H5N1 Influenza Virus (“Bird Flu”) Is Unlikely to Become a Human Pandemic

Here’s why:

In May 1997, a 3-year-old boy died in Hong Kong of influenza. His death wasn’t unusual. Every year in every country in every corner of the world healthy children die from the disease. But this infection was different; health officials couldn’t figure out what type of influenza virus had killed the boy. The CDC sent a team of scientists to Hong Kong to investigate. Standing in a wet market, where local farmers slaughtered and sold their chickens, they found the source of the deadly virus.

The H5 strain of influenza virus that infected birds in Southeast Asia—named for the type of hemagglutinin on the viral surface—was particularly deadly, killing seven of every ten chickens. On December 30, 1997, health officials, to control the outbreak of bird flu before it spread to more people, slaughtered more than a million chickens. But the virus continued to spread. Bird flu attacked chickens in Japan, Vietnam, Laos, Thailand, Cambodia, China, Malaysia, and Indonesia. Then, to the horror of local physicians, the virus infected 18 more people, killing six: a death rate of 33 percent. (Typically, influenza kills fewer than two percent of its victims.) Soon the virus disappeared. Officials waited for an outbreak the following year, but none came. And it didn’t come the year after that or the year after that.

In late 2003, six years after the initial outbreak, bird flu reappeared in Southeast Asia. This time health officials found the virus even harder to control. Again, the virus first infected chickens. Officials responded by slaughtering hundreds of millions of them. Despite their efforts, bird flu spread from chickens to ducks, geese, turkeys, and quail. Then the virus spread to mammals: first to mice, then to cats, then to a tiger in a Thai zoo, then to pigs, then to humans. By April 2005, bird flu had infected 97 people and killed 53: a death rate of 55 percent.

During the past 20 years, H5 viruses have been reported from 23 countries, infecting about 50 people per year worldwide. More recently, H5 virus has spread widely in wild birds, poultry, and other animals. A few months ago, the virus was detected in dairy cows here in the U.S. In March 2024, an adult dairy farm worker in Texas suffered from what was later identified as H5 influenza virus. The patient had no respiratory symptoms and a normal chest X-ray. He did, however, have severe conjunctivitis (inflamed eyes) and conjunctival bleeding. On May 24, 2024, a second case  of H5 virus occurred in a dairy farm worker in Michigan. More recently, a third case was detected in a dairy worker and a fourth case in Colorado, again in someone in the dairy industry. None of these patients had pneumonia.

During the last few years of his life, Maurice Hilleman, who, in 1957, became the first scientist to predict an influenza pandemic and create a vaccine in advance of its entry into the United States, watched as bird flu spread from Hong Kong outward. He also watched as bird flu spread from chickens to small mammals to large mammals to man. Months before his death in 2005, Hilleman predicted that bird flu would never cause a human pandemic. Understanding his prediction depends on knowing the biology of influenza virus.

The most important protein of influenza virus is the hemagglutinin (or H protein), which attaches the virus to cells that line the windpipe, large breathing tubes, and lungs. But influenza virus doesn’t have only one type of hemagglutinin, it has sixteen. Bird flu is hemagglutinin type 5 (or H5). Although H5 viruses can rarely cause severe and fatal disease in man, spread of H5 virus from person-to-person is extremely poor. Hilleman noted that only three types of influenza hemagglutinins have ever caused pandemic disease in man: H1, H2, and H3.  H5 viruses, on the other hand, have circulated for decades and have never caused a human pandemic. Why? This is best explained by how influenza viruses attach to cells.  

H1, H2, and H3 influenza viruses bind to cells that line the nose, throat, windpipe, then further down the respiratory tract to the large breathing tubes and lung. These viruses bind to a receptor on cells containing alpha-2,6 sialic acid. This receptor is located on cells of the upper and lower respiratory tract. H5 influenza viruses, on the other hand, don’t bind to the alpha-2,6 sialic acid receptor. Instead, they bind to the alpha-2,3 sialic acid receptor. Unlike humans, birds have this type of binding receptor throughout their respiratory tracts. And cows have this receptor on their utters. This is why H5 viruses can cause pandemics in birds and cows. But H5 viruses don’t cause pandemics in humans.

Humans express the alpha-2,3 sialic acid receptor on cells that line the surface of the eye (which explains why the dairy farm worker in Texas had severe conjunctivitis). The alpha-2,3 sialic acid receptor is also found on cells that line the lung. However, and most importantly, the alpha-2,3 sialic acid receptor is NOT found in cells that line the upper respiratory tract. This means that H5 viruses cannot reproduce themselves in the upper respiratory tract and thus be easily transmitted from one person to another. It also means that H5 viruses cannot amplify themselves in the upper respiratory tract, where hundreds of virus particles can become millions of virus particles. All these new virus particles can then travel down to the lungs and cause pneumonia. For the most part, the only people who suffer pneumonia from H5 viruses are those who have had direct contact with animals secreting large quantities of the virus, like dairy and poultry workers, where the virus would then travel directly down to the lungs without requiring amplification in the upper respiratory tract. 

Although the world in now suffering a bird flu pandemic among wild birds, poultry, cows, and other animals, it is important to note that this H5 virus has not yet developed changes in the hemagglutinin that would allow for ready binding to the alpha-2,6 sialic acid receptor located in the upper respiratory tract of humans. Should this H5 strain evolve to bind readily to cells in the upper respiratory tract of people, a major pandemic could occur. But for now, Maurice Hilleman’s prediction, that H5 viruses don’t have what it takes to become a worldwide influenza pandemic, appears to be holding up.

What about vaccines? Two H5 influenza vaccines are currently available for high-risk groups. In February 2020, the FDA licensed an H5N1 vaccine made by CSL Seqirus. The two-dose vaccine is licensed for anyone over 6 months of age. A second vaccine, also made by CSL Seqirus, is available in Europe. The European vaccine, which is available for anyone over 18 years of age, is also a two-dose product but is composed of H5N8 virus, not H5N1. In June 2024, the European Union purchased 40 million doses of the H5N8 vaccine for 15 countries. Finland was the first to offer this vaccine for people in high-risk groups; specifically, those who work in poultry, dairy, or fur (mink, foxes) farms, veterinarians, and scientists studying this virus. The CDC has not yet made such a recommendation for those in the United States who are at highest risk.