Antigenic shift is the process by which two different strains of influenza combine to form a new subtype having a mixture of the surface antigens of the two original strains. The term antigenic shift is specific to the influenza literature; in other viral systems, the same process is called reassortment or viral shift.

Antigenic shift is contrasted with antigenic drift, which is the natural mutation over time of known strains of influenza (or other things, in a more general sense) to evade the immune system. Antigenic drift occurs in all types of influenza including influenza A, B and C. Antigenic shift, however, occurs only in influenza A because it infects more than just humans. Affected species include other mammals and birds, giving influenza A the opportunity for a major reorganization of surface antigens. Influenza B and C only infect humans, minimizing the chance to mutate drastically.

Flu strains are named after their types of hemagglutinin and neuraminidase surface proteins, so they will be called, for example, H3N2 for type-3 hemagglutinin and type-2 neuraminidase. If two different strains of influenza infect the same cell simultaneously, their protein capsids and lipid envelopes are removed, exposing their RNA, which is then transcribed to DNA. The host cell then forms new viruses that combine antigens; for example, H3N2 and H5N1 can form H5N2 this way. Because the human immune system has difficulty recognizing the new influenza strain, it may be highly dangerous. Such combinations caused, for instance, the infamous Spanish Flu outbreak of 1918 which killed 40 million people worldwide. Influenza virus which have undergone antigenic shift have also gone on to cause the Asian Flu pandemic of 1957, the Hong Kong Flu pandemic of 1968, and the Swine Flu scare of 1976.

Transmission of Influenza Viruses from Animals to People

Influenza A viruses are found in many different animals, including ducks, chickens, pigs, whales, horses, and seals. Influenza B viruses circulate widely only among humans.

There are 15 different hemagglutinin subtypes and 9 different neuraminidase subtypes, all of which have been found among influenza A viruses in wild birds. Wild birds are the primary natural reservoir for all subtypes of influenza A viruses and are thought to be the source of influenza A viruses in all other animals. Most influenza viruses cause asymptomatic or mild infection in birds; however, the range of symptoms in birds varies greatly depending on the strain of virus. Infection with certain avian influenza A viruses (for example, some strains of H5 and H7 viruses) can cause widespread disease and death among some species of wild and especially domestic birds such as chickens and turkeys.

Pigs can be infected with both human and avian influenza viruses in addition to swine influenza viruses. Infected pigs get symptoms similar to humans, such as cough, fever, and runny nose. Because pigs are susceptible to avian, human and swine influenza viruses, they potentially may be infected with influenza viruses from different species (e.g., ducks and humans) at the same time. If this happens, it is possible for the genes of these viruses to mix and create a new virus.

For example, if a pig were infected with a human influenza virus and an avian influenza virus at the same time, the viruses could mix (reassort) and produce a new virus that had most of the genes from the human virus, but a hemagglutinin and/or neuraminidase from the avian virus. The resulting new virus would likely be able to infect humans and spread from person to person, but it would have surface proteins (hemagglutinin and/or neuraminidase) not previously seen in influenza viruses that infect humans. This type of major change in the influenza A viruses is known as antigenic shift. Antigenic shift results when a new influenza A subtype to which most people have little or no immune protection infects humans. If this new virus causes illness in people and can be transmitted easily from person to person, an influenza pandemic can occur.

In 2004, scientists pointed out that the avian influenza virus might undergo an antigenic shift with the human flu virus and cause a global influenza pandemic like the one in 1918.