‘The question is when to pull the trigger’: how prepared are we for human bird flu?

OA silent pandemic has been raging for the past four years. One in which the death toll is expected to be in the hundreds of millions, but which has thus far received remarkably little attention.

The pandemic in question is bird flu, the H5N1 flu strain, which has spread far beyond the bird world since 2020, spreading to mammals ranging from dairy cattle to pets, and species that live near us, such as foxes. The presence of the virus has been detected on every continent, even Antarctica. Although the ability to spread between people has yet to be developed, alarm bells were raised last month after a Texas dairy farm worker contracted the H5N1 virus, apparently from cattle.

It appears to be the first known case of bird flu jumping from another mammal to humans. “There is increasing concern at the scientific and public health level,” said Dr. Gregory Poland, director of the Mayo Clinic’s vaccine research group, who has previously likened rising infection rates among animals to “the rumbling that precedes an earthquake.”

Although H5N1 is known for its devastating impact on wild bird populations and poultry farms in the US – as of May 5 In the US, 91 million farmed birds have been infected in 48 states – Poland is particularly alarmed by reports of domestic cats contracting the virus from livestock and becoming seriously ill or dying. “We have very little research to tell us how this all happens in cattle and how it spreads,” he says.

In Great Britain, virologist Prof. Paul Digard and his team from the Roslin Institute in Edinburgh received an extra reward Last year a £3.3 million grant to scale up their research into bird fluand assess the risk that the current H5N1 strain may pose to humans.

“The flu is constantly evolving and it is clear that the current form of bird flu turned into a supercharger a few years ago,” says Digard. “Now that it appears to be quite widespread in the cow population in the US, that’s a much more direct route where it could be transmitted to humans and get the adaptations necessary to cause a pandemic.”

The Roslin team’s job is to figure out the precise changes in the virus sequence that allow cows to be infected, and then test the burden on human cells and mini-organs in the laboratory. The ultimate goal will be to make predictions about whether it is starting to become more dangerous for people and animals living close to us, and to send that information back to the relevant public health authorities.

If the findings raise concerns, it could provide the government with more evidence to start boosting national supplies of flu vaccines. Last year, reports emerged that Britain’s Health Security Agency had launched a tender to find suitable jabs, while the US had built up a national reserve of four types of flu vaccines that could provide some protection against H5N1 in the event of a future outbreak. But even this supply would not be enough for the entire country, and Digard explains that governments face a desperately difficult decision when it comes to weighing the economic costs of vaccines against trying to ensure they are as ready as possible are for an outbreak.

“The problem is trying to decide when to pull the trigger and go,” he says. “Because if you wait until it’s already a pandemic, you’re playing catch-up and you know you won’t be able to make vaccines fast enough to protect everyone.”

The vaccine bottleneck

If H5N1 starts to spread among people, the good news is that the world has a lot of recent experience rolling out mass vaccination programs. More than 13 billion doses of Covid-19 vaccines have now been administered, representing 70% of the world’s population, while at the height of the swine flu outbreak in 2009, approximately 3 billion vaccine doses were produced.

According to the U.S. Centers for Disease Control and Prevention (CDC), there are two vaccine candidates against a related flu virus strain that could be shipped within weeks if needed. Several manufacturers also have special waivers from regulators to update their flu vaccines with relevant targets of the H5N1 strain without having to apply for new permits.

The World Health Organization (WHO) says its estimates suggest that in the event of an H5N1 pandemic, 4 to 8 billion doses of flu vaccines could be produced within a year. Experts say this would require a significant expansion of global capacity for making flu vaccines, to around 1.2 billion doses.

“Remember that it takes two doses, three to four weeks apart, to achieve protective immunity,” Poland says. “You can quickly do the math and see where we end up.”

Although manufacturers have been working on H5N1 vaccines since the mid-2000s, research has always shown that they pose a much greater technical challenge than the seasonal flu vaccines distributed every year. In particular, the jabs appear to require a much larger dose to generate a sufficient immune response. A dose of the H5N1 vaccine candidate, manufactured by French pharmaceutical company Sanofi, is 90 micrograms, six times as large as a typical seasonal flu vaccine. Poland says this would make it much more challenging to produce the jab on the scale required.

WHO capacity forecasts may rely on ramping up production of adjuvanted vaccines. These use an additional ingredient, or adjuvant, that is combined with the vaccine to boost the immune response, allowing for a much smaller dose and one that is easier to produce in large quantities. Pharmaceutical company GSK says its pandemic flu vaccine Adjupanrix, which uses an adjuvant, has a dose of 3.75 micrograms. “In 2022, we signed a contract with the EU Health Emergency Preparedness and Response Authority for the reservation of the future production and supply of 85 million doses of Adjupanrix,” the company said. “In the event of a WHO-declared influenza pandemic, this will ensure the smooth production and supply of Adjupanrix to 12 EU Member States.”

However, production speed may still prove to be a bottleneck. In the event of an H5N1 pandemic, WHO estimates that 79% of vaccines produced would be made using traditional gold standard technologies, which require incubation in chicken eggs. Although a Sanofi spokesperson said that during the 2009 swine flu pandemic, vaccines were produced within three months, egg-based platforms are known to take longer, with the process taking up to six months.

Newer technologies

Instead, messenger RNA (mRNA) technology, which proved so invaluable in generating Covid-19 vaccines, could once again be an essential tool, with the platform known to be faster and more efficient than older egg-based technologies . Current clinical trials by both Modern And GSK and CureVac work together testing H5N1 vaccines on humans. However, given past problems in stimulating sufficient immune responses to H5N1, Digard says there is insufficient data to investigate the potential effectiveness of mRNA vaccines.

“It is technology that may be applicable to this,” he says. “I don’t think we have any data yet to say it works either.”

Given that H5N1 is still largely confined to the animal population, one idea to reduce transmission and limit the chance of jumping to humans could be to vaccinate poultry and farm animals on a large scale. However, Karen Grogan, associate professor at the University of Georgia Diagnostic and research center for poultryis not convinced this would make a significant difference.

“Vaccination of commercial poultry would not reduce the amount of viable virus in the environment because so much is shed by wild birds,” she says. “The spread to dairy cattle is probably related to wild birds on those dairy farms. There are no approved H5N1 vaccines for use in farm animals or pets; these would have to be developed, a process that would take about four years.”

If an H5N1 pandemic breaks out, Poland predicts that healthcare systems around the world will be partially dependent on antiviral drugs for the first six months of the outbreak, until sufficient vaccine supplies become available to provide full population-level coverage. According to the CDC, this is evident from analysis of the strains circulating among cows the virus should be susceptible to the current range of antiviral drugs approved against influenza.

But whether it’s stockpiling antivirals or instructing pharmaceutical companies to switch to producing H5N1 vaccines, Digard says governments face a difficult dilemma when it comes to the best response to the threat of bird flu.

“All this costs money,” he says. “It’s a very delicate juggling act. For example, if we shift all vaccine production to the production of H5N1 shots, this means that we will no longer make seasonal flu vaccines. So if you start an H5N1 vaccine program prematurely, you will have disrupted the supply of seasonal flu vaccines that are still needed.”

While the prevalence of H5N1 in the wild is concerning, Digard would like to point out that while the virus is widely reported to have a mortality rate of 52% in humans, based on 882 cases of infections between January 2003 and December 2023, it appears to have become much less pathogenic to humans in recent years.

“There have been human cases in Britain in recent years, but these have been very mild and generally asymptomatic,” he says. “I’m not minimizing the risk – if this were to become a pandemic, even with a very mild virus, people would eventually die because of the large numbers becoming infected. Even swine flu, the mildest flu pandemic for which we have data, still killing hundreds of thousands of people. But it wouldn’t be a science fiction-style pandemic.”