By Morgan Nwanguma
A nasal spray vaccine may be able to stop bird flu at its point of entry – the nose before the virus has a chance to spread through the body.
As bird flu continues to circulate in animals and occasionally infect humans, scientists are working urgently to prevent it from evolving into a virus that spreads easily between people. In recent animal studies, a newly developed nasal spray vaccine provided strong protection against the H5N1 strain, performing better than conventional flu shots. Because the vaccine targets the nose and lungs, it has the potential to block infection at its earliest stage.
H5N1 avian influenza, commonly known as bird flu, was first detected in the United States in 2014. Since then, the virus has expanded beyond wild birds, spreading to farm animals and eventually infecting humans. Since 2022, more than 70 human cases have been reported in the U.S., including two deaths. With the virus still circulating widely in animals, scientists warn that it has continued opportunities to evolve in ways that could enable easier human-to-human transmission, raising concerns about a possible future pandemic.
To help reduce this risk, researchers at Washington University School of Medicine in St. Louis designed a vaccine that is administered through the nose rather than by injection. Tests in hamsters and mice showed that the intranasal vaccine generated strong immune responses and protected the animals from infection after exposure to H5N1.
The researchers also tackled a major challenge for influenza vaccines. Immunity from previous seasonal flu infections or vaccinations can sometimes reduce the effectiveness of new flu vaccines. However, the team found that the nasal vaccine still worked well in animals that already had existing immunity to flu viruses.
The study’s findings were published on January 30 in the journal Cell Reports Medicine.
“This particular version of bird flu has been around for some time, but the unique and totally unexpected event where it jumped across species into dairy cows in the United States was a clear sign that we should prepare for the event that a pandemic may occur,” said Jacco Boon, PhD, a professor in the WashU Medicine John T. Milliken Department of Medicine and co-senior author of the study. “Our vaccine to the nose and upper airway, not the shot-in-the-arm vaccine people are used to, can protect against upper respiratory infection as well as severe disease. This could provide better protection against transmission because it protects against infection in the first place.”
Advancing Bird Flu Vaccine Technology
Although a vaccine for bird flu already exists, it was developed using older viral strains and may not provide strong protection against the current forms of H5N1. In addition, it is not widely available. To develop a more effective alternative, Boon and his colleagues turned to a nasal vaccine platform previously created at Washington University School of Medicine by study co-authors Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine, and David T. Curiel, MD, PhD, a professor of radiation oncology.
A COVID-19 vaccine based on this same platform has been available in India since 2022 and received approval for clinical testing in the United States last year (2025).
Designing an Immune Response That Matches the Virus
For a vaccine to be effective, the immune system must quickly recognize and respond to the virus it targets. To accomplish this, Boon and co-author Eva-Maria Strauch, PhD, an associate professor of medicine who specializes in antivirals and protein design, selected proteins from H5N1 strains known to infect humans. Using shared characteristics of these viral proteins, they engineered an optimized antigen – the part of the virus that stimulates an immune response.
The researchers then inserted this antigen into a harmless, non-replicating adenovirus, which acts as the vaccine’s delivery vehicle. This antigen-design strategy and adenovirus-based delivery system closely resemble the method used to create the COVID-19 nasal vaccine.
Strong Protection in Animal Tests
When the nasal vaccine was tested in hamsters and mice, it provided nearly complete protection against H5N1 infection. As expected, existing seasonal flu vaccines offered little defense against bird flu. In both animal models, the nasal spray vaccine delivered stronger protection than the same vaccine administered through a conventional intramuscular injection.
Importantly, the vaccine remained highly effective even at low doses and when the animals were exposed to large amounts of the virus.
Blocking Infection in the Nose and Lungs
Administering the vaccine through the nose triggered strong immune responses throughout the body, with especially high activity in the nasal passages and respiratory tract. According to Boon, this approach offers a key advantage over injected vaccines because it provides stronger protection in the nose and lungs – areas where the virus first establishes infection, potentially reducing both severe illness and the likelihood of transmission.
“We’ve shown that this nasal vaccine delivery platform we conceived, designed and conducted initial testing on at WashU Medicine can prevent H5N1 infection from taking hold in the nose and lungs,” said Diamond, the study’s co-senior author. “Delivering vaccine directly to the upper airway where you most need protection from respiratory infection could disrupt the cycle of infection and transmission. That’s crucial to slowing the spread of infection for H5N1 as well as other flu strains and respiratory infections.”
In additional experiments, the researchers investigated whether immunity from earlier flu infections or vaccinations might reduce the effectiveness of the H5N1 vaccine. Their results showed that the nasal vaccine still provided strong protection even when prior flu immunity was present. This finding is especially important for real-world use, since most people – aside from very young children – already carry immune memory from previous influenza exposure.
Next Steps for the Nasal Vaccine
The research team plans to continue testing the vaccine in further animal studies and in organoids that replicate human immune tissues. At the same time, they are developing updated versions of the vaccine aimed at minimizing the effects of existing seasonal flu immunity while strengthening the body’s antiviral response.
This research was assisted by the Cooperative Center for Human Immunology (U19AI181103) as well as the Center for Research on Structural Biology of Infectious Diseases (75N93022C00035).
The Boon laboratory got financial support from Novavax Inc to develop an influenza virus vaccine and dissimilar funding assistance from AbbVie Inc. M.S.D. is a consultant for or serves on the Scientific Advisory Board of Inbios, IntegerBio, Akagera Medicines, GlaxoSmithKline, Merck, and Moderna. The Diamond laboratory also got separate funding support via sponsored research agreements from Moderna.
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