Influenza viruses constantly evolve to evade the immune systems of their hosts, allowing them to circulate globally and cause seasonal outbreaks. While the virus is always undergoing minor adjustments, occasionally a dramatic transformation occurs that completely alters its identity. This abrupt and significant genetic change is known as antigenic shift, a process that fundamentally resets the evolutionary rules for the virus.
What Antigenic Shift Means
Antigenic shift is a sudden, major change in the surface proteins of an influenza A virus, leading to the emergence of a completely new subtype. Influenza A viruses are classified by two surface proteins, hemagglutinin (H) and neuraminidase (N). A shift results in a novel combination of these antigens, such as a switch from H1N1 to H2N2. This dramatic alteration means the resulting virus is immunologically distinct from any strain that has recently circulated. Consequently, the vast majority of people have little to no pre-existing immunity to the new virus. Antigenic shift is almost exclusively associated with influenza A viruses because their wide natural reservoir in animals like birds and pigs facilitates the necessary genetic mixing.
The Molecular Mechanism of Reassortment
The mechanism underlying antigenic shift is a genetic process called reassortment, facilitated by the unique structure of the influenza virus genome. Unlike many other viruses, the influenza A virus genome is segmented into eight separate pieces of RNA. This segmentation is a prerequisite for the genetic shuffling that defines a shift.
Reassortment requires a single host cell to be simultaneously infected by two different influenza A virus strains, a situation referred to as co-infection. For instance, a cell in an intermediate host, such as a pig, might be infected by both a human and an avian influenza strain. Pigs are often implicated because their respiratory tract cells possess receptors for both avian and mammalian influenza viruses.
Once inside the co-infected cell, the eight RNA segments from both parental viruses are replicated. As new virus particles are assembled, they randomly package eight RNA segments from the available genetic pool. This random mixing can result in a progeny virus that inherits surface antigen genes (H and N genes) from one parent strain and internal genes from the other, creating a new, mosaic virus. If this reassorted virus possesses a novel combination of H and N antigens and can efficiently transmit between humans, an antigenic shift has occurred.
Distinguishing Antigenic Shift from Drift
Antigenic shift stands in sharp contrast to the more frequent, gradual change known as antigenic drift. Drift involves small, subtle changes in the viral surface proteins that occur constantly due to point mutations during replication. These incremental changes accumulate over time, allowing the virus to slowly evade the immune system and necessitate the annual update of seasonal influenza vaccines.
Shift is a non-continuous, abrupt event where an entirely new subtype emerges, while drift is a continuous, steady evolution of existing subtypes. Drift occurs in all types of influenza viruses, including Type A and Type B. However, antigenic shift is largely confined to influenza A because its wide host range allows for the co-infection and reassortment necessary to generate truly novel H and N combinations.
The Global Health Impact
The consequence of antigenic shift is the sudden introduction of a novel influenza A virus into the human population, which can trigger a pandemic. Since people have no immunological memory against the new surface antigens, the virus encounters a fully susceptible population. This lack of existing immunity allows the new strain to spread rapidly across continents, infecting a large number of people.
Historically, every influenza pandemic has been linked to an antigenic shift event. The emergence of the H2N2 virus in 1957 and the H3N2 virus in 1968, for example, resulted from reassortment between human and avian viruses. More recently, the 2009 H1N1 influenza outbreak was caused by a reassortant virus that contained genes from avian, swine, and human influenza viruses. Antigenic shift represents the greatest threat for severe, widespread respiratory disease.