University of Melbourne immunology researchers Brendon Chua and David C. Jackson have been working together for 10 years on how to build a better vaccine. Their close collaboration sometimes results in them finishing each other’s sentences. But now, it has also resulted in a multi-tasking, powerhouse of a flu vaccine. At least in mice, that is.
When I got a flu shot in my arm a few weeks ago, it did what every seasonal flu vaccine does each year: it caused my body to produce neutralizing antibodies against the three flu strains predicted to be a nuisance this winter. Although this is my best protection against the flu, which kills more than a quarter million people each year, it won’t protect me if those predicted strains are not the ones circulating the globe or if a novel flu strain arises. It also won’t protect me if a flu virus evolves to jump from another species into humans, such as how the recent H5N1 bird flu did.
For years, Chua and Jackson have studied a vaccine additive, or adjuvant, that they suspected could provide that crucial cross-protection against other virus strains that would be key during a global pandemic. “A vaccine strategy that provides you with protection across different strains would be beneficial for the whole community,” says Chua. “That would be the holy grail.” (image: Brendon Chua (left) and David C. Jackson working together at the The Peter Doherty Institute for Infection & Immunity at University of Melbourne.)
The adjuvant is a synthetic lipopeptide—just a string of a few fatty acids and a few amino acids mimicking a component derived from the outer membrane of a pathogenic mycoplasma bacterium.
“Broadly speaking, adjuvants are things that have been found to jazz up the immune system against the vaccine antigen they are added to,” says Jackson. “Our adjuvant is a molecule that is a known danger signal that activates the innate immune system to say, ‘Get going and get the SWAT squad out here!’”
Specifically, the adjuvant activates the Toll-like receptor 2 (TLR2) on innate immune cells. Innate immunity is the body’s first line of defense activated within the first few days or so after encountering a virus. After that time, adaptive immune responses kick in. These are the responses that produce both neutralizing antibodies and T cells that identify and kill flu-infected cells.
Current inactivated flu vaccines work by stimulating antibody production. So Chua and Jackson wanted to test if their adjuvant could stimulate more varied immune responses that would offer boosted and cross-strain protection.
In a paper published in mBio (http://mbio.asm.org/content/6/6/e01024-15) this week, they show that, indeed, when they add their adjuvant to an inactivated influenza A vaccine, it protects mice better than the vaccine alone. Mice that received the adjuvanted vaccine and were infected 3 days later with the strain used in the vaccine or with another strain not present in the vaccine, had much lower levels of flu virus in their lungs.
Mice that received adjuvanted vaccine also survived a normally lethal dose of virus. The researchers showed that this was mediated through the TLR2 receptor, because mice lacking this receptor had no protection. A low-dose of the adjuvanted vaccine also produced more neutralizing antibodies in the blood and, more importantly, induced T cells in the lungs and lymph nodes compared to a low-dose of vaccine alone.
Even more impressive, those T cells also appear to provide cross-protection. Mice that received the adjuvanted vaccine and challenged 35 days later with a flu strain not present in the vaccine had significantly lower levels of virus in their lungs compared to mice that received vaccine alone. No protective antibodies against the newly encountered virus strain were present in these mice, indicating that the protection was due to clearing of virally infected cells by T cells.
“With this vaccine and adjuvant of ours, we get both an antibody and a T cell response that can protect against infection,” explains Jackson.
That T cell response, and the subsequent ‘memory’ T cells that form, are key to providing cross-protection against novel flu strains not present in the vaccine. These T cells recognize infected cells expressing a viral protein called nucleoprotein, which is conserved across most flu strains. When these memory T cells are re-activated, they react more strongly and swiftly.
Finally, the researchers showed that the adjuvant reduced transmission of the different, unmatched flu strain as well. Infected mice that had received the adjuvanted vaccine transmitted less of the virus to their unvaccinated cage-mates that they hung out with for 2 days. Perhaps because they are clearing the virus better, “they are transmitting less virus to their mates,” says Chua, using the Aussie slang for friends. In contrast, the mice that received vaccine alone transmitted high levels of virus to their unvaccinated buddies 60% of the time.
“The biggest advantage to this approach is that it doesn’t rely on getting a match between the vaccine strain and the circulating virus—it can still give some protective effect at the population level,” says Chua. In addition, the adjuvant comes with two other practical advantages: it can be added directly to pre-existing vaccines and it can reduce the amount of vaccine dose needed—both extremely useful during a worldwide pandemic.
Chua says he and Jackson can envision the adjuvant being used as a stop-gap measure if an outbreak were caused by a virus strain that humans don’t have immunity against.
The team has also been working on cancer vaccines and hormonal vaccines that rely on similar adjuvants. But they’ll have to move out of mice and into man, Jackson says: “The job we have in front of us now is persuading a pharmaceutical company to take it through clinical trials and to market.”