The History of the Flu Vaccine

Men receiving flu vaccine in 1968
Harry Todd/Getty Images

Vaccines have come a long way since Edward Jenner's famous 18th century experiment. Our great grandparents might have only received a single shot when they were children, but kids today are now protected against 16 different diseases and seven types of cancer. Perhaps the most important vaccine on the modern childhood vaccination schedule, however, is one that's recommended for everyone, every single year: the flu shot.

While the flu vaccine is just as crucial today as when it was first released, a lot has changed in its roughly 70-year history. As technology has accelerated, the vaccine has gotten safer and more effective—and with these advances, recommendations have evolved, too, expanding from select target populations to everyone over the age of six months. Here's how we got here.

Identifying the Virus

The flu virus was isolated for the first time in the early 1930s with a little help from some unwitting ferrets. People were still reeling from the 1918 flu pandemic that took more than 50 million lives and affected one in five people worldwide. Identifying the culprit behind this massive devastation was the first step to developing a vaccine to prevent it from happening again.

Staff from the Medical Research Council took mouth-washings (gargles) from human patients sick with influenza, filtered them so that no bacteria were present, and then introduced the resulting fluids—along with some samples of swine flu—into ferrets.

When the animals got sick, scientists noted how long it took to develop symptoms and whether a sick ferret passed on the disease to a healthy ferret occupying the same cage. Interestingly, researchers also discovered that after recovering from one disease, the ferrets appeared to be protected against other forms of influenza.

Wilson Smith, Christopher Andrewes, and Patrick Laidlaw published their findings in the Lancet and set the stage for the development of a vaccine.

Live Vaccines

A few years later, researchers in the USSR were the first to leverage this research to make a viable vaccine. They took a live version of the flu virus and passed it some 30 times through egg embryos. The replication process attenuated the virus as it adapted to an egg host, weakening it enough to be safe to give to humans.

Human trials were then conducted, and the vaccine was administered to factory workers in order to see if it could reduce absenteeism due to respiratory illnesses like the flu. While historical records show the vaccine to be effective, it’s important to note that the methodologies used at the time likely would not pass muster today. Regardless, derivatives of this vaccine would go on to be used for more than 50 years in what is now known as the former Soviet Union.

While research on flu vaccines continued in the decades following, it wouldn't be until 2003 that a live version of the flu vaccine would become available in the United States. The live attenuated influenza vaccine (LAIV) was administered as a nasal spray rather than an injection, providing an alternative option for kids and adults who were afraid of needles.

The LAIV proved to be more effective in older children and younger adults and so was recommended for those ages 2-49. However, after a few years of research showing the vaccine wasn't as effective as the flu shot, the recommendation was withdrawn, and now only inactivated and recombinant vaccines are recommended for use in the United States.

Inactivated Vaccines

In the 1940s, while the USSR was making and testing its flu vaccine, other countries like the United States and the United Kingdom took their own stab at developing a shot using a different technique using inactivated—or “dead”—versions of the flu virus.

 An estimated 1 in 67 soldiers died from flu during the 1918 pandemic, and developing a vaccine to protect troops was a priority for the U.S. government as it braced itself for World War II.

Like the Soviets, the flu virus was passed through egg embryos among other animal hosts, but U.S. researchers took advantage of advances in technology that were new at the time, like centrifugation and freezing and thawing the necessary fluids from chicken eggs. They also used two strains, not just one. The army rigorously tested their vaccine in thousands of volunteers, using pretty innovative techniques for the time, such as shielding both participants and researchers from knowing whether the vaccine or a placebo was administered—a now-common research technique known as a double-blind study. The lessons learned from this research would go on to inform future vaccine development, including the discovery that the virus strains can mutate over the course of seasons, and that protection from some strains doesn't guarantee protection from others.

Scientists would also later go on to discover new techniques that involved mixing and matching components of flu viruses to make more effective and safer vaccine strains—a process called genetic recombination that is still used today.

Recombinant Vaccines

While not all flu vaccines are made using eggs, many still are—leaving some individuals with severe allergies at risk of a reaction. This concern sparked a series of innovations in flu vaccine technologies. One of the most recent developments was the creation of a recombinant vaccine. This type of vaccine takes proteins created by the flu viruses that will likely be circulating that flu season and combines them with a different virus that will grow well in the laboratory. The viruses replicate and make more proteins in insect cells—not chicken eggs—and that protein is what researchers need to make the vaccine.

The process is much quicker than the traditional method of using eggs because it doesn't rely on egg supply or on using only flu viruses that grow well in eggs. This could mean a faster response time in the event of a deadly influenza pandemic in the future. So far, only one vaccine is available in the United States using this technology, and it was released in 2013.

Multiple Vaccine Strains

The first flu vaccine developed in the former Soviet Union was a monovalent—or single-strain—vaccine. At the time, only one type of flu had been identified: Influenza A. In the early 1940s, however, a second type of flu was identified that was fundamentally different than the first: Influenza B. When the U.S. military developed its inactivated vaccine, it included strains of both types to maximize protection. Years later, a third strain was integrated into the vaccine to protect against a second form of Influenza A, and in 2012, the first quadrivalent—or four-strain—vaccine was approved for use in the United States. Most flu vaccines in use today, however, are still trivalent, or three-strain, vaccines.

A Moving Target

Every year the flu vaccine formulation must be altered to adapt to the ever-changing influenza virus. Imagine your immune system is the police on the search for a fugitive. At first, they were told to search for a perpetrator in a blue coat. But over the course of the year, the perpetrator's coat faded in the sun, and months later, the coat is now light gray. If the police aren't updated on the changed appearance, they'll still be looking for someone in a blue coat—allowing the fugitive to evade capture. Because the flu virus and its various stains can change so rapidly, our bodies need a reminder of what to look for, so we can better prepare our defenses in the event of an infection.

The process of identifying which strains of the virus should be included in the next season's vaccine formulations often happens months in advance. Officials look at a wide variety of research, including what strains are circulating around the world, and how severe certain strains appear to be, and then they give that information to the vaccine manufacturers so they can start the process of mass producing the vaccine and be tested for safety in time for the flu season.

While the process of selecting the vaccine strains is research-based, it's impossible to tell the future, and sometimes the strains included in the vaccines don't match the viruses circulating when flu season comes around. When this happens, the effectiveness of the vaccine takes a hit. It's important to note, however, that even when the vaccine isn't a perfect match, it is still the best way to prevent hospitalization or death as a result of the flu. For example, the flu vaccine during the 2014-2015 flu season was estimated to be only 19 percent effective at preventing cases of the flu. But even with the relatively low success rate, vaccination during that season still prevented an estimated 1.9 million cases of the flu, and roughly 67,000 hospitalizations. This was despite an astonishingly low vaccination rate of less than 50 percent for adults under 65—far below the threshold needed to achieve herd immunity.

Recommendations

It's been a long time since the 1918 flu pandemic, but the virus is still one of the deadliest vaccine-preventable diseases in the United States right now—killing anywhere from 12,000 to 56,000 people every year. As data have been collected about the virus and its potential threats, recommendations have expanded to include more and more populations.

At first the vaccine was only recommended for people who were at an increased risk of complications from the flu, like adults over 65 or anyone older than 6 months with a chronic medical condition that affects the heart or lungs. Over time, however, it became clear that more people needed to be vaccinated in order to prevent death and hospitalization, so the recommendation was expanded to include young children and pregnant women. Then adults over 50 were added, and later, all children up to age 18. Because the flu kills so many people each year—more than all other vaccine-preventable diseases combined in the United States—the ACIP voted in 2009 to expand its recommendation to everyone over the age of 6 months.

Since that time, the flu vaccine has been the only vaccine universally recommended for people of all age groups and conditions. That being said, some individuals—such as those who have life-threatening allergies to a flu vaccine—should not be vaccinated, but those cases are extremely rare, and often an alternative vaccine formulation may be used to avoid adverse effects.

Future Developments

Because of the complex and dynamic nature of the virus, a universal flu vaccine is the holy grail of flu vaccine development. Research teams around the globe are furiously working on a vaccine that could—with only a single dose or series—provide protection against all kinds of flu strains and for a much longer period of time, making the need for annual flu shots a thing of the past.

Sources:

Barberis I, Martini M, Iavarone F, Orsi A (2016) Available influenza vaccines: immunization strategies, history and new tools for fighting the disease. J Prev Med Hyg. 2016;57:E41–46. 

Centers for Disease Control and Prevention. Influenza ACIP vaccine recommendations.

Hannoun C. The evolving history of influenza viruses and influenza vaccines. Expert Rev Vaccines. 2013;12(9):1085–94.

The History of Vaccines. Influenza. The College of Physicians of Philadelphia.

Continue Reading