Influenza

• 1. Introduction

  ›

  Influenza infects between 5 and 15 percent of the global population in a typical year. The math is staggering. Somewhere between 3 and 5 million of those cases turn severe, and as many as 650,000 people die of respiratory illness from the flu each year. Most listeners know the symptoms by heart. Fever, a sore throat, a dry cough, the aching muscles that send you to bed for days. What fewer people know is that this familiar winter visitor is one of the fastest-evolving threats medicine tracks. It hides in the bodies of ducks and pigs, swaps genetic parts like a card shark trading cards, and resurfaces every decade or so as something humanity has never seen. Why does the flu come back every winter when other diseases can be defeated once and for all? Why must a new vaccine be designed every single year? And how did a virus first written about in Greek texts from the 5th century BC become the model organism that taught scientists how viruses work? The answers run from the inside of a single cell to the great pandemics that reshaped the 20th century.

• 2. Four Families, One Name

  ›

  Aquatic birds carry the original. Ducks, geese, shorebirds, and gulls are the primary reservoir of influenza A virus, the form responsible for most severe illness, seasonal epidemics, and the occasional pandemic. From this avian source the virus has spread into pigs, horses, marine mammals, and people. Influenza A is sorted into subtypes by two proteins on its surface, haemagglutinin and neuraminidase, abbreviated H and N. Almost every possible pairing of H types 1 through 16 and N types 1 through 11 has been pulled from wild birds. In humans, only two combinations circulate widely, H1N1 and H3N2.

  Influenza B virus tells a different story. It mainly infects people, though it has turned up in seals, horses, dogs, and pigs. Rather than subtypes it splits into two lineages with cumbersome names, the B/Victoria/2/1987-like and B/Yamagata/16/1988-like strains. Both have circulated in humans since 1983, and both fall hardest on children. The Yamagata lineage may have gone extinct in 2020 or 2021, possibly wiped out by the distancing measures of the COVID-19 pandemic.

  Influenza C virus rounds out the trio that affects people, usually as a mild cold in young children, and it has been detected in pigs, dogs, camels, and cattle. The fourth member, influenza D virus, was a latecomer. Discovered in 2011 in pigs in Oklahoma, it counts cattle as its natural reservoir. Cattle workers have occasionally tested positive for past infection, yet influenza D has never been shown to make a human sick. These last two evolve far more slowly than their A and B cousins, which is exactly why they spawn so few new lineages.

• 3. The Cell Invasion

  ›

  Sialic acid is the key. The viral haemagglutinin protein latches onto sialic acid receptors studding the surface of a target cell, and that single act of binding begins the infection. The cell then swallows the virus inside a bubble called an endosome. Acid floods that bubble, twisting the haemagglutinin into a new shape that fuses the viral envelope with the membrane around it. Hydrogen ions pour through the virus's M2 ion channels, the internal scaffolding loosens, and the genetic cargo spills into the cell.

  Negative-sense RNA is what spills out, a genome split into pieces. Influenza A and B carry eight segments encoding ten major proteins, while C and D carry seven. Once inside the nucleus, the viral polymerase commits a small theft. It snatches the 5-prime caps off the cell's own RNA to jump-start the manufacture of viral messages. The hijacked ribosomes of the host then crank out new viral proteins by the thousand.

  Budding is the exit. New virus particles push out through the cell membrane, wrapping themselves in a stolen patch of it loaded with haemagglutinin and neuraminidase. At the very last moment the neuraminidase acts like scissors, snipping the sialic acid that still tethers the new virus to its parent cell so it can float free and infect again. When the cell finally fills with viral RNA, it triggers its own programmed death, a last-ditch attempt to stop the copying. The virion itself takes no single shape, appearing filamentous, rod-like, or spherical, with the spherical form running about 120 nanometers across.

• 4. Drift And Shift

  ›

  A few amino acid changes are all it takes. Antigenic drift is the slow accumulation of mutations in the genes for haemagglutinin and neuraminidase, and in the head region of haemagglutinin even a handful of swaps can let a new strain slip past antibodies the body built last year. This is the engine of seasonal flu, and the reason vaccines must be rebuilt annually. Drift runs fastest in influenza A, slower in B, and slowest of all in C and D.

  Reassortment is the sudden alternative. When two different strains infect the same cell, their segmented genomes can shuffle together and produce hybrid offspring, a process called antigenic shift. Because every influenza virus has a segmented genome, every one can reassort, though it happens most among influenza A viruses in birds. Pigs, bats, and quails are the dangerous middlemen here. Their respiratory tracts carry receptors for both bird and mammal viruses, making them mixing vessels where an animal strain can fuse with a human one. When that produces something capable of human-to-human spread, the result can be a pandemic.

  To watch for that moment, the World Health Organization runs the Global Influenza Surveillance and Response System, which tests several million specimens every year. The same machinery that updates the vaccine also stands as an early-warning network for the next shift no one can predict.

• 5. Spread And Severity

  ›

  Two meters is the danger zone. Respiratory droplets from coughing, sneezing, talking, and even breathing are relatively large, traveling less than two meters before settling onto nearby surfaces, and most flu transmission happens in that radius around an infected person. Smaller aerosols hang in the air longer and drift further. The virus can also survive for hours on hard, non-porous surfaces, so a contaminated hand brought to the face is enough to start an infection.

  Children ages 2 to 17 are the engine of spread. They are considered the primary and most efficient spreaders, and those who have not yet built up exposure to multiple flu strains shed the virus in greater amounts and for longer than other children. A healthy adult sheds for up to three to five days, but children and people with weakened immune systems can remain infectious for weeks. The flu is usually transmissible from one day before symptoms appear to five to seven days after.

  Where the virus lands shapes how bad it gets. Strains like H1N1 that settle in the upper respiratory tract tend to be milder but more contagious, while strains like H5N1 that strike the lower respiratory tract cause more severe illness yet spread less easily. In the worst cases the lungs fill with virus and the immune system overreacts in a flood of inflammatory signals known as a cytokine storm. Severe disease often comes not from the virus alone but from pneumonia, sometimes from a secondary bacterial invader. About a third of primary pneumonia cases are followed by a secondary one, most often caused by Streptococcus pneumoniae or Staphylococcus aureus.

• 6. The Yearly Defense

  ›

  Six to eight months in a chicken egg. That is how long it takes to grow most commercial flu vaccines, which are propagated in embryonated chicken eggs. Because flu seasons differ between the northern and southern hemispheres, the World Health Organization meets twice a year, once for each, to decide which strains to include. Modern vaccines are trivalent or quadrivalent, defending against an H1N1 strain, an H3N2 strain, and one or two influenza B lineages. Most are inactivated and injected into muscle, while live attenuated versions are sprayed into the nose. They only work when the vaccine strains match what is actually circulating.

  Oseltamivir is the front-line drug. Taken orally and approved for children as young as two weeks, it is one of a class called neuraminidase inhibitors that mimic sialic acid to jam the enzyme the virus needs to escape a cell. Zanamivir is inhaled, peramivir injected, and baloxavir marboxil works by a different route entirely, attacking the endonuclease activity of the viral polymerase. These antivirals work best within the first 48 hours after symptoms begin.

  An older class has fallen out of favor. The adamantanes amantadine and rimantadine block the M2 ion channel, but resistance to them spread through H3N2 starting in 2003 and became worldwide by 2008, so they are no longer recommended. Oseltamivir resistance, by contrast, faded after the 2009 pandemic H1N1 strain, itself resistant to adamantanes, displaced the resistant strains in circulation. Today resistance is mostly seen in patients undergoing treatment, especially the immunocompromised and young children.

• 7. Centuries Of Outbreaks

  ›

  The first convincing pandemic on record struck in 1510. It began in East Asia, swept into North Africa, then Europe, and was followed by further pandemics in 1557 and 1580. The 1557 outbreak may have been the first time the flu was linked to miscarriage and the death of pregnant women. Long before that, epidemics named influenza had crossed Europe in 1173 to 1174 and again in 1387, though it stayed unclear whether the flu was truly the cause.

  The word itself carries old superstition. Influenza comes from medieval Latin influentia, meaning visitation or influence, and the 14th-century phrase influenza di stelle, influence of the stars, blamed the disease on unfavorable astrology. The shortened flu first appeared as flue in 1839, with the spelling flu confirmed in 1893.

  The deadliest chapter ran from 1918 to 1920. The Spanish flu, an H1N1 strain, likely began in the United States and spread worldwide through soldiers during and after the First World War. Its first wave was mild, but the second later in 1918 carried a far higher death rate. By the end of 1920, roughly a third to half of all people on Earth had been infected, with tens of millions dead, falling disproportionately on young adults. That catastrophe reshaped science. Richard Shope's three papers in 1931 identified a virus behind swine influenza and reignited the field. By 1933 influenza A virus was pinned as the cause of human flu, influenza B followed in 1940, and the first vaccine was licensed in the United States in 1945.

• 8. Beasts And The Next Wave

  ›

  Seventy-five percent is the threshold. A classification system from 1981 calls an avian strain highly pathogenic if 75 percent or more of deliberately infected chickens die, while a low pathogenic strain causes mild or no symptoms. The genetic signature of the dangerous kind is a multibasic cleavage site in the haemagglutinin protein. A highly pathogenic H5N1 subtype was detected in geese in Guangdong, China in 1996, surfaced in Hong Kong poultry a year later, and has caused sporadic human cases with a high fatality rate since 1997.

  Migratory birds carry the threat across continents. In 2005 an H5N1 strain infected birds at Qinghai Lake in China, a breeding and stopover site, and from there reached more than 20 countries across Asia, Europe, and the Middle East. Ducks act as the crucial bridge, moving the virus from wild birds to free-range flocks and then into poultry, where the absence of biosecurity lets it take hold. Avian H9N2 draws special worry, because although it is low pathogenic it is a frequent donor of genes to H5N1 and H7N9 during reassortment.

  Pigs are the other great mixing vessel, carrying both the α-2,3 and α-2,6 sialic acid receptors that let bird and mammal viruses infect them alike. That dual access produced the 2009 swine flu pandemic, which originated in Mexico from a reassortment of human, swine, and avian viruses and caused hundreds of thousands of deaths. Since then H1N1, H3N2, and both influenza B lineages have circulated together as seasonal flu. Avian H7N9 began infecting people in 2013, starting in Shanghai and Anhui. With future pandemics of avian origin viewed as almost inevitable, and globalization making any new strain easier to spread, the work of preparation never stops.