The quest for a universal influenza vaccine has been a long and difficult journey for scientists. Each year, millions of people are vaccinated to protect against the severe respiratory illness caused by the influenza virus. However, the effectiveness of current vaccines varies, with protection ranging from 10% to 60% depending on the vaccine strain and season.
This discrepancy occurs because influenza viruses mutate rapidly, making it difficult to predict which strains will predominate each season. As a result, seasonal vaccines often fail to protect against the most virulent influenza strains.
Researchers are currently exploring innovative ways to create a universal influenza vaccine that provides protection against all types of viruses and could last for multiple seasons. One such effort, recently published in the Journal of Virology, offers new hope.
Researchers at the Cleveland Clinic’s Lerner Institute have made significant progress toward developing a universal influenza vaccine that has shown promising results in animal models. The experimental vaccine elicited a strong immune response and protected animals from severe infection after exposure to the influenza virus.
Diagram of ferret vaccine research. In the preimmune vaccine group, ferrets that had been exposed to A/California/2009 3 months previously were infected intranasally with A/Panama/1999 and B/Hong Kong/2001 60 days before vaccination. (Credit: ASM Virology Journal)
The research team, led by Dr. Ted M. Ross, director of global vaccine development at the Cleveland Clinic, is building on previous work to achieve broader protection. The group is using a cutting-edge technology called COBRA (Computationally Optimized Broadly Reactive Antigens) to design the vaccine.
COBRA analyzes thousands of genetic sequences of influenza strains over multiple seasons and determines which amino acids in the virus’ proteins remain consistent. By focusing on these conserved proteins, researchers aim to develop vaccines that target the most important parts of the virus that are less likely to change from season to season.
The research team identified proteins from several influenza subtypes, including H1, H3, H2, H5, and H7. These subtypes are important because subtypes such as H5 (avian influenza) pose a serious pandemic risk. Avian H5N1 influenza has previously caused human deaths, and the virus was discovered in dairy cows in Texas in March 2024.
Since then, the virus has spread to multiple species, affecting both humans and animals. This extensive coverage highlights the importance of developing vaccines that can protect against more than just common seasonal strains.
“This shows that our H5 vaccine covers many different clades,” said Dr. Naoko Uno, the study’s principal investigator. He explained that COBRA’s methodology allowed the team to “narrow down” the list of potential proteins to include only those most effective at eliciting a sustained immune response. The vaccines created are designed like a “greatest hits” album, containing only the best proteins to stimulate the immune system.
The vaccine was tested in animals by intranasal administration, a method that is gaining attention for influenza vaccines. Unlike traditional intramuscular influenza injections, intranasal administration targets the mucosal surfaces of the nose and respiratory tract, where influenza viruses frequently enter.
Octavalent COBRA vaccination induces IgG antibody responses in ferrets. (Credit: ASM Virology Journal)
This method not only induces a strong systemic immune response, but also stimulates local immune responses in the areas most vulnerable to the virus. After vaccination, the animals developed antibodies against the virus and were protected from developing a full-blown infection when exposed to the influenza pathogen.
This approach could significantly reduce the spread of the virus and make it difficult to spread from person to person. Additionally, intranasal administration is easier and less painful to administer than injections, which may improve patient compliance. As Dr. Uno explained, “This method may also be effective against other viral diseases such as dengue fever.”
Current influenza vaccines are made from inactivated or attenuated influenza viruses, most of which are grown in embryonated chicken eggs. Although these vaccines are effective, they have limitations, especially for older adults and immunocompromised people. Recombinant protein vaccines, like the one Ross’ group is developing, could be a better alternative.
Octavalent COBRA vaccination induces HAI antibody titers against pre-pandemic viruses in ferrets. (Credit: ASM Virology Journal)
These vaccines are not grown in eggs, which avoids egg-adapted mutations that could weaken the vaccine’s effectiveness. Additionally, recombinant vaccines have shown better protection against influenza-related hospitalizations in women, younger people, and people without high-risk conditions.
COBRA technology has the potential to revolutionize the way vaccines are made, not only for influenza but also for other diseases. By generating consensus sequences from thousands of virus isolates, researchers can create vaccines that provide broad protection against a wide range of strains.
Studies have previously shown that when COBRA-derived vaccines were administered intramuscularly to vaccinated mice, they developed protective immune responses against both seasonal and pre-pandemic influenza strains.
Most current influenza vaccines are administered by injection and stimulate a systemic immune response, but less so a local immune response in the respiratory tract. Intranasal delivery, on the other hand, provides strong local protection at the site where the virus enters the body.
Octavalent COBRA vaccination increases postvaccination serum NAI antibody titers in ferrets. (Credit: ASM Virology Journal)
This can significantly reduce the chance of infection and transmission. Vaccines delivered this way may also have practical advantages, such as reduced hygiene costs and ease of administration. However, for them to be effective, they must be formulated with an adjuvant, a substance that increases the body’s immune response to the vaccine.
Cleveland Clinic researchers are hopeful that human trials of a universal influenza vaccine could begin within one to three years. In the meantime, they continue to work with international teams in India and the European Union to advance the development of this promising candidate.
If successful, this vaccine could change the way we protect ourselves from influenza and help prevent future pandemics.
