by For the past four years, a silent pandemic has been looming. The death toll is believed to be in the hundreds of millions, but little attention has been paid to date.
The pandemic in question is bird flu, the H5N1 flu strain, which since 2020 has moved well beyond the avian world and into mammals from dairy cattle to house pets, and living species on the doorstep, like foxes. The presence of the virus has been detected on every continent, even in Antarctica. Although the ability to spread between people has not yet evolved, alarm bells were raised last month after a dairy farm worker in Texas contracted H5N1, apparently from cattle.
This appears to be the first known case of bird flu jumping to humans from another mammal. “There is growing concern about the scientific and public health levels,” says Dr. Gregory Poland, director of the Mayo Clinic’s vaccine research group, who has previously compared rising infection rates among animals to “the rumblings before an earthquake.” .
It is clear that a few years ago, the current strain of bird flu has changed to be supercharged
While H5N1 is well-known for its devastating impact on wild bird populations and poultry farms in the United States – as of May 5, 91m farmed birds in the United States were infected across 48 states – Poland particularly alarmed by reports of pet cats picking up the disease. virus from cattle and become seriously ill or dying. “We have very little research to tell us how this is happening in cattle, and how it’s being spread,” he says.
In the UK, virologist Professor Paul Digard and his team at the Roslin Institute in Edinburgh were awarded an additional £3.3m grant last year to increase their research into bird flu, and to assess the potential risk the current H5N1 strain in humans. .
“Influenza is constantly changing, and it’s clear that the current strain of bird flu is changing from a few years ago to be supercharged,” says Digard. “Now that it appears to be fairly widespread in the U.S. cow population, that’s a much more direct way for it to be transmitted to humans and get the adaptations it needs to become pandemic.”
Roslin’s team’s task is to figure out the precise changes in the viral sequence that appear to allow them to infect cows, and then test the strain on human cells and micro-organisms in the lab. The ultimate goal will be to predict whether it is becoming more dangerous for people and animals that live close to us, and feed that information back to the relevant public health authorities.
Related: America’s cows now get bird flu too – but it’s time to plan, not panic Devi Sridhar
If the results prompt concern, it could provide more evidence for the government to begin bolstering national supplies of flu vaccines. Last year, reports emerged that the UK’s Health Security Agency was running a procurement exercise to find suitable jobs, and the US has built up a national stockpile of four types of flu vaccine that could provide some protection against H5N1 in case of any future outbreak. But even this stockpile would not be sufficient for the whole country, and Digard explains that governments face a very difficult decision in balancing the economic cost of vaccines and trying to ensure that they are as ready as possible for outbreak
“The question is trying to decide when to pull the trigger to go,” he says. “Because if you wait until it’s already a pandemic, then you’re playing catchup, and you know you’re not going to be able to make enough vaccine quickly enough to protect everyone.”
The vaccine bottleneck
If H5N1 has started to spread among humans, the good news is that the world has recently had plenty of experience in rolling out large-scale vaccination programs. More than 13bn doses of Covid-19 vaccines have now been given, covering 70% of the world’s population, and at the height of the swine flu outbreak in 2009, around 3bn doses of vaccine were given out.
According to the US Centers for Disease Control and Prevention (CDC), there are two candidate vaccines against a related strain of flu virus that could be launched within weeks, if needed. Various manufacturers also have special concessions from regulators to update their flu vaccines with relevant targets from the H5N1 strain, without the need to seek new licensing.
The World Health Organization (WHO) says its estimates suggest that 4-8bn doses of flu vaccines could be produced within a year in an H5N1 pandemic. Experts say a significant expansion of global capacity to make flu vaccines, put at around 1.2bn doses, would be needed.
“Remember that it takes two doses, three to four weeks apart, to achieve protective immunity,” says Poland. “You can do the math quickly and see where that leaves us.”
Although manufacturers have been working on H5N1 vaccines since the mid-2000s, research has consistently shown them to be 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 manufactured by the French pharmaceutical company Sanofi is 90 micrograms, six times the amount of a typical seasonal flu vaccine. Poland says this would make it much more challenging to produce the job at the scale required.
The WHO’s capacity projections may depend on increasing the production of adjuvant vaccines. These use an additional ingredient, or adjuvant, that is combined with the vaccine to boost the immune response, enabling a much smaller dose, and a dose that is easier to produce in large quantities. Pharmaceutical company GSK says its Adjupanrix pandemic flu vaccine, 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 to reserve the future production and supply of 85m 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, the speed of production could still be an obstacle. In the case of an H5N1 pandemic, the WHO estimates that 79% of the vaccines produced would be made using traditional gold standard technologies, which require incubation in chicken eggs. Although a Sanofi spokesperson said vaccines were produced within three months during the 2009 swine flu pandemic, egg-based platforms are known to take more time: the process can take up to six months.
Newer technologies
Instead, messenger RNA (mRNA) technology, which was so invaluable in generating Covid-19 vaccines, could once again become a vital tool, and the platform is known to be faster and more efficient than older egg-based technologies. Moderna and GSK and CureVac are collaborating on ongoing clinical trials testing H5N1 vaccines in humans. However, given past difficulties in inducing adequate immune responses to H5N1, Digard says there is insufficient data to examine the potential efficacy of mRNA vaccines.
“It’s the technology that could be applicable to this,” he says. “I don’t think we have the data yet to say it works that well.”
Since H5N1 is still largely confined to the animal population, large-scale vaccination of poultry and farm animals may be considered to reduce transmission and limit the possibility of jumping to humans. However, Karen Grogan, an associate professor at the University of Georgia’s Avian Diagnostic and Research Center, is not convinced this would make a significant difference.
If we divert all vaccine production into H5N1 jobs, that means we’re not making seasonal flu vaccines.
“Commercial poultry vaccination would not reduce the amount of viable virus in the environment because wild birds are shedding so much,” she says. “It is likely that the spread of dairy cattle has something to do with wild birds on those dairies. No H5N1 vaccine is approved for use in farm animals or domestic pets; those would need 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 would have to rely partially on antiviral medication for the first six months of the outbreak, until sufficient stocks of vaccines are available to provide full coverage at a level supply the population. According to the CDC, analysis of the strains circulating among cows indicates that the virus should be susceptible to the current range of antivirals approved against the flu.
But whether it’s stockpiling antivirals or instructing pharmaceutical companies to switch to H5N1 vaccine production, Digard says governments face a difficult dilemma about how best to respond to the bird flu threat.
Related: The risk of bird flu spreading to humans is a huge concern, says the WHO
“All of this costs money,” he says. “It’s a very delicate juggling act. With vaccines, for example, if we start diverting all vaccine production to make H5N1 jobs, that means we don’t make the seasonal flu vaccines. So if you start the H5N1 vaccine program prematurely, you’re disrupting the supply of seasonal flu vaccines, which are still needed.”
While the prevalence of H5N1 in the wild is a concern, 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 is cause for concern. humans seem to have much less pathogens in recent years.
“There have been human cases in the UK over the last few years, but they have been very mild and generally asymptomatic,” he says. “I’m not minimizing the risk – if this pandemic were to happen, even with a very mild virus, people would die because of the sheer number of people infected. Even the swine flu, which is the smallest flu pandemic we have records of, killed hundreds of thousands of people. But it wouldn’t be a science fiction style pandemic.”
