ohFor the past four years, a silent pandemic has been raging. One in which the death toll is believed to number in the hundreds of millions, but which has so far received remarkably little attention.
The pandemic in question is bird flu, the H5N1 strain of flu, which since 2020 has moved well beyond the avian world and into mammals ranging from dairy cattle to domestic animals, and species that live on our doorsteps, such as foxes. The virus’ presence has been detected on every continent, even Antarctica. Although it has yet to develop the ability to spread between humans, alarm bells were rung last month. a dairy farm worker in Texas contracted H5N1apparently of cattle.
This appears to be the first known case of bird flu jumping from another mammal to humans. “There is growing concern at the scientific and public health levels,” said Dr Gregory Poland, director of the Mayo Clinic’s vaccine research group, who previously compared rising infection rates among animals to “the rumble before an earthquake”.
While H5N1 is well known for its devastating impact on wild bird populations and poultry farms in the US – as of May 5, 91 million farmed birds are infected in the US in 48 states – Poland is particularly concerned about reports of pet cats contracting the virus from cattle and becoming seriously ill or dying. “We have very little research to tell us how it all occurs in cattle and how it’s spread,” he says.
In the UK, virologist Prof Paul Digard and his team at the Roslin Institute in Edinburgh are an additional £3.3m grant last year to step up their research into bird fluand evaluate the risk that the current strain of H5N1 may pose to humans.
“Influenza is constantly evolving, and it’s clear that a few years ago the current strain of bird flu changed to become supercharged,” says Digard. “Now that it appears to be fairly widespread in the cow population in the US, it’s a much more direct route to where it can transfer to humans and get the adaptations it needs to prevent pandemics.”
The Roslin team’s task is to find the exact changes in the viral sequence that seem to infect cows, and then test the strain on human cells and mini-organs in the lab. The ultimate goal will be to make predictions about whether it is becoming more dangerous for humans and for animals living in close proximity to us, and to feed that information back to the relevant public health authorities.
If the findings raise concerns, it could give the government more evidence to start bolstering national stocks of flu vaccines. Last year, reports emerged that the UK Health Security Agency has conducted a procurement exercise to find suitable jabs, while the US has accumulated a national reserve of four types of flu vaccine that could provide some protection against H5N1 in case of any future outbreak. But even this supply would not be sufficient for the entire country, and Digard explains that governments face a desperately difficult decision when it comes to balancing the economic cost of vaccines against trying to ensure they are as ready as possible. possible for an outbreak.
“The problem is trying to decide when to pull the trigger,” he says. “Because if you wait until it’s already a pandemic, then you’re playing catch-up, and you know that you’re not going to be able to make a vaccine fast enough to protect everyone.”
The vaccine bottleneck
If H5N1 has indeed started to spread among humans, the good news is that the world has very recent experience when it comes to rolling out large-scale vaccination programs. More than 13 billion doses of Covid-19 vaccines have now been administered, covering 70% of the world’s population, while at the height of the 2009 swine flu outbreak, around 3 billion vaccine doses were cut out.
According to the US Centers for Disease Control and Prevention (CDC), there are two candidate vaccines against a related strain of flu viruses that could be shipped within weeks, if needed. Several manufacturers also have special dispensations from regulators to update their flu vaccines with relevant targets of the H5N1 strain, without seeking new licensing.
The World Health Organization (WHO) says its estimates suggest that 4-8 billion doses of flu vaccines could be produced within a year in an H5N1 pandemic. Experts say this would require a significant expansion of global capacity for making flu vaccines, to about 1.2 billion doses.
“Remember that it takes two doses, three to four weeks apart, to achieve protective immunity,” Pole says. “You can quickly do the math and see where that leaves us.”
While manufacturers have been working on H5N1 vaccines since the mid-2000s, research has always indicated that they pose a much greater technical challenge than the seasonal flu vaccines distributed each year. In particular, the jabs appear to require a much larger dose to generate an adequate immune response. A dose of the H5N1 vaccine candidate produced by French pharmaceutical company Sanofi is 90 micrograms, six times the size of a typical seasonal flu vaccine. Poles say this will make it much more challenging to produce the stitch at the required scale.
The WHO’s capacity forecasts may rely on increasing the production of adjuvant vaccines. It uses 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’s Health Emergency Preparedness and Response Authority for the discussion of future production and supply of 85 million doses of Adjupanrix,” the company says. “In the event of an influenza pandemic declared by the WHO, this will ensure the ready production and supply of Adjupanrix to 12 EU member states.”
However, production speed can still be a bottleneck. In the event of an H5N1 pandemic, the WHO estimates that 79% of the vaccines produced will be made using traditional gold standard technologies, which require incubation in chicken eggs. While a Sanofi spokesperson said vaccines were produced within three months during the 2009 swine flu pandemic, egg-based platforms are known to be more time-consuming: the process can take up to six months.
Newer technologies
Instead, messenger RNA (mRNA) technology, which has been so invaluable in generating Covid-19 vaccines, could once again be a vital 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 in humans. But, given previous difficulties in stimulating sufficient immune responses against H5N1, Digard says there is insufficient data to examine the possible effectiveness of mRNA vaccines.
“This is technology that may apply to this,” he says. “I don’t think we have the data yet to say that it works that well.”
Since H5N1 is still largely confined to the animal population, one idea to reduce transmission and limit the potential to jump to humans is to vaccinate poultry and farm animals on a mass scale. Karen Grogan, an associate professor at the University of Georgia Poultry Diagnostic and Research Centrenot convinced it will make a significant difference.
“Vaccination of commercial poultry will not reduce the amount of viable virus in the environment, as so much is shed by wild birds,” she says. “The spread to dairy cattle is probably linked to wild birds on those dairies. There are no approved H5N1 vaccines for use in farm animals or household pets; it will have to be developed, which is a process that takes about four years.”
If there is an H5N1 pandemic, Poland predicts that healthcare services around the world will have to rely partially on antiviral medications for the first six months of the outbreak, until sufficient vaccine supplies become available to provide full population-level coverage. According to the CDC, analysis of the strains circulating among cows shows that the virus must 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 H5N1 vaccine production, Digard says governments face a difficult dilemma when it comes to how best to respond to the bird flu threat.
“All this costs money,” he says. “It’s a very delicate juggling act. With vaccines, for example, if we start redirecting all the vaccine production to make H5N1 vaccines, that means we’re not making the seasonal flu vaccines. So if you start an H5N1 vaccine program prematurely, you have disrupted the supply of seasonal flu vaccines that are still needed.”
While the prevalence of H5N1 in nature is alarming, Digard is keen to point out that although the virus is widely reported to have a 52% fatality rate 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 the UK over the past few years, but they have been very mild and generally asymptomatic,” he says. “I’m not discounting the risk – if it were to be pandemic, even with a very mild virus, people would end up dying because of the sheer numbers that get infected. Even swine flu, which is the mildest flu pandemic we have records have, still killed hundreds of thousands of people. But it wouldn’t be a science fiction-style pandemic.”
