Why Is It So Hard to Make a Universal Flu Vaccine?

Your annual flu shot protects you from some types of flu, usually the ones that got people sick the year before. But if a new strain of flu shows up, the shot may not work for it. That's why a holy grail of medicine is to create a universal flu vaccine.

A universal flu vaccine can't come soon enough, especially for particularly vulnerable populations, such as children, the elderly and the immune-compromised. More than 650,000 people around the world die of seasonal influenza every year, according to the World Health Organization. Seasonal flu also costs the U.S. healthcare system and society in general, a pretty penny, about $11.2 billion in 2018.

And those figures don't include the people who have contracted coronavirus, a disease with similar symptoms to influenza, which is caused by a different type of virus from the several strains of influenza virus. As of March 12, there were 125,048 cases confirmed and 4,613 deaths from coronavirus, according to the World Health Organization. Several companies are racing to develop a coronavirus vaccine.

So why is it so hard to develop a vaccine for flu, if the threat and impact are so great? It has to do with the fact that influenza is incredibly cunning. "You can hardly imagine a more promiscuous virus," says Dr. Greg Poland, spokesperson for the Infectious Diseases Society of America (IDSA) and professor of medicine and infectious diseases at the Mayo Clinic in Rochester, Minnesota, noting that trillions of new strains can develop in mere minutes. "Fortunately 99.999 percent don't have genetic fitness, they can't survive."

However, those that remain can pack a pretty serious punch. The survivors either experience antigenic shift or antigenic drift. Those that undergo antigenic shift morph into novel strains that can turn into pandemic-level flu, such as H1N1 and avian influenza. This hardly ever happens, with four influenza pandemics in the last 100 years, according to the Centers for Disease Control and Prevention (CDC).

By comparison, antigenic drift happens all the time with influenza, resulting in many small virus changes, which makes it tricky for vaccine developers to nail even the annual flu virus squarely on the head. "So, what happens is about a quarter of a million viruses are isolated every year and sequenced to give us an idea of what is circulating," Poland says. "It takes six months or so to develop and distribute the flu vaccine. By that time many of the strains have drifted to the point where they have next to no protection."

It's worth noting here that even a mis-matched vaccine is known to reduce the severity of symptoms and length of overall illness, so it's still important to get the vaccine annually. Better to be bed-ridden for three days than seven, or worse, end up in the hospital!

Indeed, there are multiple roadblocks to developing a universal influenza vaccine, but a number of biotech companies and academics are currently working to overcome them. "The whole idea is to develop broadly neutralizing antibodies," Poland says, noting that these antibodies would ideally protect against every influenza strain.

How the Influenza Virus Works

A lot of the problem in developing an accurate seasonal vaccine is that it changes so much, so fast. This issue is only compounded when developing a universal vaccine, as there are so many more changes to consider.

Simply put, the influenza virus is made up of H and N proteins and a stalk. Current vaccines attempt to hit the H and N proteins, which are what the virus uses to attach and infect human cells. The problem is that those drift and shift all the time. By comparison, "the stalk portion is relatively invariant," Poland explains. "So, the variant has been why don't we shift how we technologically make flu vaccines to the portion of the virus that doesn't drift and shift?"

Another complexity is that flu viruses only infect the outermost cells lining the respiratory tract. They don't replicate throughout the body, known as systemic replication. "If you look at vaccines that provide good lifelong immunity, like measles, one of the differences there is the kind of recall you get from a systemic infection is different and much better than the kind of infection you get in the superficial cells of the respiratory tree," explains Dr. Jeffery Taubenberger, virologist with the National Institute of Allergy and Infectious Diseases. "There's something we're not understanding about how immunity at the mucosal level sets up long-term immunity. This kind of protective immunity is hard to establish. We have to come up with ways to bolster the mucosal immune responses to give us better protection from these kinds of vaccines."

Advances in Flu Vaccines

Once this complex concept gets worked out, it could prove helpful in the development of universal vaccines for other respiratory ailments, such as coronavirus. "I think that once we understand more about immune response and memory response with mucosal infections with flu it would help vaccine efforts against those viruses as well," Taubenberger explains.

With any luck, one or more of the numerous vaccine development efforts currently going on will pan out. A version developed by the pharmaceutical company SEEK is about to enter phase III clinical trials, and Dr. Taubenberger's own team is hoping to start human clinical trials on their vaccine in 2020. Don't expect a universal flu vaccine to be ready too soon, though, as it's an arduous undertaking that requires a lot of trials to get FDA approval. "Typically it takes 10 or more years and it costs about $1 billion," Poland explains.