The flu kills over 250,000 people every year. Flu viruses change constantly, so they can evade our immune systems, the immune systems of other host species, and the vaccines we throw at them. Each seasonal vaccine can, at best, protect only against the current circulating strain of virus—but not emerging variants. (Just so we’re clear on this, YOU SHOULD STILL GET VACCINATED. Reread the first sentence.) And we currently have no way of knowing which strain might become a pandemic, or when or where such a strain might arise.

Making a universal vaccine, or at least one that could counter more than one subtype of the virus, is a priority. Efforts thus far have failed, because most of the proteins that are conserved between the different influenza subtypes are inside the virus rather than on its surface, which typically makes them tough for antibodies to access. But researchers have recently found a way to render one vaccine protective against a number of different subtypes.

Irony number one in this story: it hinges on the use of the immunosuppressant rapamycin. This drug is normally given to people who had organ transplants in order to reduce the chance that their immune system will reject the new tissue.

The researchers behind the new results immunized mice against one subtype of flu (HKx31). Along with the vaccine, some of the mice also got rapamycin, while others didn’t. Then all the mice were infected with a different, highly lethal flu strain (ΔVn1203). Fewer of the mice who got rapamycin with their initial vaccine died from this lethal strain. When they gave some of the mice rapamycin alone, without the HKx31 vaccination, the lethal flu strain killed just as many treated mice as controls—so both the virus and vaccine are required to elicit the protective effect.

The team performed the same experiment with the HKx31 vaccine and then two other lethal flu strains, and they got the same results. But when they used the HKx31 vaccine and later infected the mice with the lethal Sendai virus—i.e. not the flu—none of the mice were protected. Thus, rapamycin enhanced the protective effect of the HKx31 vaccine, expanding it so that it worked against three other flu subtypes.

Given that rapamycin is a known immunosuppressant, what on earth made them think that it might enhance the efficacy of a flu vaccine? Well, despite its immunosuppressive effects, rapamycin has been shown to promote the generation of memory CD8+ T cells. These cells cannot prevent flu viruses from infecting other cells, but they help get rid of infected cells and thus decrease influenza-related mortality.

Irony number two: the researchers picked the right drug for the wrong reason—that’s not how rapamycin is working here. It enhanced the protective effect of the HKx31 vaccine against ΔVn1203 even in mice that completely lack CD8+ memory cells.

So how does it work? The researchers found that rapamycin must be present for 15 days after vaccination for the protection to work. And, although CD8+ memory T cells were dispensable for this effect, CD4+ T cells were required—these activate B cells and turn them into antibody producing factories. The team speculated that rapamycin somehow modulates the antibody response induced by the vaccine. To test this idea, they took serum from mice that were given vaccine and rapamycin and injected it into untreated mice. The untreated mice were now protected against infection by ΔVn1203, supporting the idea that antibodies are involved.

It turns out that rapamycin worked by inhibiting a process called class switching. Antibodies have two parts: a variable region that recognizes a specific antigen, like a flu protein, and a constant region that defines its class. The first antibodies that are made upon initial exposure to a pathogen are called IgM class antibodies. As the infection progresses, any highly specific antibodies get upgraded into IgG class antibodies.

This upgrading of specific antibodies never happened in the drug treated mice. Rapamycin suppressed class switching, so mice that got it along with their vaccine had more IgM class antibodies, many of which tended to be less specific to HKx31. Irony number three: these less specific antibodies might not bind as strongly to the HKx31, but it is precisely this reduced affinity that may allow them to bind to the equivalent protein on other flu strains.

The authors suggest that using rapamycin may help make vaccines that are effective against multiple strains of flu or against multiple strains of other rapidly mutating viruses—like HIV.

Nature Immunology, 2013. DOI: 10.1038/ni.2741 (About DOIs).