a bout of flu, our bodies produce swarms of defenders called killer T-cells, which destroy infected cells. These swarms can counter a broad range of flu viruses but they’re short-lived. Once their job is done, they die off. “To a certain extent, we produce universal protection, but it doesn’t last long,” says Gilbert.
But our immune system doesn’t suffer from total amnesia. A type of immune cell called central memory T-cells lurks within our lymph nodes, carrying a record of infections past. They can generate fresh squads of killer T-cells if we get infected by an old virus. Unfortunately, this response is slow and flu is fast. Infections can come and go before T-cell reinforcements are summoned. “The central memory T-cells are very good for mopping up and helping with recovery but they don’t prevent illness,” says Gilbert.
Gilbert’s approach is to rouse the memory T-cells ahead of time, creating fresh T-cell patrols that can guard against incoming viruses. Her vaccine uses two of a flu virus’ most common proteins—NP and MP1. These are smuggled into a cell by a different virus that cannot make copies of itself. The cell never dies, but it looks like it has been infected by a flu virus. In small, preliminary trials, Gilbert’s team showed that the vaccine is safe and boosts T-cell numbers by 10 times. Unlike licensed vaccines, it’s just as effective in older people as it is in the young. “That’s not surprising,” she says. The current vaccines force the immune system to mount a fresh response every year - an ability that falters with age. “We’re trying to boost memory that already exists.” Now, they have to check whether this protects against fresh flu infections, and how long this protection lasts for.
Even if this vaccine works, it won’t last for life. The T-cell army will have to be continually reinforced by stimulating the memory T-cells again and again. You cannot just give someone one or two shots as a child and expect them to be protected indefinitely. “You’d have to get it regularly, but not every year,” says Gilbert. “I think if we got to the point where you needed to vaccinate every 5 years, we’d be doing very well.”