Inside the Making of the Flu Vaccine
An in-depth look at the CDC process. (It’s basically a high-stakes game of biological matchmaking.)
Toward the end of last year’s flu season — in about the middle of winter — flu experts noticed that the number of infections was not dropping, but picking up. A new virus seemed to be emerging, and it was making many Americans sick.
The virus was a type of H3N2 strain, and it started rapidly spreading among people in the United States before spreading into Europe, Canada, and South America. This put scientists worldwide who are tasked with determining what’s in the yearly flu vaccine on high alert. Did the flu vaccine for the 2019–2020 flu season need to be updated to protect against this new virus strain? The next flu season was still many months away, but it was time to scramble.
“Almost every year there is some kind of challenge,” says Dr. David Wentworth, a leading flu expert and chief of the U.S. Centers for Disease Control and Prevention’s (CDC) Virology, Surveillance, and Diagnosis Branch. “The thing about the flu is you have to be nimble.”
One of the trickiest tasks for public health experts worldwide is creating the annual flu vaccine. The number of people who get sick from the flu each year depends largely on how well scientists predict what strains of the flu will be circulating and match them with a successful vaccine. “The flu virus evolves so fast,” says Wentworth. “It’s important to update the vaccine when it changes significantly enough to warrant it.”
The process of identifying the “right” viruses and producing enough flu vaccine for the nation starts with year-round study of flu viruses globally and ends with millions of Americans being vaccinated, the CDC says. While the effectiveness of each year’s flu vaccine can vary, the vaccine still prevents millions of illnesses, tens of thousands of hospitalizations, and thousands of deaths every year in the United States. And this year, the new vaccine does contain a new H3N2 strain. Flu experts worldwide, Wentworth says, are always prepared for the unpredictable.
“We get kind of used to it with influenza because there are a lot of curveballs you need to respond to very rapidly,” he says.
Wentworth and the CDC’s flu team led Elemental through their process for making this season’s flu vaccine.
Step 1: Study the flu viruses year-round
How well the flu vaccine works in a given year depends partly on the match between the viruses used to make the vaccine and the viruses spreading among people during a given flu season. That’s why a year ago flu researchers started considering the newer H3N2 strain for this year’s vaccine. In fact, Wentworth and his team are already thinking about the vaccine for the 2020–2021 flu season.
“A lot of people around me, including my family, think I just work really hard a couple weeks before [the season],” says Wentworth. “But it’s actually a continuous treadmill where we are always trying to identify new groups of viruses, and then once we identify them, we track them.”
The CDC studies flu viruses that are spreading worldwide and making people sick, and based on that, the agency helps select which viruses should be included in the flu vaccine. The CDC may also look at how effective a vaccine is in the current season to determine if changes are needed for the next year. It was clear to the team last year that an H3N2 update was worth considering based on how many people were getting sick at the end of the season.
Scientists in more than 100 countries do similar surveillance for flu viruses year-round. This includes receiving and testing thousands of flu virus samples from people. These laboratories send some of the flu virus samples to one of five World Health Organization (WHO) Collaborating Centers for Reference and Research on Influenza, and the CDC is one of the five.
At the CDC alone, about 6,000 flu viruses undergo full genetic sequencing as a first step when they arrive, to better understand the viruses. A subset of 2,000 of those viruses will undergo further tests, the CDC says.
Step 2: Select the flu viruses
Twice a year, flu experts from the CDC and other labs review the results of global flu virus surveillance as well as clinical studies. They also look at what vaccine viruses are available for experts to use to make vaccines. This team of experts then recommends which specific flu viruses should be used to make vaccines for the upcoming season. Based on this recommendation, each country then makes its own decision about which viruses should be included in vaccines licensed in their country.
“There’s a lot of data that is worked through in the course of these discussions,” says Wentworth. “It’s rarely completely obvious to everybody what the selection should be until the meeting happens and all the data can be analyzed together.”
With multiple experts in the room, not everyone is immediately aligned on what the recommendations should be, but Wentworth says that’s part of what makes the process successful. “Sometimes after that there’s very rapid agreement on what should be done, and other times there’s a lot more discussion and more intricate looking into the data,” he says. “We are very critical of each other. You are trying to figure out how much you trust a particular piece of information because you are putting a lot of weight on it.”
The late H3N2 infections at the end of last year’s season underlined the need for more research. “There was such a problem with the emergence of that late last year that we delayed the selection of that particular group of virus [for the vaccine] for about three to four weeks,” says Wentworth. “That was the unusual feature of that strain selection.”
The specific viruses that the United States decided to use this year are:
- an A/Brisbane/02/2018 (H1N1)pdm09-like virus
- an A/Kansas/14/2017 (H3N2)-like virus
- a B/Colorado/06/2017-like (Victoria lineage) virus
- the Quadrivalent (four-component) vaccines also include a B/Phuket/3073/2013-like (Yamagata lineage) virus
“The interesting things about this year’s vaccine are it has a very recent H3N2 virus that’s representative of the significant disease last year, and it also has an updated H1N1 virus which is well suited to all the viruses that are circulating,” says Wentworth.
Step 3: Make a “candidate vaccine virus”
In order to make a flu vaccine, experts at the CDC need to develop so-called candidate vaccine viruses. These are flu viruses prepared by the CDC for manufacturers to use to produce flu vaccines. Part of the delay for this year was the need for the team to quickly create a candidate vaccine virus for the particular H3N2 strain.
According to Wentworth’s team, a good candidate vaccine virus is one that’s similar to the virus circulating in people. Viruses that are spreading among people — which are called “wild-type” viruses — are not directly used to make vaccines because they don’t grow well. The CDC and other partners take flu viruses and adapt them so they can grow faster and more efficiently in a lab. (Specifically, they need to grow better in eggs and cells — but more on that later.) The goal is to adapt the viruses without changing them too much. They need to be similar enough to the circulating wild-type viruses.
The CDC makes sure the candidate viruses they’ve created are similar to the wild-type viruses and then makes them available to manufacturers who start producing the vaccines. Every year the CDC produces about 50 candidate vaccine viruses, and only four are ultimately needed.
Step 4: Begin production of flu vaccine
There are three ways that flu vaccines are made in the United States: egg-based production (the most commonly used), cell-based production, and recombinant technology production.
More than 80% of flu vaccines in the U.S. are made using a 70-year-old egg-based process. Why eggs? Because the flu virus grows well in them and they are easily available. Manufacturers inject the candidate vaccine viruses into fertilized hen’s eggs and incubate them to allow the viruses to replicate. After several days, a virus-containing fluid is harvested from the eggs and a virus particle is purified. This process requires thousands of eggs and can take many weeks, if not months, to produce.
The cell-based method is newer and faster and has been used since 2012. In this process, the candidate vaccine viruses are grown in animal cells. Manufacturers can also use a “recombinant technology” method, which involves inserting genes from the flu virus into insect cells.
The CDC does not recommend one flu vaccine method over another. However, as Nature reports, President Trump recently signed an executive order to develop a strategy for wider use of the faster methods for seasonal vaccine production.
As a final step, the U.S. Food and Drug Administration (FDA) tests the vaccines, and then manufacturers can distribute them to customers, which include places like doctors’ offices and pharmacies.
How this may change in the future
A longer-term goal for flu vaccines is the development of a universal vaccine that would protect people from many flu strains at once, and would replace the need to create a new flu vaccine year after year. But for now, getting a traditional flu vaccine is important.
The CDC says that every flu season can be unpredictable and it does not yet know what kind of flu season is expected. What the agency does know is that the number of people who get sick from the flu usually starts to rise in October and November, and most of the time, peak flu activity happens between December and February. In some years the flu season can last into May.
No matter what happens this season, the vaccine will prevent millions of illnesses and severe diseases, says Wentworth. “People spend a lot of time worrying about exactly how it matches current virus strains, but what we know is that no matter what, it protects a lot of people and saves a lot of lives.”
It bears repeating: The best thing you can do to protect yourself and others from getting the flu is to get a vaccine.