Researchers have identified one more important reason flu shots don't usually work very well — it's because they are grown in chicken eggs.
Flu viruses mutate every year and it turns out the methods used to make flu vaccines cause them to mutate even more, the researchers found.
"How you prepare the vaccine can have profound effects on how humans respond to it," said Scott Hensley of the University of Pennsylvania, who helped lead the study.
It's one more reason the world needs to develop more modern methods of making flu vaccines, says Dr. Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases (NIAID).
"We need to get away from the antiquated production model, which the egg is," Fauci said.
It's not a big surprise that eggs are not a great way to make vaccines. Vaccine makers, doctors, immunologists and other experts have known for years that the way flu vaccines are made is slow, clunky and prone to errors.
However, Hensley and colleagues have shown specifically why, with a specific vaccine — last year's part of the flu vaccine that targeted H3N2 flu virus. That's the main strain that made people sick in the U.S. last year.
According to the Centers for Disease Control and Prevention, last year's influenza vaccine reduced doctors visits for flu by 42 percent. When people were tested specifically for flu strains, the vacine reduced H3N2 disease by just 34 percent.
Every flu vaccine is a cocktail, aimed at either three or four of the most common flu strains. It's reformulated every year, because flu viruses mutate constantly. That's one problem — the constant so-called drift of flu viruses that makes it hard to keep up with them.
The second problem is how flu vaccines are made. Most of them are grown in eggs. It's a slow and tricky process, one that takes weeks or months and that can go wrong easily.
And because flu viruses are so mutation-prone, the very process of growing them in eggs makes them mutate.
"Any influenza viruses produced in eggs have to adapt to growing in that environment and hence generate mutations to grow better," said Ian Wilson of the Scripps Research Institute in La Jolla, California
In fact, they won't grow at all unless they mutate, Hensley said.
"This has been a big problem for a while but it becomes a particular problem over the past few years," Hensley said. "H3N2 grows very poorly in eggs."
To make a flu vaccine, producers inject a "seed" virus strain into eggs and then incubate them as the virus grows. Then they purify the virus, and either weaken it or kill it to make a vaccine.
There are many different production methods and more than a half-dozen different flu vaccines on the market as a result. Only two on the U.S. market are not made in eggs: Flucelvax, which is grown in canine kidney cells, and FluBlok, which uses an insect virus called a baculovirus grown in caterpillar cells.
Hensley and colleagues identified several mutations that occur when the viruses are made in eggs, and report in Monday's issue of the Proceedings of the National Academy of Sciences that these mutations help make the flu vaccine perform poorly last year.
"This is a mutation that has never been seen before," Hensley said.
Most flu vaccines contain a piece of the flu virus and almost all of them aim at a structure called hemagglutinin, which helps flu viruses attach to the cells they infect.
This one makes the virus grow a big sugar compound on top of hemagglutinin, Hensley said. It stops the body's immune virus from responding to the vaccine.
This particular mutation showed up after 2014, Hensley said. Flu vaccines are still worth getting, he said. They prevent some serious illness from H3N2 and they still protect well against H1N1 and influenza B virus strains.
"It's much better to get the vaccine than not to get the vaccine," Fauci said.
These mutations don't explain why FluMist, the inhaled vaccine, failed to work well in recent years, Hensley said. Vaccine experts think it's related to a problem caused by growing virus in eggs, but it's not one of the new mutations. FluMist won't be available on the U.S. market again this year, much to the dismay of parents and pediatricians who like having a needle-free alternative to offer kids.
But the mutation may explain why Australia just had a particularly bad flu season, Hensley added.
Flu puts hundreds of thousands of Americans into the hospital every year, and kills anywhere from 3,000 to 49,000 people, including many young, perfectly healthy people. This year so far, one child has died from the flu, the Centers for Disease Control and Prevention reports.
So will the non-egg vaccines be a better bet for protecting people from flu? Hensley thinks so.
"We examined antibodies in humans that received the egg-adapted vaccines, and compared them to people who got vaccines made using insect cells. Sure enough, we found the vaccine prepared in insect cells produced better immune responses," he said.
"The solution in this case is fairly simple. We should basically be producing these vaccines through systems like that baculovirus."
Related: Caterpillar Vaccine Works Better
Fauci said there are many reasons why the industry still relies on methods developed in the 1940s, but he hopes studies like these will kick producers into the 21st century.
The best production methods wouldn't rely on growing a virus at all, but instead on quicker methods that just use a piece of genetic material instead.
Fauci sees two problems: the slow and unreliable methods used to make flu vaccines, and the vaccine target itself.
He and other infectious disease experts are hoping for a so-called universal vaccine —one that would protect against all flu strains even as they mutate, and maybe that even wouldn't have to be freshly given every year.
It's really important because every 20 years or so, a new pandemic strain of flu emerges and kills many more people than usual. When a nearly new strain emerges, no one or almost no one has any immune defenses against it and it affects more people and causes more serious disease.
The last one was H1N1 swine flu in 2009. It didn't cause a particularly bad pandemic, but still sickened millions more than usual. Flu experts are expecting a worse one at any time.
And with slow vaccine production methods, that usually means months before people are vaccinated.
"Every time there's a pandemic we always find we are behind the eight ball in terms of never getting the vaccine ready before it peaks," Fauci said.
Why haven't vaccine makers jumped all over the idea of making a better flu vaccine? For one thing, it's an uncertain market. Every year, the CDC says everyone 6 months old and older should get a flu vaccine, but every year, not even half of people do.