Lakeside, California—Hilliker’s Ranch Fresh Eggs in this San Diego suburb has 30,000 chickens in three “cage-free,” open-air barns, where birds crowd the floor like rush-hour riders on a big city subway. “A cage-free aviary is a very interesting science experiment,” says Frank Hilliker, who runs the farm his grandfather started in 1942. He worries mightily about infections spreading through the massed birds. On his iPhone, he pulls up a list of the vaccines his chickens get: against Newcastle disease, infectious laryngotracheitis, coryza, colibacillosis, salmonella, infectious bronchitis, and fowlpox.
There is one disease for which his chickens have not been vaccinated: a highly pathogenic avian influenza (HPAI) that’s now racing around the world, killing 90% or more of the poultry it infects. Endemic in migratory birds, this HPAI emerged in U.S. poultry in February 2022, and to date has killed or required the culling of a record 58 million chickens, turkeys, and ducks in commercial and backyard flocks.
Hilliker, who despite the unusually chilly February morning is wearing cargo shorts and a zip-up sweatshirt—this is San Diego—has a no-nonsense demeanor mixed with a tinge of superstition from years of worrying about his chickens. His farm has never detected an HPAI, he says, knocking on a wood wall. “We’re pretty isolated here,” he says, giving another rap. But he might well use an HPAI vaccine to protect his birds, he says, if it was priced right—and allowed.
The goal of vaccination is not just to protect poultry. Well before COVID-19, epidemiologists were nervously watching two kinds of highly pathogenic influenza viruses, H5 and H7, fearing they could erupt into a human pandemic reminiscent of the 1918 flu. HPAI can infect mammals, and the current, massive outbreak has killed seals, bears, and farmed mink and infected at least seven people, killing one. Thankfully, there is no evidence the virus can spread from mammal to mammal, let alone person to person—so far. But fears are growing that the more mammals it infects, the higher the odds that it will adapt to humans.
Slowing the spread among birds could reduce the risk. “I think it is time to give serious consideration to vaccinating commercial poultry in the United States,” says Robert Webster, an emeritus influenza researcher at St. Jude Children’s Research Hospital. But despite strong evidence that HPAI vaccine programs can work—mainly from China, which has aggressively vaccinated poultry over the past 2 decades—the U.S. Department of Agriculture (USDA) does not give farmers like Hilliker the option. Instead, the country has fought HPAI by combining intensive surveillance, strict biosecurity at farms, and culling.
Skeptics of poultry vaccination say that’s the right approach. Immunizing flocks, they argue, could allow the virus to spread silently—not reducing the threat of an avian flu pandemic but simply making it more difficult to detect. And the current practice of “stamping out” outbreaks has worked: Before the current HPAI strain surfaced in U.S. flocks in February 2022, no HPAI had swept through since 2015. But in the face of the largest HPAI outbreak on record, both the United States and Europe are rethinking their hesitancy.
Many questions remain about how, exactly, to use a vaccine in countries that have relied on culling. And because of the uncertain U.S. market, companies are reluctant to invest in moving beyond the initial steps of making vaccines against the current variant and embarking on the rigorous and costly process of seeking regulatory approval. “There’s no incentive at all,” says microbiologist Mahesh Kumar, who heads global biologics R&D for Zoetis, which makes vaccines for pets and livestock and sells an HPAI vaccine outside the United States. “It’s very, very difficult for anybody to continue to invest in that space.”
And something else has kept the brakes on HPAI vaccination in both the United States and Europe: trade. Some countries—including the United States—won’t allow imports of meat or eggs from vaccinated birds.
Scientific evidence doesn’t support those bans. But as Nancy Reimer, a poultry veterinarian who provides care for Hilliker’s birds, puts it, “Some of this is political science, not poultry science.”
The first glimpse of the HPAI strain now wreaking havoc came in 2010 in China’s Jiangsu province, when researchers from Yangzhou University isolated a new variant of a known subtype, H5N8, from a duck sold in a market. (The H and N refer to two viral surface proteins, hemagglutinin and neuraminidase.) Three years later, a similar virus was spotted in another duck, about 300 kilometers south in Zhejiang. When relatives surfaced a third time, in Korean breeder ducks the next year, a new clade was christened: 18.104.22.168b.
The march of 22.214.171.124b took an ominous turn at an island in Qinghai Lake on the Tibetan Plateau. The lake, the largest in China, provides a temporary home to some 150,000 migratory birds each year flying between Russia and India or Australia. On 1 May 2016, researchers discovered the carcass of a brown-headed gull, the first of some 150 gulls and geese at the lake found to have been infected with variants of 126.96.36.199b. The virus was evidently headed north.
That summer and fall some of the same variants turned up near the Ural mountains in Russia, and then the virus took hold in Western Europe. The resulting HPAI epidemic in poultry, researchers wrote in the Proceedings of the National Academy of Sciences, was “the largest and most widespread … ever recorded in Europe.”
By October 2020, the virus had undergone a significant genetic change, swapping N8 for N1, but the new H5N1 188.8.131.52b proved just as transmissible as its predecessor. It spread to Africa and back to Asia. Then, in November 2020, came evidence it had jumped the Atlantic Ocean: Researchers documented a sick great black-backed gull on Newfoundland. In the following weeks and months it established multiple beachheads in North America.
By now, 184.108.40.206b has evolved a niche unlike any HPAI ever seen. Usually HPAI infections die out in a season, but the 220.127.116.11b clade is present year-round in migratory birds. It infects so many species in so many locales that no country’s poultry flocks are ever safe.
Despite their name, HPAIs can cause mild or no disease in some avian species, including ducks. But their arrival on an unvaccinated chicken farm can be devastating. Birds may become weak and listless, stop laying eggs, develop severe diarrhea, stumble, and struggle to breathe. An entire flock can die within 2 days. By USDA regulations, just a single bird infected with HPAI requires stamping out a flock, a gruesome procedure that entails cutting off ventilation in barns or suffocating the birds with carbon dioxide or fire-fighting foam. USDA has a program that compensates producers who are forced to cull, but rebuilding the business can still mean a major financial hit.
Globally the toll is enormous. The intergovernmental World Organisation for Animal Health has tracked stamp-outs triggered by H5 and H7 infections. Between January 2005 and 2022, more than 8500 H5 outbreaks led to the culling of nearly 400 million birds, with another 30 million sacrificed to fight more than 100 outbreaks of H7s.
In 1995, Mexico pioneered an alternative approach to combating HPAI, becoming the first country to use a vaccine as well as culling to stop a virus designated H5N2. The vaccine, which cost pennies per dose, was made like the human one, by growing the virus in eggs and then inactivating it with chemicals. The campaign eliminated the virus from Mexico’s flocks in short order.
China in November 2005 upped the ante in the face of a frightening H5N1 strain that spilled over to nearly 100 humans in Asia that year. In addition to culling, it set out to vaccinate all 14 billion chicken, geese, and ducks then consumed in the country each year—the largest single vaccination effort ever for any species, according to the Food and Agriculture Organization of the United Nations. The government provided the vaccine at no cost to farmers, who were required to use it. Thirteen other countries also used H5 vaccines in poultry by 2010, but China alone accounted for 91% of the total shots given to birds—nearly 100 billion doses.
Later, China faced a new threat: an H7N9 strain that spread through flocks in multiple waves starting in 2013. People caught it, too, mainly from farming or live poultry sold at markets, and by 2017 it had sickened 1500, killing 39% of them. The human tragedy and the economic loss led China in 2017 to introduce a bivalent H5/H7 vaccine for poultry.
China’s HPAI vaccines have had limitations, says virologist Chen Hualan at the Harbin Veterinary Research Institute, who with her colleagues studied the country’s vaccination campaign. The evolution of new variants, which immune pressure from vaccines helped to speed up, forced repeated vaccine updates. And domestic ducks—which often did not get vaccinated—provided a haven for the virus.
China’s farmers rear about 4 billion ducks each year, mostly in open fields where they mingle with wild birds and are regularly exposed to flu and other viruses. But because ducks rarely become ill from HPAI, only about 30% of duck farmers vaccinated their birds. “This explains why even though the H5 vaccine has been used in poultry in China for over 10 years, H5 virus can still be detected in the live poultry markets, mainly from ducks,” Chen and her colleagues wrote in 2018.
Some Chinese farmers shunned HPAI vaccination because of worries that it could allow infections to spread without being detected by surveillance. Farms that raise chickens for their meat (the “broilers” that are slaughtered when they are about 6 to 8 weeks old) also had less financial incentive to vaccinate than farms with egg layers, which typically produce for a year or longer.
Still, Chen’s group found that about 70% of the chickens they sampled had antibodies from the H5N1 or the H5/H7 bivalent vaccines. As a result, she and her colleagues wrote in Emerging Microbes & Infections on 2 December 2022, “even though the globally circulating H5 viruses have been detected in many species of wild birds and occasionally in ducks or geese in recent years, they have never caused problems on routinely vaccinated poultry farms in China.”
China’s success in vaccinating against H7N9 is even more compelling. The Chen team sampled more than 50,000 poultry at some 1500 markets and farms before and after the H7N9 vaccine campaign began. They found the prevalence of the virus dropped by 93.3%, and the spread of H7N9 to humans stopped altogether. No human case of H7N9 has been reported since 2019.
The effort benefits both poultry and farmers, Chen told Science, because the government does not require culling an entire farm if the virus is found in one bird. “If it is in a farm with several barns, just birds in that barn will be destroyed,” she says.
Given that success, “We recommend that any unnecessary obstacles to vaccination strategies should be removed immediately and forever,” she and her colleagues wrote in a review paper this year.
Webster also sees lessons in China’s vaccination effort, which not only tamped down HPAI in China but likely kept H7N9 influenza viruses from spreading worldwide. “It is remarkable,” he says. “I believe that Chen is justified in believing that vaccination played an important role.”
The European Union in May 2022 conceded that vaccinating might make sense and is now testing candidates against 18.104.22.168b. At an October 2022 meeting in Paris, organized under the aegis of the International Alliance for Biological Standardization, participants called for “removing unnecessary barriers” for vaccination to control HPAI.
“We cannot keep doing the same thing over and over again,” said David Swayne, a veterinarian who for 28 years ran USDA’s main HPAI research group and co-organized the meeting, which brought together academic scientists, vaccinemakers, and representatives of European governments. “The virus has changed. We’ve got to change.”
In the United States, the National Chicken Council is not convinced. The organization, which represents broiler farmers, has long argued that using HPAI vaccines would lead to trade restrictions, based in part on fears of silent infections that could contaminate chicken products.
Swayne dismisses that concern, which his own group’s experiments may have helped fuel. They gave vaccinated birds extraordinarily high “challenge” doses of virus to see how well the vaccine prevented death and reduced viral shedding. The high doses meant that vaccinated birds sometimes got infected but showed no signs of illness. But the silent infection concern is “a misinterpretation of that data,” Swayne says. Vaccinated birds exposed to more realistic, real-world virus doses, he says, are unlikely to become infected.
Even if farms missed infections, the main U.S. export is meat, usually frozen—not live birds. No evidence exists that frozen meat can transmit influenza viruses. “When you look at risk analyses, they would say the chances of that happening are low or negligible,” Swayne says.
The bottom line is that business worries often trump science, says James Sumner, who served as president of the USA Poultry and Egg Export Council from 1990 to 2022 and remains a consultant there. “Many countries look for excuses to restrict trade,” he says—and many already have grievances against the United States. “The products that we export the most are the leg quarters, and we export those at a pretty low price because our industry makes its money on the upper half of the chicken, on the breast and the wings,” which Americans prefer, Sumner explains. Farmers in foreign countries “consider that unfair trade, and it is often classified as dumping,” he says. Refusing to import chicken meat from the United States if it vaccinates is a tempting retaliatory measure.
On the flip side, farmers who raise turkeys, another big branch of the U.S. poultry meat market, are more pro-vaccine because their birds are particularly susceptible to HPAI and they live for up to 6 months. “There are these divided camps,” Sumner says.
Still, the unprecedented H5N1 outbreak in the United States has altered the conversation. Vaccination “is discussed much more widely now, and there are some people who are pushing for it,” Sumner says. “We all recognize that there are situations where vaccination would be beneficial.”
Poultry vaccinemakers say they stand ready to develop products if the market exists. Kumar says it would be wise for the government to at least order doses for USDA’s National Veterinary Stockpile now, as it did in 2016 to prepare for a variant of an H5N1 strain that had devastated poultry flocks the year before. (In response to a Freedom of Information Act request, USDA told Science that the stockpile currently contains no HPAI vaccines.)
Zoetis has produced what’s known as a master seed to make vaccine against 22.214.171.124b, Kumar says, and done initial safety and efficacy studies. Boehringer Ingelheim told Science that it, too, had “completed efficacy tests against clade 126.96.36.199b.” But both companies are waiting for a signal from USDA that it will allow use of the vaccines. “It’s not like you just turn on the button, and you have vaccine ready, right? It takes time to get it done,” Kumar says.
In March, USDA began to test four different HPAI vaccines made by agency scientists, Zoetis, and Merck. Erica Spackman, acting director of USDA’s Exotic and Emerging Avian Viral Diseases unit, says her team will challenge vaccinated chickens to see how well they’re protected against the 188.8.131.52b strain. The commercial vaccines target earlier H5 strains, but Spackman says a mismatch between a genome used to make a vaccine and the virus in circulation sometimes doesn’t matter. “Some strains are very immunogenic and that overcomes the mismatches,” she says. Spackman has little concern about vaccines creating silent infections. “Within the context of a population monitored by a surveillance program, as would be the case here, infection is not silent,” she says.
In a statement to Science, USDA said if the vaccines work, which the agency should know by June, it will look for manufacturers to produce them. (It will also consider data from European labs now testing vaccines against 184.108.40.206b, Spackman says.) Then, “there are 20 discrete stages to complete” before companies can submit data for regulatory approval, the statement says. It typically takes 2.5 to 3 years to complete that process, the agency said, but “in emergency situations manufacturers may expedite development, resulting in a shortened timeframe to licensure.”
Reimer, the veterinarian who cares for the birds at Hilliker’s farm, does not expect to be vaccinating chickens soon enough to protect them from the current HPAI wave. “I’ve had these discussions before,” Reimer says. “With this particular outbreak, I’m guessing we won’t resolve anything.” But by the time the next HPAI outbreak hits, she says, her charges may not have to face the virus unprotected.