Universal flu vaccine protects against infection in mice

Annual flu vaccines protect against serious infections, but their effectiveness varies and they are not always adapted to the most virulent strains of the season. The implementation of a universal flu vaccine, which would protect people against all strains, and ideally for longer than a single season, remains a utopian dream.

Results published this week in the Journal of Virology Researchers at Cleveland Clinic’s Lerner Research Institute announced that their universal influenza vaccine, tested in animal models, elicited a strong immune response and provided protection against severe infection after exposure to the virus. This new work builds on previous, equally promising preclinical studies conducted in mice from the same group, led by Ted M. Ross, Ph.D., director of global vaccine development at Cleveland Clinic.

The researchers hope to launch human clinical trials within 1 to 3 years, said virologist Naoko Uno, Ph.D., who led the new study. “We want to make sure our vaccine can span multiple seasons, not just one, and protect against all strains that affect humans,” she said.

Scientists have identified four types of influenza viruses, but two of them—influenza A and influenza B—pose the greatest risks to humans. Seasonal flu vaccines contain proteins from three or four circulating subtypes of these viruses, including H1N1, H3N2, and IBV. But because the virus mutates so quickly, predicting which strains will pose the greatest risk—and thus which ingredients to include—is a guessing game.

Researchers in Ross’s lab designed their new vaccine candidate using a methodology called Computationally Optimized Broadly Reactive Antigens (COBRA). They began by downloading thousands of genetic sequences of pathogenic influenza strains, spanning multiple seasons, from an online database. They then digitally analyzed these sequences to identify amino acids (the building blocks of proteins) that are conserved across viruses and seasons.

The researchers identified groups of proteins for different subtypes. To develop a broader vaccine, Uno said, the group identified eight proteins from previous studies associated with a sustained immune response.

“We were able to narrow that list down and say these are the best ones that span multiple seasons and elicit a broadly reactive immune response,” she said. “It’s like creating a greatest hits album. We want to put only the best ones back into the vaccine.”

Among the biggest hits are proteins from influenza viruses such as H1 and H3, Uno said, but also proteins from H2, H5 and H7 viruses, which are strains that most people don’t have antibodies to. Some of these have pandemic potential, Uno added.

Previous outbreaks of avian influenza, or H5N1, have resulted in high human mortality rates, and in March 2024, the virus was discovered in dairy cows in Texas. Since then, four people who worked with cattle have been diagnosed. In addition, the virus has spread to dozens of herds in several states and to other species, including sea lions, birds, cats, and alpacas.

“We have shown that our H5 vaccine covers many different clades,” Uno said.

For the new study, Cleveland Clinic researchers administered the vaccine candidate intranasally. Blood tests showed that 4 weeks later, the animals had developed antibodies to the virus and that when exposed to the pathogen, they were protected from developing infection.

Ross is currently leading his group’s efforts to advance testing of the candidate in the United States, and Uno is collaborating with researchers in India and the European Union on an international effort.

Uno stressed that the COBRA methodology is not limited to finding and assembling recombinant proteins for influenza. It could be used to analyze mRNA or other biomolecules, she said, or explored to develop vaccines for viral diseases like dengue. “This can be used for many viruses,” she said.