To create a flu vaccine, you have to peer into the future — or try to, anyway.
“It’s a bit of crystal ball gazing because, you know, these viruses have to be selected six to nine months before the viruses circulate in the community,” says Ian Barr, who leads a research team for the World Health Organization. “The main problem is the lag from when we see the viruses to when vaccines are available.”
This lag means the virus used to create the vaccine may not be the same virus that gets people sick when the shot is ready. Each time the virus replicates, its antigens — the surface proteins our immune system can recognize and develop immunity against — can change slightly, according to the Centers for Disease Control and Prevention.
So the vaccine manufacturing process is a race against the clock, which begins when the World Health Organization (WHO) and the U.S. Food and Drug Administration (FDA) each decide which four specific mutations of the flu this year’s shot should protect against. These four components, that make up the “quadrivalent” vaccine, are strains from both B-lineages and A-lineages — the two lineages of the flu that most commonly make people sick.
However, specific variations within these lineages can change from season to season, so the WHO and FDA have to decide which variations should be in this year’s vaccine.
“When the recommendations come out, you know that’s the starting pistol for all in the influenza business,” says Ethan Settembre, vice president of research at Seqirus, a vaccine maker that is a division of the Australian biotech company CSL.
There are several ways to make a flu vaccine; the oldest and still most common method is to use chicken eggs — a lot of them.
“We were taking delivery of 225,000 eggs a day, six days a week, six months a year,” remembers Rockefeller University biotechnologist Jill Horowitz, who worked at Pfizer when it developed flu vaccines.
The eggs are injected with the flu virus, which grows in the chick embryos, Horowitz says. After letting the virus grow in the eggs for several days, the manufacturers extract the virus from eggs. Then they halt its ability to replicate — generally done by adding formaldehyde or β-propiolactone, organic compounds which damage the virus’s RNA. Finally, they use a centrifuge to separate out the killed virus to make the vaccine.
Eggs are generally an effective way to quickly produce a lot of vaccines. But some viruses don’t reproduce well in the eggs. The H3N2 flu virus, for example, morphs on its own inside chicken eggs, which means the egg-grown virus may differ from the circulating virus by flu season, Settembre says.
The egg supply chain can also be problematic. When manufacturers depend on eggs, the timing has to be just right or the virus won’t grow correctly. Vaccine makers have to plan their egg orders in advance to have enough eggs at the right age. But if the virus recommendation is delayed, rescheduling orders for millions of eggs may be expensive and cause more delays.
These deficiencies don’t necessarily mean the egg method should be replaced, argues Richard Webby, who leads the Center for on the Ecology of Influenza in Animals at the WHO. But, exploring alternative manufacturing methods can help, he says.
Mammal cells can be used instead of eggs, so manufacturers don’t have to worry about timing an egg order. At Seqirus, for example, the flu virus is grown in mammalian cell cultures, which do the incubation work traditionally done in eggs — although at a higher cost. But mammal cells aren’t the only option.
The manufacturer Sanofi Pasteur uses insect virus cells to produce some of its vaccine doses. They grow the antigens — those surface proteins of the flu virus — by inserting flu genetic material into insect virus cells. The virus cells then prompt the creation of antigens. This way, manufacturers don’t have to worry about the genetic adaptation that occurs in eggs, according to Dr. David Greenberg, medical doctor and a vice president at Sanofi Pasteur.
However the flu antigens are prepared, once they’re ready, they are packaged into the flu shot. Those shots — over 162 million for the U.S. alone this year — are then shipped off to clinics, ready to be injected into your arm.
But the chase isn’t over after the flu shots are administered. By comparing the number of people who got the vaccine and still got sick to the number of people who received the vaccine but stayed healthy, scientists can estimate if the shot is working against circulating viruses.
Globally, the effectiveness typically varies from region to region and between different flu strains, according to Sheena Sullivan, an epidemiologist and flu specialist at the University of Melbourne’s Doherty Institute in Australia. H3N2 strains are often a problem because they tend to have the most genetic variation, she adds.
For H3N2, 50% effectiveness can be considered a success, according to Sullivan. “Even if a vaccine is only 40% effective, that’s still saving a lot of people from going to hospital,” she says.
Knowing the effectiveness helps the WHO and the FDA make their recommendations for next year. If effectiveness is particularly low, it means that the virus has won the race, and it’s time to pick a new strain for next season, according to Sullivan. In this way, monitoring data leads to small improvements each season.
The biggest improvement, however, would come from a vaccine that protects against all strains.
Many scientists are working on an improved flu vaccine. The University of Georgia recently received $8 million from the National Institutes of Health to create a better vaccine. President Donald Trump even signed an executive order emphasizing the need to move away from eggs and towards a universal vaccine.
So far, we don’t have a universal vaccine, but one candidate is undergoing clinical trials in elderly patients and results are expected by the end of 2020. It contains bits of antigen that are found in many flu viruses and theoretically offers protection against many flu strains.
“The holy grail, as everybody knows, would be a universal flu [vaccine] where it would protect you against all strains,” says Clement Lewin, a researcher at Sanofi Pasteur. But until then, he says, the task is to make incremental improvements to the current vaccine, “because while it’s good, in terms of it prevents a significant amount of morbidity and mortality, it can clearly be better.”