The Making of a Flu Vaccine

The Making of a Flu Vaccine

Inside the Australian Lab That Helps the WHO Try to Determine the Best Way to Stop the Virus

By Shirley S. Wang in the Wall Street Journal

Melbourne, Australia

The annual fight to keep the flu under control starts here.

Doctors are studying nose and throat swabs from flu sufferers sent from laboratories around the world, from Texas to the Solomon Islands. They are trying to predict which flu viruses will be most potent and common and should be included in the vaccine.

Scientists at the World Health Organization Collaborating Centre for Reference and Research on Influenza in Melbourne—one of six such centers globally—face an imprecise prediction process. This helps explain the vaccine’s varying effectiveness year to year. The U.S. Centers for Disease Control and Prevention said earlier this month that this year’s immunization may be less effective due to a mutation to a particular virus strain.

“We’re always playing catch-up with these viruses,” says Ian Barr, deputy director of the WHO’s Melbourne operation. “We have to crystal ball what’s happening and what’s going happen.”

In addition to studying flu viruses, the collaborating centers grow what are known as seed viruses for vaccine manufacturers, the first step in producing traditional flu vaccines in industrial-sized proportions. Most flu vaccines are inactivated forms of viruses that prompt the body to generate antibodies meant to fight an active flu bug in the body.

The WHO has spent more than six decades monitoring flu. Flu virus, which primarily infects the upper respiratory tract, is responsible for up to an estimated 500,000 deaths globally each year, the WHO says, including up to 50,000 people in the U.S., according to the CDC.

While vaccines for measles or polio are nearly 100% effective, immunizations against flu work moderately at best, topping out around 60% in the general population. Some years, like this one, they do far worse, experts say.

Only two flu-vaccine manufacturers are licensed by the Food and Drug Administration to produce the new, four-strain flu vaccine in the U.S. Seven makers produce a three-strain version. In the 2013-14 U.S. flu season, about 59% of adults and 42% of children and teens were immunized, according to the CDC. GlaxoSmithKline , one large flu manufacturer, expects to ship 27 million doses to the U.S. for this flu season, though it has the capacity to supply more if needed, a spokesman says.

That unpredictability stems in part from guessing which strains will circulate each flu season. Other factors include how few people are vaccinated. Many of those are elderly people with weak immune systems.

Flu viruses change quickly, making certain prediction nearly impossible. What is known is that the flu virus comes in three main types—A, B and C—though human infections mostly come from A and B viruses. Viruses of the A strain include the bird flus H5N1 and H7N9.

Viruses of the A strain are also more difficult to predict because they change more frequently and subtly. Previous versions die out more quickly, rendering the previous year’s vaccines less effective, said Martha Nelson, a research fellow who studies flu at the National Institutes of Health’s Fogarty International Center in Bethesda, Md.

In years where one type of A dominates, flu vaccines are about 50% effective. When there’s a mix of A strains, vaccines tend to be much poorer at protecting people, Dr. Nelson says.

The Melbourne center, along with those in Atlanta, Beijing, London and Tokyo, document which strains are circulating now in humans and forecast what that means for next season, how the bugs have changed and if any new strains have surfaced. (The sixth collaborating center, in Memphis, Tenn., focuses on human-animal virus interactions.)

When a virus’s genes mutate, scientists must figure out whether the mutations matter. Has the virus become more infectious or deadly? The biggest question of all: Will the current vaccines work against these strains?

Dr. Barr has worked on this riddle for 14 years at the Melbourne center. When samples come in, his team studies in a lab dish how human cells react to the virus. Do they recognize it as foreign and produce antibodies against it? How strong is the response?

Molecular biologists then sequence the virus’s DNA. They use this genetic fingerprint to map out a family tree of sorts, called a phylogenetic tree, a timeline of viruses and how they relate to one another. Each phylogenetic tree has so many spidery branches that often the virus names are too small to read without a magnifying glass. Dr. Barr keeps one handy in his office.

The scientists compare the sample virus to previous ones, or determine that it’s mutated enough to represent a new branch.

If a number of samples of the same strains come in, suggesting the virus is on the rise, the scientists pay closer attention. New viruses often start in China or Southeast Asia for reasons that aren’t clear. Climates that allow viruses to circulate yearlong in crowded conditions likely play a role. China also widely monitors for viruses.

The team then studies how a mutation affects the workings of the virus to develop tests to better study the new strains. Scientists examine human fluid samples, plus the immune reactions the virus causes when ferrets are infected with it. The animals pass it to each other and even sneeze and cough like people.

Each year, some eight months before the first patients roll up their sleeves for a flu shot, more than 20 experts meet at the World Health Organization’s Geneva headquarters to decide which virus strains the next season’s flu vaccine should protect against.

Ultimately, the recommendations come down to experts’ opinions about the data and nine votes in Geneva. The votes come from representatives of all six collaborating centers and other main WHO laboratories.

H5N1 first cropped up in 1997, and again early last decade, and has caused millions of poultry infections but only several hundred human ones. But for the past year or two doctors have been most worried about a rise in a type of bird flu called H7N9, which is silent in birds but kills humans. It could be dangerous if it started circulating widely, but “there’s no good reason at this stage to include them in seasonal vaccines,” Dr. Barr says. Seed viruses have been produced already in case this changes and a vaccine for it must be produced.

There’s also a practical consideration in recommending a vaccine update: Can the centers grow enough of the new virus for vaccine makers to make large quantities? Seed viruses are grown in fertilized chicken eggs. If there’s a problem with growing enough virus, scientists select a related or previous strain instead to recommend for inclusion in the vaccine. Scientists inject trays of eggs with the virus in sterile biosafety cabinets. Then they seal up each hole using a dab of glue from a pen that looks like what a child might use for an art project.

The overall accuracy of the WHO’s recommendations is difficult to determine because there are so many A strain viruses. Predicting B strain viruses in the U.S. and Europe has been little better than chance in the decade up to 2011, according to a 2012 study published in Human Vaccines & Immunotherapeutics.

Since only two B strain family viruses commonly circulate, doctors now recommend both for inclusion in the four-strain vaccine.

“Instead of saying, ‘Get your flu shot so you won’t get the flu,’ we should say, ‘The flu shot will cut your chance of getting flu in half, and if you get it, you’ll have a milder form of it,’ ” the NIH’s Dr. Nelson says.