As cases of avian influenza continue to rise in cattle in the United States, countries are preparing for the possibility that the virus could start spreading in people. Many nations are ramping up surveillance, as well as purchasing vaccines or developing new ones.

“This virus in its current state does not look like it has the characteristics of causing a pandemic. But with influenza viruses, that equation could entirely change with a single mutation,” says Scott Hensley, an immunologist at the University of Pennsylvania in Philadelphia.

The highly pathogenic avian influenza H5N1 has so far been detected in 145 cattle herds and 4 farm workers in a dozen states across the United States. Researchers say many more cases in cows and people have probably gone undetected. The chances of quashing the outbreak get “more slim by the day”, says Angela Rasmussen, a virologist at the University of Saskatchewan in Saskatoon, Canada.

Studies suggest that the virus is spreading between cows through contaminated milking equipment1,2, rather than airborne particles. The biggest risk is that it could evolve to infect mammals more effectively, including through the respiratory system, which would make it more difficult to contain. Given the close and regular contact that cows have with people, airborne transmission could spark a pandemic.

Efforts to prepare for that possibility include risk assessments, modelling and outbreak predictions. “There is loads of planning and preparedness going on internationally,” says Michelle Wille, a virus ecologist at the University of Melbourne in Australia.

Nicole Lurie, who heads preparedness and response at the Oslo-based Coalition for Epidemic Preparedness Innovations (CEPI), says the coalition’s approach “for the moment is one of ‘calm urgency’” — “like putting our shoes on in case we need to start running”.

Vaccinating people

A key focus of pandemic preparedness efforts is vaccines, which would protect people from getting ill should the virus spread more widely. Vaccinating people would also reduce the risk of H5N1 mixing with seasonal influenza viruses that are already well-adapted to spread in humans.

In May, the World Health Organization in Geneva, Switzerland, initiated a review of available influenza candidate vaccines, and confirmed that they would work against the H5N1 virus circulating in cattle. “Although the current public health risk is low, WHO is operating in a constant state of readiness for a potential influenza pandemic,” says Maria Van Kerkhove, who heads epidemic and pandemic preparedness and prevention at the WHO.

Last month, the European Commission purchased roughly 700,000 doses of a flu vaccine manufactured by CSL Seqirus, in Maidenhead, UK, with the option to buy another 40 million. The vaccine protects against H5 strains of influenza A. Also in June, Finland began vaccinating people against avian influenza, focusing on high-risk workers at fur and poultry farms.

Other countries, especially the United States, should also consider vaccinating high-risk workers, says Rasmussen. In May, the US Department of Health and Human Services (HHS) purchased almost five million more doses of the CSL Seqirus influenza vaccine for its stockpile.

Most available vaccines rely on inactivated strains of viruses grown in chicken eggs, which are cheap, but slow, to produce. Researchers are also developing vaccines using mRNA technology; these are more expensive but quicker to manufacture, and their formulation can be updated to target emerging strains. “It really is a game-changer,” says Hensley, who has developed an H5 mRNA vaccine candidate and tested it in ferrets3. “In the case of a pandemic, you can expect that these vaccines will be used widely.”

Last week, the HHS announced that it had provided the pharmaceutical company Moderna, based in Cambridge, Massachusetts, with US$176 million to develop an mRNA-based vaccine against H5 influenza.

CEPI is working to ensure that the response is equitable worldwide. Half of existing vaccine supplies are already tied up in contracts or export controls, says Lurie, and it’s important to make sure that the remaining doses reach the people who need them. “As we saw during the COVID-19 pandemic, low- and middle-income countries could once again be pushed to the back of the queue.”

Doses for cows

Countries including the United States are investigating the possibility of vaccinating cattle to reduce transmission. “This could be a phenomenal mitigation effort” and would be practical to implement as part of existing drives to vaccinate livestock, says Jenna Guthmiller, an immunologist at the University of Colorado Anschutz Medical Campus in Aurora.

Several research teams are in the early stages of developing vaccines for cattle. But there are challenges to overcome. Studies suggest that the virus spreading in cattle finds safe harbour in the mammary glands and epithelial cells2 of the udder. This could be a challenging site in which to elicit a protective immune response, says Diego Diel, a virologist at Cornell University in Ithaca, New York, who is developing candidate vaccines against highly pathogenic avian influenza that use harmless DNA viruses to deliver genetic material. Hensley is currently testing his mRNA vaccine in cattle and swine.

But one concern is that vaccines could cover up symptoms in animals that are still infectious, which would increase the risk to people, says Thomas Peacock, a virologist at Imperial College London.

Vaccines should be seen as a measure of last resort, after implementing all other layers of containment, says Martin Beer, a virologist at the Federal Research Institute for Animal Health in Greifswald, Germany. They protect against “a worst-case scenario”.

Surveillance

To stay ahead of the virus, countries are also tracking its spread through increased testing of people and animals. Before the US outbreak, researchers didn’t think cattle could be infected with avian influenza. They are now scrambling to develop tests specific to this host.

Isabella Monne, who studies the molecular epidemiology of animal viruses at the Experimental Zooprophylactic Institute of Venice in Legnaro, Italy, is developing and evaluating tools to help laboratories across Europe to detect viral particles and antibodies, which are evidence of past infection, in cow blood and milk. Groups across Europe, Canada and the United States have started testing cow blood or bulk milk samples.

Researchers are also monitoring sequences of the virus’s genome for changes that would improve its ability to infect cells found in the upper airways. These mutations would increase the risk to people.

One group has created4 a library of every possible amino-acid mutation on the haemagglutinin protein, which the virus uses to enter cells. The researchers tested in human cells how well the mutated proteins bind to upper-airway receptors, and their stability in acidic environments — traits “known to correlate with viruses going from avian to mammalian hosts, and becoming pandemics”, says Peacock, a co-author of the study, which has not been peer reviewed. Scanning for those mutations could allow real-time risk prediction, he says.