At any time, there are dozens of different strains of influenza virus infecting birds and animals around the world. Now and again, one of them makes headlines after jumping into humans. Most recently, that’s H5N1, which has been circulating in wild birds since the 1990s with periodic jumps into other species, including humans. In 2024, it jumped into cattle, surprising many scientists, and soon into other mammals, humans included. 

Since the start of 2024, only around 100 people have been infected globally, and the virus isn’t currently able to spread between people. But the planet-wide spread of H5N1 among birds and the jumps to mammals, combined with reduced funding for infectious disease research and vaccine development in parts of the world, are keeping many people on high alert.  

Influenza pandemics have occurred throughout history and most experts agree another one is inevitable – whether H5N1 or a different strain. Spotting it early and having the right knowledge and tools available will be crucial to managing it well. As part of our work on infectious diseases, the Novo Nordisk Foundation is committed to supporting the science that will help make that possible. 

We spoke with three scientists about some of the key areas where knowledge and innovation are needed to help the world prepare for the inevitable.  

‘Universe of viruses’
Pandemic influenza occurs when a new strain of flu virus jumps from animals to humans and starts spreading between people globally. These strains have different properties to seasonal influenza viruses, so people have very little, if any, immunity and existing vaccines and drugs may not be effective.  

Flu poses a particular threat for several reasons. Firstly, it can infect a wide range of hosts, including birds, pigs, cows and humans. This creates many opportunities for cross-species transmission and reassortment – when multiple strains infect the same cell, mix and create a new strain. Secondly, it’s extremely infectious. Thirdly, it’s very unpredictable. 

A further factor of concern is that we don’t know exactly how pandemics start.  

Kanta Subbarao, Professor of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity in Melbourne and Canada Excellence Research Chair at Université Laval, explains further: “Does it start with a few infections that stutter and die out, and then eventually something happens that makes it take off? We don’t know that event.” 

Developing this understanding is crucial for devising countermeasures that can reduce the risk of these events happening or recognise them when they do. Surveillance is one such countermeasure. 

“There’s a universe of influenza viruses out in nature,” says Subbarao. “They’re in wild birds, waterfowl, shore birds, and periodically they get into poultry or pigs or now cows. We need surveillance because we need to see what’s out there in animals, and we need to see when a virus crosses into humans.” 

Seasonal flu adds an extra complication, she explains: “Against that background of seasonal influenza, how would you know if an animal virus crossed into a person? You would only know that if you were looking. What we really need are rapid diagnostic tests that can distinguish between seasonal flu and an animal influenza virus. We don’t have those.” 

‘A ticking bomb’
For Lars Erik Larsen, veterinary virologist at the University of Copenhagen, it’s critical that surveillance initiatives and research efforts on flu aren’t limited to the most obvious threat – currently H5N1 – but remain broad.  

While the repeated jumps from birds to mammals are alarming, Larsen believes the risk of a H5N1 pandemic is low. He is much more concerned that a strain of swine influenza could jump to humans, as it did in 2009, the last influenza pandemic. He and his team have spent the past few years trying to identify the factors that make a virus more likely to jump from pigs to humans through the FluZooMark project, funded by the Foundation’s Challenge Programme. 

“We know some of the markers for bird to human jumps, but we’re still unsure when it comes to jumps between swine and humans,” says Larsen. “We have some candidates, but we haven’t solved the mystery yet. What we do know is that the receptor distribution in pigs and humans is very similar, meaning that the barrier between pigs and humans is less than between birds and humans. It’s a ticking bomb.” 

A new type of vaccine?
If a new strain of flu virus makes the leap from animals into humans and acquires the ability to spread from human to human, effective vaccines and antiviral treatments will be crucial countermeasures to prevent the outbreak from spreading and becoming a pandemic. 

The Foundation is supporting the latter through the Pandemic Antiviral Discovery Initiative, including with a grant to a team led by Subbarao working on a long-acting antiviral drug effective against multiple influenza strains. 

On vaccines, airway immunity is a potential gamechanger. While conventional vaccines generate a system-wide response, this new type would create a protective immune response where the virus enters the body, i.e. in the airways. This could help to prevent even mild infection and, crucially, stop the virus spreading between people. 

Figuring out how to generate airway immunity is a focus for research groups around the world, including those at the Novo Nordisk Foundation Initiative for Vaccines and Immunity (NIVI), a partnership between the Foundation and the University of Copenhagen launched in 2024. 

New paths to airway immunity
Gabriel Kristian Pedersen, Head of Adjuvant Research at the Center for Vaccine Research in Denmark’s Statens Serum Institut and affiliated group leader at NIVI Research Center, is one of those working on the problem. 

He explains that one approach is to “trick the immune system”. This involves adding some components to a conventional vaccine that cause immune cells to be “pulled” into the airways where they help bolster the level of protection. Pedersen and his team have shown how vaccines can cause immune cells to be pulled into the intestinal immune system, but the airways present a different challenge. 

“We aren’t yet sure how to trick the cells into going to the airway after a vaccine, but I think it could be possible,” he says. 

A second approach is to deliver the vaccine – and therefore trigger the immune response – in the airway itself by administering it through the nose. Such nasal vaccines have been available for flu since the 1990s, but at present they are no more effective in protecting the vaccinated person against the disease than conventional vaccines. 

Pedersen and many others still believe in the potential of nasal spray vaccines to generate robust, long-lasting airway immunity and significantly reduce human-to-human transmission. Studies he was involved in during COVID-19 were particularly promising. 

“We showed that you can give an animal a vaccine intranasally and they will not transmit the virus. But if you give it intramuscularly, they will,” he explains. 

Alongside the work at NIVI, the Foundation is supporting ongoing clinical studies in Denmark and the UK comparing the immune response in the airways during infection and after vaccination, both with conventional intramuscular vaccines and with nasal sprays. 

‘A work in progress’
There’s still a lot for scientists to uncover about influenza viruses and how to prevent or manage a future pandemic. And with some major sources of science funding drying up, there’s concern that progress could falter. 

However, Subbarao, Larsen and Pedersen are all encouraged by a new willingness to collaborate across borders and disciplines that emerged during and after the 2020 pandemic. It’s most tangible in various initiatives and working groups formed under the banner of ‘One Health’, an approach pioneered several decades ago that has gradually been gaining ground. 

“There’s a recognition that you cannot have human health without paying attention to animal and environmental health,” explains Subbarao. “But even though institutions and organisations are committed to One Health, breaking down those barriers is a work in progress. We need to find the energy, the interest and the funds to continue that.” 

Overall, there’s broad consensus that the world is better prepared for an influenza pandemic than we were for COVID-19. But, in Larsen’s words, “there’s a long way to go.” 

What the Foundation is doing
As part of our mission to improve human health, we want to decrease the burden and threat of infectious diseases around the world. We do this by supporting the development of scientific knowledge that can catalyse the development of innovative tools and solutions, and by supporting the development of effective, scalable, and affordable medical interventions that have global impact. 

We currently support several projects and initiatives related specifically to influenza and respiratory pandemics. These include: 

• The Novo Nordisk Foundation Initiative for Vaccines and Immunity (NIVI): A partnership with the University of Copenhagen that aims to harness airway immunity through innovative vaccine research and development. 

• The Pandemic Antiviral Discovery Initiative: A global philanthropic initiative with Gates Foundation and Open Philanthropy aimed at catalysing the discovery and early development of antiviral medicines in preparation for future pandemics.  

• FluZooMark: A research project anchored at the University of Copenhagen that aims to identify the molecular markers that can help us predict the zoonotic potential of influenza viruses in pigs.  

• Collaborative cLinical research program for Airway Immune Monitoring (CLAIM): A two-pronged study in the UK and Denmark investigating how the immune response in the respiratory tract differs between influenza infection and vaccination. 

• Infectious Diseases Catalyst Grants: An open competition grant programme that provides catalytic funding for exploratory research projects in several areas, including harnessing innate immunity.