Wild birds and poultry flocks alike continue to drop dead from the highly pathogenic bird flu that began spreading globally in 2020. Almost 59 million commercial birds have already been culled in the United States.
It’s the broadest outbreak of this type of avian flu, known as H5N1, since it was first identified in China in 1996.
The virus's proliferation and high fatality rate have prompted questions about two types of possible vaccines: those for birds and those for humans. H5N1 kills almost all the birds it infects; among reported cases in people since 2003, the death rate has been 56%.
The U.S. Agriculture Department announced in April that it had started testing several vaccine candidates for poultry.
Vaccines for people, meanwhile, would only be considered if the virus eventually undergoes a complicated string of mutations that allow it to spread from person to person. There’s no evidence of that yet. The U.S. recorded its only human case of H5N1 last April — the person was involved in culling poultry with presumed infections in Colorado. The United Kingdom reported two cases Tuesday, both poultry workers with asymptomatic infections detected via routine testing. Chile reported one infection in March and Ecuador one case in January.
But scientists have long considered H5N1 to have pandemic potential. The U.S. has a stockpile of H5N1 flu shots in case such a crisis arises, but three experts said it would likely prove insufficient should this particular type of avian flu start infecting people. The shots have only been administered in trials and were derived from strains that circulated in 2004 and 2005.
"You would expect that those vaccines based on those older strains would likely offer little protection against what’s circulating today," said Scott Hensley, a professor of microbiology at the University of Pennsylvania.
Developing new, better-tailored shots for the current strain would be complicated, though, because most flu vaccines are grown in chicken eggs — "a slow process fraught with production issues," according to Dr. Gregory Poland, founder and director of the Mayo Clinic’s Vaccine Research Group. The process requires individually inoculating each egg with a modified virus and, of course, depends on an ample supply of healthy chickens.
"In a real pandemic situation, the poultry will be at threat, and then the supply of the eggs will be highly compromised," said Dr. Suresh Mittal, a virology professor at Purdue University. The U.S. does, however, keep a stockpile of chickens to ensure it can continue producing flu vaccines.
Better options may be on the horizon. Vaccine researchers are developing shots that could be updated to target whatever mutated strain of H5N1 gains a hold in people someday. But no human trials are underway yet.
"What we need is a library of H5N1 vaccine candidates that are ready to go," Poland said, adding, "we’re putting people and economies at cataclysmic risk by not being prepared."
Preparing for a spillover to humans
In general, scientists start to worry about bird flu spilling over to people when there's mammal-to-mammal transmission, Hensley said. Scientists saw evidence of that during an October outbreak in minks in Spain.
“We’re afraid that those kind of events will lead to a mutant form of this virus that could transmit among humans,” Hensley said.
Since arriving in the U.S. last January, avian flu has spread from birds to several other mammals: mountain lions, bobcats, bears, seals, red foxes, coyotes, raccoons, skunks and possums, as well as an otter and a bottlenose dolphin.
Poland compared these infections to “the rumbles prior to an earthquake."
He suggested that a bird flu pandemic would most likely start as a small outbreak among poultry workers or swine workers, since pigs can pass the virus from birds to humans. Such an outbreak might be contained right away, he said — or not.
So vaccine researchers are preparing. Moderna said that later this year, it expects to begin clinical testing of an mRNA vaccine specific to the strain now circulating in birds, called 126.96.36.199b. mRNA technology offers an advantage because it allows vaccines to be produced and updated quickly. Given that experts think a future bird flu pandemic would be caused by a strain of H5N1 that hasn’t evolved yet, the ideal vaccines could be easily tweaked to target it.
Hensley leads a research team that is testing another mRNA vaccine to target 188.8.131.52b. Data published in April, which hasn’t been peer reviewed, showed that it elicited an immune response in mice and ferrets.
"Making a vaccine that looks like what’s circulating right now gives us a higher chance of having cross-protection against something slightly different, but very related," Poland said.
Meanwhile, two other pharmaceutical companies, CSL Seqirus and GSK, have partnered with the U.S. government to manufacture experimental vaccine doses that are also closer matches to the current strain. GSK's trial is set to begin this year, but the company did not specific the type of technology it uses. CSL Seqirus said a phase 2 trial to assess the safety and immune response of an inactivated virus vaccine is scheduled to start in June.
Mittal said a universal flu vaccine, which would target a wide variety of flu strains, could also provide cross-protection against whatever version of bird flu one day finds its way into humans. Several such vaccines are being developed, but none has advanced to a late-stage trial. The National Institutes of Health announced this month that it has started testing a universal mRNA flu vaccine among 50 volunteers.
Could the older vaccines be updated?
The Health and Human Services Department declined to specify the quantity or manufacturers of the bird flu vaccine products in the national stockpile. However, NBC News verified that three approved H5N1 vaccines have been stockpiled, two of which are produced using eggs.
One of those shots, from the pharmaceutical company Sanofi, was approved for adults in 2007. In a trial of around 100 people, two doses elicited a protective immune response in 45% of the recipients, according to the Food and Drug Administration. As of 2007, the U.S. had stockpiled enough of that vaccine for 6 million people.
When tested against strains circulating in 2016 and 2017, the vaccine prompted a modest antibody response, according to a 2019 study.
However, a dose is 90 micrograms — much bigger than the seasonal flu vaccine. In a pandemic situation, that could make it challenging to quickly manufacture shots for everyone who needs them, Poland said.
"You have to produce the equivalent of six normal doses for one dose of that H5N1 vaccine," he said. "Those become real numbers when you're talking about tens and hundreds of millions of people."
The FDA approved a second shot for adults in 2013, manufactured by a GSK subsidiary, to add to the stockpile. The company said in 2006 that two doses produced a strong immune response in 80% of the recipients.
A GSK spokesperson said the company was awarded contracts last year with the U.S., Canada, the European Union and the World Health Organization to supply its vaccine in the event of a flu pandemic. Under those agreements, the spokesperson said, the company could provide at least 200 million doses to governments around the world.
The third stockpiled shot, from CSL Seqirus, was approved in 2020 for recipients ages 6 months and older. It's grown in cultured cells instead of eggs.
The company said the U.S. has stockpiled millions of doses' worth of bulk antigen — the ingredient in the vaccine that stimulates an immune response — targeting a variety of strains. In the event of a bird flu pandemic, any of those antigens found to cross-react with circulating strains could be formulated into doses, it said.
The company added that it could produce 150 million doses within six months.
But Poland said even these pledges from manufacturers would still fall short of the Biden administration's National Biodefense Strategy, which aims to produce enough vaccine for the entire U.S. within roughly four months of a future pandemic's onset.