Since it was first detected in the United States in 2014, H5N1 avian influenza, commonly known as bird flu, has jumped from wild birds to farm animals and then to people, causing more than 70 human cases in the United States since 2024, including two fatalities. The virus continues to circulate among animals, giving it the opportunity to develop the ability to spread among humans and potentially cause another pandemic.
To mitigate the risk of such an event, researchers at Washington University School of Medicine in St. Louis (WashU Medicine) developed an intranasal avian influenza H5N1 vaccine that elicited strong immune responses when tested in hamsters and mice, and prevented infections in exposed animals. Pre-existing immunity from prior seasonal influenza infection or vaccination could potentially diminish the efficacy of H5N1 vaccines, so the team also confirmed that their vaccine remained effective regardless of prior flu exposure.
“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 Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine. “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.”
Co-senior author Diamond and colleagues published details of their work in Cell Reports Medicine, in a paper titled “An intranasal adenoviral-vectored vaccine protects against highly pathogenic avian influenza H5N1in naive and antigen-experienced animals.”
“H5N1 avian influenza, a highly pathogenic strain of the influenza A virus (HPAI), poses a threat to the poultry and livestock industry and human public health,” the authors wrote, noting the potential for circulating H5N1 viruses to adapt to animal and human hosts. “Thus, it is critical to develop vaccines that mitigate the threat of a future pandemic of H5N1 and other related influenza strains.”
Although a bird flu vaccine already exists, it was developed based on older strains of the virus, may not be effective against current variants, and is not widely available. To create a new vaccine to better protect against bird flu, Diamond, together with co-senior author Jacco Boon, PhD, a professor in the WashU Medicine John T. Milliken Department of Medicine, and collaborators, leveraged the nasal vaccine technology developed at WashU Medicine by Diamond and co-author David T. Curiel, MD, PhD, a professor of radiation oncology. A COVID-19 vaccine based on their approach has been available in India since 2022 and was approved for clinical testing in the United States last year.
Strong immune responses depend on how well the body can recognize a pathogen. To develop the intranasal H5N1 vaccine, Boon and co-author Eva-Maria Strauch, PhD, an associate professor of medicine who specializes in antivirals and protein design, developed and tested in rodents a series of chimpanzee adenoviral-vectored vaccines encoding different H5 HA proteins from HPAI H5 viruses representative of those circulating bird flu viruses that had infected humans. The vaccines were delivered intranasally and intramuscularly. A control vaccine, ChAd-CTRL, lacked a transgene. “We developed a series of ChAd-vectored vaccines encoding the HA protein from distinct H5N1 clades and evaluated their immunogenicity and protective efficacy against currently circulating H5N1 strains in mice and Syrian hamsters,” the investigators stated.
Tests showed that the ChAd-Texas intranasally (IN) delivered vaccine provided near-complete protection against viral infection in hamsters and mice. In comparison, and as expected, current seasonal influenza vaccines provided little protection against H5N1 infection. Both animal models showed better protection against H5N1 infection from the nasal spray vaccine than from the same formula administered through traditional intramuscular (IM) immunization.
“Intranasal delivery of the ChAd-Texas vaccine elicits mucosal antibody and T cell responses and confers greater protection than intramuscular immunization,” the authors stated. Further, strong protection emerged even when the nasal vaccine was given as a low dose against a high exposure to bird flu. “High viral loads were detected in the lungs and nasal turbinates of ChAd-CTRL-immunized mice …” the team stated. “In contrast, ChAd-Texas immunization conferred near-complete protection, with virus titers barely detectable, even at the highest challenge dose …”
Nasal delivery of the vaccine generated a strong immune response throughout the body, especially in the nose and respiratory tract. A particular advantage of this compared to intramuscular immunization, Boon noted, is that it provides much better protection against infection in the nose and lungs and therefore likely protects against transmission as well as against severe disease.
In addition to testing the vaccine’s effectiveness, the researchers investigated whether existing immunity from other flu vaccines would negatively affect the H5N1 vaccine’s performance. They found that even with pre-existing immunity, the intranasal vaccine still provided strong protection, a critical feature if the vaccine is to be of practical use, since most individuals, except young children, have many prior immune experiences with influenza virus or vaccines.
“Prior seasonal influenza virus immunity did not impair antibody responses or protection conferred by IN ChAd-Texas vaccine,” the authors stated. “Collectively, our study provides evidence that an IN-delivered ChAd-Texas vaccine elicits robust systemic and mucosal H5-specific neutralizing antibody and T cell responses, conferring strong protection against contemporary HPAI H5N1 infection, even in the context of pre-existing immunity to seasonal influenza viruses.”
Boon said, “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. 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.”
The researchers said the next steps are to conduct additional studies of the vaccine in animals and in organoids representing human immune tissue, as well as to develop new versions of the vaccine that further minimize the effects of prior seasonal influenza infection and that promote greater antiviral responses. In their paper, the team concluded, “These results support the development of mucosally administered ChAd-Texas HA vaccines as an effective platform for HPAI H5N1 preparedness.”
