How pandemic influenza emerges

Antigenic drift

Influenza viruses constantly change through a process called antigenic drift. This is the random accumulation of mutations in the haemagglutinin (HA), and to a lesser extent neuraminidase (NA) genes, recognized by the immune system. It is most pronounced in influenza A viruses. 

As is the case in all RNA viruses, mutations in influenza viruses occur frequently because the virus' replication machinery does not have a proofreading mechanism. When such changes cause mutations in the antigenic sites of the HA or NA genes, which reduce or inhibit the binding of neutralizing antibodies (the basis for resolving infection in an individual), the virus may evade the immune system. 

This process explains the occurrence of seasonal influenza epidemics that may differ in severity and age groups affected. It also accounts for vaccine mismatch when one of the strains selected for the vaccine does not optimally match the circulating strains. As a result, annual changes in the composition of influenza vaccines are necessary.

Antigenic drift in the NA can lead to resistance against neuraminidase inhibitors. Antigenic drift may also allow a virus to cross the species barrier to a new host.

Antigenic shift

Of greater public health concern is the process of antigenic shift –  also called reassortment – through which at least two different viruses combine, resulting in exchange of the HA (for example H3 replaced by H5) and consequently the formation of a mosaic virus. This may happen when two different influenza viruses infect a cell and the genome segments are exchanged during replication.

Since swine can be infected by not only swine but also avian and human influenza viruses, they are thought to be a potential "mixing vessel" from which a virus with pandemic potential could emerge. Genome reassortment is also frequently seen in waterfowl, especially ducks, which, though seldom symptomatic, shed the virus in their faeces for several months.

Viruses arising as a result of antigenic shift may cause pandemics, since they appear suddenly in populations that may have no immunity and against which no existing vaccine may confer protection. Both the H2, which appeared in 1957 (A(H2N2) or Asian influenza), and the H3, which appeared in 1968 (A(H3N2) or Hong Kong flu), came from influenza viruses circulating in birds. Based on historical patterns, influenza pandemics can be expected to occur, on average, 3 to 4 times each century.

Adaptive mutation 

In addition to antigenic shift, a pandemic virus may arise by the process of adaptive mutation in, for example, a virus that has crossed the species barrier, such as avian influenza A(H5N1) infections of human beings. Adaptive mutation may increase the capacity of the virus to bind to human cells during subsequent rounds of infection, thus increasing its transmissibility among human beings.