The flu is going to be brutal this year. The Centers for Disease Control and Prevention is already seeing more cases than usual, and we've yet to hit peak flu season. To make matters worse, this year's flu vaccine is less effective than usual, thanks to decisions that were made nearly a year ago. Making the flu vaccine is like predicting the future, and predicting the future is hard.

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Flu vaccine production is a slow, old-fashioned process of growing viruses in chicken eggs. It hasn't changed much since 1940s. That's why flu vaccines have to be formulated months beforehand, and that's why the flu vaccine is less effective than usual this year. It's still worth getting a shot, especially if you're young, elderly, or otherwise immune-compromised; this year's dose protects against three out of the four strains it's targeting. But there's no guarantee it'll work, which is why we're seeing this:

U.S. influenza surveillance report for week ending Dec. 20th, CDC

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The reason influenza is so widespread this year comes down to the complexities of getting the flu vaccine just right. It involves a hundred million chicken eggs, and a dose of luck.

Flu Prognostication

Next month—while many of us are wheezing our way through this flu season—the making of next year's flu vaccine will begin. Each February, the World Health Organization identifies the three or four strains to include in the vaccine for the next year's onslaught.

The vaccine always includes a strain from each of three categories (H1N1, H3N2, influenza B) and sometimes a bonus fourth. (Most influenza vaccines protect against the first three viruses, though some will protect against all four.) This year, the WHO recommended the following four viruses for this year's flu vaccine:

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  • an A/California/7/2009 (H1N1)pdm09-like virus
  • an A/Switzerland/9715293/2013 (H3N2)-like virus
  • a B/Phuket/3073/2013-like virus
  • a B/Brisbane/60/2008-like virus

A network of labs working around the world is always on the lookout for new and emerging viruses year-round. These viruses are then tested against human blood serum; the ones that provoke the least immune response are the ones that are most novel and dangerous to the population.

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But flu viruses naturally mutate, which is, after all, why we have to formulate a new flu vaccine each year. This year, the H3N2 virus mutated faster than usual, so the vaccine we now have is less effective against the H3N2 virus that is circulating most widely. The new H3N2 was first detected in March of 2014, and it became common by September. And now it's too late to add it to this year's flu vaccines altogether, thanks to the decades-old process we use to create vaccines in the first place.

A Hundred Million Eggs a Year

Inside a Chinese vaccine factory. AP Photo/Greg Baker

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Eggs are cheap, plentiful, and packed with protein. This makes them good for breakfast and great for making vaccines.

The basic process is simple enough: A virus is injected into a fertilized egg, where the virus reproduces and reproduces and reproduces. After two or three days, each egg white contains millions of live flu viruses. The viruses are purified from the egg and killed with chemicals. Each dose requires one to two eggs, so vaccine makers need about a 100 million eggs for the 150 million doses of flu vaccines for the U.S. alone. In the end, what's left are particles of viral protein that make up the core of our flu vaccines. Our immune system learn to recognize these viral proteins, so when the live virus comes along, they know what to do.

This may not sound overly complicated; in fact, it may not even sound like it should take very long. But making a 150 million doses of vaccine is like piloting a huge, lumbering ship that can't easily change course. Where the time starts to mount are things like scaling up and ensuring safety, which you want to make darn sure of when you're dealing with live flu viruses.

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Here are two examples of what takes so long. First, the virus injected into eggs is not simply the virus you find off a street. Once the WHO has identified the strains for the year, it takes each strain and crosses it with a lab strain that was especially developed to grow well inside chicken eggs. The hybrid virus ends up with 1) the properties of the lab strain that makes it reproduce well in eggs and 2) the antigens—a type of protein—that identify it as of that particular strain. The making and testing of this hybrid virus takes about six weeks.

Second, the WHO also creates reference reagents, which is fancy way of saying a kit for making sure every vaccine comes out to just the right dose. Without getting too technical, reference reagents are made up of antibodies, molecules made by immune systems in response to a virus's antigens. How do we get the antibodies? By infecting sheep with the virus and extracting it from their blood. The WHO notes this is often a bottleneck for making vaccines and takes at least three months.

Beyond Eggs

The vaccine-egg industrial complex is massive and well-established, but it is, obviously, not without its drawbacks. There are currently a couple alternative flu vaccine making techniques that are a little bit faster. For example, flu viruses can also be grown in mammalian cells in petri dish or recombined with a different type of virus to grow inside insect cells. These vaccines are made in only relatively small batches, though, usually for people allergic to eggs.

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Further down the pipeline, scientists are trying even wilder ideas, like growing virus particles in tobacco plants or using a DNA production process. All of these processes could be faster and more flexible because they aren't dependent on a supply of fertilized chicken eggs. They are, of course, dependent on their own supply chains and necessary quality controls.

With the ever present threat of new avian or swine flu epidemics, public health officials are definitely worried about how long takes to manufacture a vaccine. That's little comfort for this year, though. And probably for the next few as well.

Image by Jim Cooke