Each year, millions head to their doctors' offices for a shot to protect them from the strains of influenza that keep many in bed sick come the winter months.
Simply developing that vaccine is a complicated process, involving guesswork, observation and even a trip to the farm.
The process actually begins in February, as scientists from the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) select the strains of flu virus they expect to be most prevalent in the upcoming year.
Typically they are chosen based on the most prevalent strains in the southern hemisphere during their flu season in the months prior, according to CDC spokesperson Arleen Porcell.
But as past years have shown, selecting the right strains is not a perfect science.
"There's a certain amount of science and a certain amount of art to it," said Stephen Morse, an epidemiologist at the Mailman School of Public Health at Columbia University.
According to Dr. Andrew Pavia, chair of public health committee of the Infectious Diseases Society of America and a professor of professor of pediatrics at the University of Utah, the vaccine has been a good match 18 of the past 21 years.
"Some years the predictions are not perfect," he said.
Because of the WHO involvement in the annual meeting, vaccinations are relatively standard everywhere during our flu season.
"Wherever you get it in the Northern Hemisphere, if it's been made properly, it will be identical," he said.
Banking on Three Viral Strains to Fight Flu
Ultimately, three strains of influenza virus are chosen for the vaccine: a variant of H1N1, a variant of H3N2 (both influenza A viruses) and a strain of the influenza B virus. Influenza A viruses are the strongest, and vary the most from year to year, while B viruses rarely make anyone but the most vulnerable people sick.
Influenza C viruses are not part of the vaccine, largely because they rarely vary and typically physicians think it would be better to just develop immunity from catching it, said Morse.
The influenza A viruses are named for their variants of hemagglutinin, a protein that helps the flu virus cling to cell surfaces, and neuraminidase, an enzyme that helps it separate from cell surfaces to move in the body.
H1N1 was the strain responsible for the influenza pandemic of 1918-19. It was dormant for many years before it resurfaced in the late 1970s. While the reasons remain unclear, many in the scientific community suspect that it was brought back from a strain someone had preserved in a lab.
H3N2 was responsible for the pandemic of 1968-69. Since no major pandemic has occurred in the past 40 years, H3N2 has remained the dominant strain of the virus.
"When you say you've got the flu... it's usually because of H3N2 circulating," said Morse.
The pandemic of 1956-57 was caused by the H2N2 strain. Since the H component of a flu virus changes more rapidly, the flu vaccine targets that particular protein.
But while the virus remains similar from year to year, some small variations in its structure enable it to slip by the defenses of whatever version the body might have encountered the year before.
"Over time, essentially what happens is that variants, mutants, appear that have an amino acid that has changed a little bit," said Morse.
For this reason, a new flu vaccine is required each season.
"Even if the vaccine were perfect... what comes out at the end of the season, as the virus circulates, are those that have essentially been selected out by the immune system. The ones that are left are to the ones to which we don't have a good immune response," he said.
Eggs Instrumental in Flu Vaccine Production
Once the strains have been selected, they are farm-raised in the finest eggs that can be found, much as they have been since the 1950s.
"The process for growing it is very much the same," said Morse.
The eggs must be fertilized and FDA certified that they are safe from infections and other pathogens.
"These are especially high quality," he said.
That raising technique also explains why it is sometimes hard to produce enough of the vaccine. Each dose of the vaccine requires three eggs--one for each strain.
"If they have to make more, it's often hard to get it," said Morse.
The hemagglutinin from the desired strain is grown on a version of the flu virus that is known to grow well in eggs. Once the strain has developed in the fertilized egg, it is purified and extracted and injected as part of the flu vaccine.
For the spray variant of the vaccine, FluMist, a similar process is used, although the virus itself is grown on an attenuated, or weakened, form of a flu virus, which is the reason why people who get the spray version of the vaccine initially have a runny nose.
Building a Better Flu Vaccine
But while flu vaccines have helped reduce rates of infection, they still have plenty of ways to advance.
"For some reason, the immunity we get to influenza is pretty good, but it's not wide-ranging," said Morse. "I wouldn't put all my faith in it, but I do get it every year, except in the case where we have a shortage."
Among the major changes on the way is the ability to grow the virus in cell cultures, rather than in eggs, a development which should enable manufacturers to make the vaccine in greater quantities.
As scientists combat the source of annual flu, many remain worried about the possibility of a pandemic, much like the ones in 1918, 1956 and 1968, that killed significant numbers of people.
Because the virus targets specific strains, and because immunity only develops to strains the body has encountered, a pandemic's source is going to be from an entirely new virus.
"In most cases, a pandemic strain is going to be quite different from what's already circulating."
But for all modern science has been able to tell us about the flu, it cannot tell us what strain is likely to cause the next influenza pandemic.
"It would have to be one that's essentially novel to most of the population," said Morse, noting that H2N2, which last struck before most of today's populace was born, is a potential candidate.
"We probably won't know until it happens, which is a sad thing to admit," he said. "So far, we've learned a lot, but we still can't do that kind of prediction."
But scientists are optimistic that changes in how we fight flu may help us fight it better.
Pavia points to a change in who gets the vaccine as a way of avoiding who gets the flu.
"The big change in the last 10 years has been the realization that vaccine works best in the people who are at less risk of complications," he said.
In this way, younger people can avoid catching a virus they might spread to elderly and at-risk populations, who are not as well protected by the vaccine.
"That's why this year we're pushing the vaccine for all kids under 18," he said.
Future developments, Pavia hopes, will allow us to use fewer proteins from an individual vaccine in the virus, allowing for a vaccine that will combat more strains. And with faster production speeds, manufacturers may be able to respond to new strains by making new vaccines during the flu season.
"Hopefully in the future they're going to lead to the ability to get a better immune response with much less vaccine," he said.