For most people, getting a flu shot ranks just below dental visits and spring cleaning on the list of annoying annual chores. If Peter Palese, Adolfo García-Sastre, and Florian Krammer have their way, it could be taken off the list entirely.
Palese is the Horace W. Goldsmith Professor of Medicine (Infectious Diseases) and Professor and Chair of the Department of Microbiology at the Icahn School of Medicine at Mount Sinai, and he and his colleagues are developing a universal flu vaccine that, he says, “would protect against all different variants of the influenza virus, and would offer long-lasting or even lifelong protection.”
That would be no mean feat.
“There are four branches of influenza virus that are changing: two influenza A strains and two B strains,” says Palese. “As a result of this constant change, each year there is a different influenza vaccine, containing either three or four components; and every year, at least one will change.”
How is it possible to protect against a virus that doesn’t yet exist? By looking for the parts that don’t change, says García-Sastre, Professor of Microbiology and Medicine (Infectious Diseases) and Director of the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine.
“The current vaccine is actually very good at inducing response to the variable regions of the virus,” says García-Sastre. “But there are other parts of the structure of the virus that remain unchanged, or conserved. Our idea for the universal vaccine is to induce antibodies against the conserved areas.”
The flu virus resembles a ball with little mushrooms sprouting all over it; the mushroom-shaped proteins are called hemagglutinin, and they are responsible for helping the virus particle bind to and fuse with the targeted human cells. “Each hemagglutinin protein has a head and a stalk. What we realized is that the changes, or variability, occur on the head,” says Palese. “The stalk of the protein is more stable, so we are making antibodies against the stalk.”
With recent advances in genome sequencing, the team was able to more clearly assess the molecular structure of influenza’s various surface proteins, including hemagglutinin. “Taking advantage of techniques developed at Mount Sinai, in particular, about the reverse genetics of influenza viruses, we were able to synthesize in the laboratory vaccine constructs,” Palese says. “When given to different animal models, those induced long-lasting protective immune responses against different influenza challenge viruses.”
García-Sastre, Palese, and Krammer, an Associate Professor of Microbiology at the Icahn School of Medicine, are now testing their vaccine in phase I/II clinical trials. “The first thing we need to demonstrate is that there are no adverse effects,” García-Sastre says. “The second thing we need to prove is efficacy—that the vaccine is effective not only against the current strains, but others, including future strains.”
Another effort, funded by a grant from the Bill & Melinda Gates Foundation and conducted in collaboration with the global health research organization PATH, is placing a live-attenuated vaccine into a phase I trial that Palese, Krammer, and García-Sastre helped design. “Whereas we are mostly working with an inactivated vaccine, in which the virus has been grown in embryonated eggs and then killed, the trial funded by the Gates Foundation uses a different platform: a live-attenuated vaccine, which delivers pathogens that are still alive but weakened,” says Palese. “While the CDC recommends inactivated vaccine for most population groups, the live-attenuated vaccine is cheaper to produce and deliver—and less painful. Instead of being injected with a needle, this vaccine would be delivered via a nasal spray.”
How close is the universal flu vaccine to becoming reality? “Our initial findings are promising, but we still need to conduct phase II and phase III trials,” says García-Sastre. “Hopefully, the vaccine could be ready in five years.”
Whenever it arrives, García-Sastre says, “The impact of a universal influenza virus vaccine will be enormous. Influenza is one of the biggest killers in the world, taking between 291,000 and 646,000 lives a year, and during pandemic years, it is even worse. A universal flu vaccine could reduce the huge costs associated with responding to and treating influenza; and most importantly, it could save millions of lives.”
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