Why We're Finally Closing In On a Game-Changing Universal Flu Vaccine

Flu season rolls around each year like clockwork, bringing with it the reminders to get your flu shot (consider this your reminder.) Every other vaccine requires a finite dosage and confers long-term immunity—it’s only the flu shot that must be taken annually.

While that may not seem like a big problem, having to get a vaccine annually is at best a hassle, and at worst a barrier. In fact, the U.S. hasn’t surpassed 50 percent flu vaccine coverage at any point in the past decade, according to data from the Centers for Disease Control and Prevention. Reaching 50 percent coverage is a critical threshold for herd immunity, which in theory prevents sustained transmission of the virus from occurring.

Within the past decade, the CDC estimates that the flu resulted in $10.4 billion in medical costs and between 12,00 and 61,000 deaths annually.

This is due to many reasons, including vaccine hesitancy and simple indifference, but a big one is barriers to access. Under the Affordable Care Act, health insurers must cover the cost of a flu shot, but that coverage can result in higher insurance premiums. People without insurance, meanwhile, must pay out of pocket for the shot.

While not a panacea, what if all you needed was one shot to be protected for life? That’s the theory behind a universal vaccine for influenza. Scientists have been researching the foundations of it for over a decade, yet recent advances have given experts renewed hope that a universal vaccine is within grasp.

“There is an urgent need to develop influenza vaccines that provide broader and more durable protection,” said Alan Embry, chief of the Respiratory Diseases Branch of the National Institute of Allergy and Infectious Diseases (NIAID). “Realizing a universal influenza vaccine is one of NIAID's highest priorities, and we believe it can be achieved with significant and sustained effort.”

Vaccines work by presenting our bodies with a weakened, inactivated, or partial version of a pathogen in order to prime our immune cells to be able to recognize and destroy the real deal. 

Proteins called antibodies are at the center of this equation: our immune systems make them from scratch, and they attach themselves extraordinarily well to other proteins on the surface of viral particles. Once they’re in place, immune fighter cells can recognize the virus’ presence and destroy it, but it takes weeks to produce an antibody that has high binding affinity to a given pathogen’s surface proteins as well as the antibody "factories" that make them at scale.

There are four different types of flu, named A-D, but influenza A viruses are the ones that cause pandemic flus and are the main targets of a universal vaccine. As defined by a 2017 NIOSH panel chaired by Anthony Fauci, a universal vaccine would be at least 75 percent effective against all influenza A viruses and confer durable protection for at least a year across all age groups, though a vaccine you’d take once is still the goal.

The surface protein on influenza A viruses that vaccines and our immune systems target is called hemagglutinin (Ha). Ha consists of a head and stem region, and our immune systems tend to generate antibodies that bind well to the head region, said Arup Chakraborty, a chemical engineering, physics, and chemistry professor at MIT who studies the immune response to pathogens. The reason flu shots are annual, he explained, is that the head region mutates rapidly enough so that last year’s antibodies won’t be able to target the Ha proteins found on this year’s flu.

Using the Ha protein, “it's almost like the virus is waving this flag and saying, 'Hey look at me,’ and the immune system does,” said Daniel Lingwood, an assistant professor in medicine at Harvard Medical School. “That's why it's a constant arms race, a game of cat and mouse.”

A universal vaccine, on the other hand, would propel our immune systems to produce antibodies that bind to a region that doesn’t mutate so quickly, such as the stem region of the Ha protein.

There are two main reasons why some flu vaccines are less effective than others, according to Embry: first, the World Health Organization holds an annual conference to predict which flu strains will be more prevalent in the upcoming flu season and make recommendations about the composition of the Northern Hemisphere’s flu vaccine, and sometimes their predictions are off. 

“A universal influenza vaccine would provide broad protection against all influenza viruses, so you wouldn't have to predict which virus was going to emerge,” he said.

Another entry point for error is the egg-based manufacturing process, which produces over 90 percent of flu vaccines. Flu strains that have been injected into chicken eggs can acquire mutations not present in the circulating strains they’re meant to represent, leading to a mismatch between the antibodies the vaccine helps people develop and the target proteins on the flu viruses. A universal vaccine would also carry the benefits of not having to be manufactured using chicken eggs.

There are a handful of vaccine candidates being tested in American and European clinical trials that target regions other than the Ha head, although to date, the trials that have been completed haven’t given “extremely positive signals,” according to Embry.

One new approach identifies vaccine candidate proteins using computational immunology, a burgeoning arm of research that uses computer algorithms to model the structures of proteins. Lingwood and Chakraborty were the senior authors on a study that took such a combined computational and experimental approach. Their paper, published in October in the journal Cell, modeled how the immune system mounts a response when given different pieces of a pathogen. Then, they applied their findings to engineer a vaccine and create a regimen that gave mice robust immunity in the form of “broadly neutralizing antibodies,” or ones that bind well to many subtypes of flu. 

In other words, Lingwood and Chakraborty's effort appears to be on the right path, albeit early along. 

Researchers aren’t completely sure why universal vaccine candidates that looked promising on paper did not live up to expectations in clinical trials in the past, but immunological imprinting may have something to do with their failures. Essentially, different people may have different levels of susceptibility to flu infection based on their first bout with the virus. Upon being reinfected with a similar strain of flu, the body may respond as if it caught the first strain again and produce antibodies that are less specific to the new infection.

“There's growing evidence that the first encounter we have with influenza might significantly impact our subsequent immune responses as we age,” Embry said. NIAID is currently supporting two cohort studies that will follow groups of children and track their first flu and subsequent infections.

Despite the challenges, Embry said that researchers are “very likely” to make strides within the next decade and move toward realizing universal flu vaccines.

New approaches such as computational immunology could help get us there. For years, researchers had treated vaccines and immunity like a black box, Chakraborty said. Computational approaches seek to explain how and why immunity develops, in order for researchers to have more control over it.

Other vaccine candidates are at various stages in preclinical and clinical trials, including a plant-derived vaccine that slightly improved protection to flu based on Phase 3 trial results published in November, and a nanoparticle-based one that is wrapping up a Phase 2 trial.

NasoVAX, a universal flu vaccine candidate that is a nasal spray, is also now being studied as a possible treatment for coronavirus infection. Altimmune, the company that manufactures the vaccine, plans to finish collecting data in early 2021.

Not only could the vaccine itself be useful for other viral infections, the process for developing a universal vaccine could also pave the way for others, especially against viruses that mutate rapidly. A prime example, according to Chakraborty, is the novel coronavirus.

“Complicated pathogens like HIV and influenza may be helpful if we someday have to think about pan-coronavirus vaccine.”