To reduce the risk of widespread transmission, researchers at Washington University School of Medicine in St. Louis developed a vaccine delivered through the nose rather than by injection. When tested in hamsters and mice, the intranasal vaccine triggered strong immune responses and prevented infection after exposure to H5N1.

The team also addressed a key challenge facing bird flu vaccines. Immunity from prior seasonal flu infections or vaccinations can sometimes weaken responses to new flu vaccines. In this case, researchers found that the nasal vaccine remained effective even in animals with existing flu immunity.

The findings were published Jan. 30 in 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."

Updating Bird Flu Vaccine Technology

Although a bird flu vaccine already exists, it was designed using older virus strains, may not work well against current versions of H5N1, and is not widely available. To create a more effective option, Boon and his colleagues relied on nasal vaccine technology previously developed at WashU 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 built on this same platform has been available in India since 2022 and received approval for clinical testing in the U.S. last year.

Designing an Immune Response That Matches the Virus

For a vaccine to work well, the immune system must be able to quickly recognize the virus it targets. To achieve this, Boon and co-author Eva-Maria Strauch, PhD, an associate professor of medicine with expertise in antivirals and protein design, selected proteins from H5N1 strains known to infect humans. Using shared features of these viral proteins, they engineered an optimized antigen, the portion of the virus that prompts an immune response.

That antigen was inserted into a harmless, non-replicating adenovirus, which serves as a delivery system for the vaccine. This method of antigen design and adenovirus delivery closely mirrors the approach used for the COVID-19 nasal vaccine.

Strong Protection in Animal Studies

When researchers tested the nasal vaccine in hamsters and mice, they observed near-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 provided stronger protection than the same vaccine delivered by a traditional intramuscular injection.

Notably, the vaccine remained highly effective even when administered at low doses and followed by high levels of virus exposure.

Blocking Infection in the Nose and Lungs

Delivering the vaccine through the nose produced strong immune responses throughout the body, with particularly high activity in the nasal passages and respiratory tract. Boon noted that this approach offers a major advantage over injected vaccines by providing better protection in the nose and lungs, which likely reduces both severe illness and the spread of infection.

"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 examined whether immunity from previous flu infections or vaccinations would interfere with the H5N1 vaccine's performance. They found that the nasal vaccine continued to provide strong protection even when prior flu immunity was present. This is an important factor for real-world use, since most people, except young children, already have immune memory from past influenza exposure.

Next Steps for the Nasal Vaccine

The research team plans to conduct further studies in animals and in organoids that model human immune tissue. They are also working on updated versions of the vaccine designed to further reduce the influence of prior seasonal flu immunity and to enhance antiviral responses.

This study was supported by the Cooperative Center for Human Immunology (U19AI181103) and the Center for Research on Structural Biology of Infectious Diseases (75N93022C00035).

The Boon laboratory has received funding from Novavax Inc for the development of an influenza virus vaccine and unrelated funding support 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 has received unrelated funding support through sponsored research agreements from Moderna.