P

eople grumble a lot about the shortcomings of the flu vaccine, which some years offers less protection than expected. (Warning: This year may be one of them.) What they may not know is that the source of at least some of the problems is a common item found in all grocery stores and many fridges.

The egg.

The overwhelming majority of flu vaccines are made from viruses grown in eggs. This production process is inexpensive and time-tested; flu vaccines have been made this way as long as flu vaccines have been made.

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But the process is not ideal — and it leads to issues that can undermine the vaccine’s effectiveness. Increasingly, experts are questioning whether the pros of egg production are worth putting up with the cons.

“We need to do a lot to improve existing vaccines. And getting away from eggs would be very valuable,” said Dr. Kanta Subbarao, director of the World Health Organization’s influenza collaborating center in Australia.

To produce flu vaccine, most manufacturers must grow lots of flu viruses, which are later killed or weakened before they are put into the vaccine. In all but a few cases, those viruses are grown in hens’ eggs.

But flu viruses must mutate — adapt — to grow inside eggs. Sometimes those mutations aren’t huge or aren’t on important spots on the virus and they don’t undermine the effectiveness of the vaccine. But when they are, the impact can be substantial. It’s as if the antibodies the vaccine generates are looking for Superman — but they encounter Clark Kent. The glasses, the suit, the tie confuse them; the antibodies don’t see Superman and the mild-mannered newsman as the same person and they don’t respond.

Researchers have known for a while that this can happen. In a study released just Monday, scientists said that the disappointing performance of the vaccine last year was the result of a mutation that developed when the viruses for the vaccine were grown in eggs. The upshot: The antibodies generated by the H3N2 vaccine didn’t adequately target the viruses that were making people sick.

STAT reporter Helen Branswell explains why it’s so difficult to predict the severity of the upcoming flu season. Alex Hogan/STAT

The H3N2 component in this year’s flu vaccine is identical to the one in last winter’s, so the vaccine could fail to provide strong protection again if H3N2 flu viruses are in high circulation this winter.

“To make a prediction about this flu season, it does appear if H3s do circulate, there will be this problem of this egg mutation,” said Scott Hensley, an associate microbiology professor at the University of Pennsylvania and senior author of the study, which was published in the Proceedings of the National Academy of Sciences.

Moving out of egg-based production would improve the performance of the vaccine, many experts believe.

“If you were to start now with a new vaccine for flu, would it be grown in eggs? No.”

Dr. Daniel Jernigan, CDC

Officially, the Centers for Disease Control and Prevention doesn’t have a preference for how flu vaccine is made — as long as the resulting product is safe and effective. But if you ask Dr. Daniel Jernigan, director of the CDC’s influenza division, if eggs are the future of flu vaccines, his answer is telling.

“If you were to start now with a new vaccine for flu, would it be grown in eggs? No,” Jernigan said.

The U.S. government office charged with preparing the country to deal with public health emergencies like flu pandemics has recognized the limitations of egg-based flu vaccine production for a while. For more than a decade BARDA — the Biomedical Advanced Research and Development Authority — has been working with manufacturers to encourage them to move some portion of production out of eggs.

Its funding helped foster development of the two flu vaccines on the market that aren’t made in eggs — FluBlok, a recombinant vaccine developed by Protein Sciences (recently acquired by Sanofi Pasteur) and Flucelvax, produced in the U.S. by the Australian company Seqirus.

The former is made of influenza hemagglutinin proteins — the main target of flu vaccines — that are generated by viruses that infect insect cells, while the latter is made of flu viruses grown in dog kidney cell lines.

(Any time flu viruses have to adapt to grow in the cells of a new host — as in the case of the dog kidney cells — there can be mutations. But the egg-induced mutations seem more problematic. “I think historically just what we know about putting flu viruses in cells versus putting them in eggs is that generally the stability of the sequence is greater in mammalian cells,” said Jacqueline Katz, deputy director of CDC’s influenza division.)

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Producing too much of the nation’s ​flu vaccine supply in a single medium is literally as dangerous as putting all your eggs in one basket — especially given that some of the flu viruses that threaten to cause pandemics, such as H5N1 and H7N9, infect chickens, either killing them or reducing egg production.

“When I look at a need to produce 600 million doses of influenza vaccine in a very short timeline of a pandemic, it’s going to be really important that we have all horses in the race. So eggs and cells and recombinant,” said BARDA Director Rick Bright.

“Some [flu viruses] might grow well in eggs and some well in cells, and some better in recombinant systems,” he said. “So that’s been part of our strategy to make more capacity available domestically and also to diversify this for the various unpredictable attributes of influenza.”

There are a few key hurdles for those interested in seeing more seasonal production move out of eggs. The first is that there isn’t much evidence yet that the vaccines produced in other mediums perform better than those made in eggs. Experts believe the FluBlok and Flucelvax may be more effective against H3N2 viruses this winter than the egg-based vaccines, but companies won’t be motivated to make what would be a very expensive production shift on belief alone.

In fact, some companies that had been working on cell culture flu vaccines abandoned the work. “There wasn’t convincing evidence that it was better so why would anyone spend extra money to buy that?” noted Dr. John Treanor, a flu vaccine expert at the University of Rochester.

“The business case was tough, and I think a lot of these enterprises did not make it partially because of that.”

To be clear, it’s not that these vaccines have been shown to be less effective or no more effective than vaccines produced in eggs. It’s that in the main, proof that they are better is sparse to date.

Researchers in the U.S., Canada, and parts of Europe conduct studies every year that estimate how effective flu vaccine was at preventing illness. But those studies are not enormous and most of the people in them would be getting flu vaccine produced in eggs, so teasing out an answer from that research may not be possible.

Manufacturers themselves could study the question, and in a very crowded flu vaccine market may actually have motivation to do so. The CDC’s Jernigan noted that a few years back Sanofi Pasteur, the largest supplier of flu vaccine, funded a trial that compared a high-dose formulation it wanted to sell to seniors against its regular vaccine. The high-dose vaccine was found to be more effective, and the company is allowed to target individuals 65 and older, the demographic most likely to get flu shots.

Studies that show convincingly that flu vaccines produced in cell culture or using other non-egg methods are better could lead the expert panel that counsels the CDC on vaccines, the Advisory Committee on Immunization Practices, to preferentially recommend those vaccines over vaccines produced in eggs.

“I think that kind of pressure — if there are preferential recommendations related to that — will drive change in industry,” said Dr. Danuta Skowronski, an influenza expert at the British Columbia Center for Disease Control and lead author of a study that showed an egg-mutation problem in the 2012-2013 flu season.

Others aren’t so sure the industry would be willing to make a major production shift, which would require manufacturers to conduct expensive trials, apply for new regulatory licenses, and build and certify new production facilities.

The vaccine triggers the immune system to create antibodies, preparing the body for viral battle. Alex Hogan/STAT

“It’s a pretty big manufacturing lift. Or at least regulatory lift,” Jernigan said.

The other hurdle is the fact that many in industry, government, and public health have their eyes on a bigger prize. Rather than a small change that might offer modest improvements to the performance of flu vaccines, they’re looking to a radical shift — a flu vaccine that offers long-term protection against most or all known flu viruses. It’s the Holy Grail of flu, the so-called universal vaccine.

“In some ways, the whole discussion now about universal or game-changing vaccine has somewhat shifted the landscape. Because now people are going to say, ‘Wait a minute. Am I going to invest in an intermediate stage of vaccine production … and do this kind of fix on the current vaccine as an intermediate stage or interim stage?’” said Michael Osterholm, director of the Center for Infectious Diseases Research and Policy at the University of Minnesota.

“This is where you’re talking about the business of vaccines as much as you are the science. The business of the vaccine has been in part why we haven’t seen the science further along. Everybody felt like they had a nice business model going with what they had.”

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  • “Some [flu viruses] might grow well in eggs and some well in cells, and some better in recombinant systems,” he said. Does he not realize that an egg IS a cell?!

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