Spreading across the globe among birds and mammals, even to unprecedented areas like the Antarctic, a new strain of H5N1 avian influenza A that appeared in 2021 has raised concerns about the virus’s threat to humans. While human H5N1 infections have only occurred sporadically since 1997, more than half of these cases have been fatal.

Among those alarmed by a possible future pandemic risk were the University of Pittsburgh’s Simon Barratt-Boyes, a PhD professor of infectious diseases and microbiology in the School of Public Health, and Douglas Reed, a PhD associate professor of immunology in the School of Medicine. The researchers created an improved model to test ways to prevent the disease. They’ve found some promise in seasonal vaccines—but also see potential in alternatives that could protect people very quickly should an outbreak in humans arise.

Animal models that mirror the pathology of fatal human H5N1 infection are crucial for studying the virus and testing disease prevention measures. However, Barratt-Boyes and Reed saw that macaques—a monkey often used as a model organism in biomedical research—that were exposed to lethal H5N1 through traditional inoculation of liquid in the nose and throat didn’t get sick.

Surprised that a deadly virus suddenly wasn’t deadly, Barratt-Boyes and Reed thought that exposure might come from inhaling the virus as an aerosol. “People are working with poultry, the virus, feathers and various things that are getting aerosolized,” explains Barratt-Boyes, who has a secondary appointment in immunology in the School of Medicine.

To mimic aerosol exposure, Reed used a vibrating mesh nebulizer with a glovebox biosafety cabinet. The device creates a fine mist by passing an electric current through a metal mesh, causing it to vibrate and separate any liquid traveling through it into tiny droplets.

As a mist, the virus showed its true nature. “In the immunological analyses, we saw a massive inflammatory response to the infection. And that’s almost identical to what’s been reported in humans,” says Reed.

That out-of-control immune response, called a cytokine storm, caused severe inflammation and damage to the barrier in the lungs between air and blood. In turn, that damage caused acute respiratory distress syndrome—a life-threatening condition.

Looking to use their model to test ways to prevent the disease, the researchers noticed evidence that people with prior exposure to seasonal flu had lower rates of avian flu infection. Barratt-Boyes and Reed wondered if they could mimic this protective effect in their model with an adjuvanted influenza vaccine, a seasonal influenza vaccine containing an additive that enhances the immune response.

In 2017, they were the first to develop a macaque model of severe disease. In a 2023 follow-up paper published in iScience, they reported that vaccinated macaques still got very sick, but the infection was no longer lethal when they were exposed to a lower dose of the virus.

While their results indicate that vaccines are possible, they hope to do even better. “One of the things we saw with SARS-CoV-2 was the use of monoclonal antibodies and antivirals, like remdesivir and Paxlovid, as potential therapies,” says Reed, who has a secondary appointment in infectious diseases and microbiology in the School of Public Health.

Barratt-Boyes and Reed are currently studying whether a monoclonal antibody that is protective against several viruses can also protect against H5N1 in their infection model.

Monoclonal antibodies provide rapid immune protection by targeting and neutralizing the virus, much like the protection babies receive from antibodies in breast milk . “You’d give them the antibody and they would be protected that day,” says Barratt-Boyes. Vaccines, on the other hand, require the body to generate an immune response, which could take weeks.

Says Barratt-Boyes, “The antibody that we’re working with at the moment could be used as a single dose at the beginning of a flu outbreak and protect for the season.”

Read more from the Winter 2024 issue.