MadSci Network: Virology

Re: How exactly does influenza evolve into new strains so often?

Date: Wed Nov 24 14:02:21 1999
Posted By: Edward Balkovic, Ph.D., Pharmaceutical Microbiology (Quality Control), Genzyme Corporation
Area of science: Virology
ID: 943359589.Vi

Question: How exactly does influenza evolve into new strains so often?

Influenza virus has a number of factors going for it in regards to its ability to evolve into new strains.

Historical Background

Influenza viruses were probably a major cause of disease in ancient times; retrospective tracing has dated the occurrence of influenza epidemics back to at least 1173. There is a nearly continuous record of epidemics, which are periodically interspersed with extensive pandemics (i.e. world-wide epidemics). During the past century, serologic testing of samples from elderly persons has permitted a more certain assessment of epidemic disease. In 1889, a pandemic occurred with a type A virus containing an H3-like hemagglutinin and an equine-like neuraminidase. Little is known of influenza in the intervening years preceding the devastating pandemic of 1918, which was caused by a H1N1 (formerly called swine flu) virus. During that epidemic about 20 million people died worldwide with approx. 500,000 people dying in the United States.

The modern history of influenza began with its isolation from humans in 1933. This virus was later shown to be antigenically related to a virus isolated in swine two years earlier. In 1940, a second antigenically distinct human virus was isolated and it was designated influenza B, to distinguish it from the earlier virus which was then designated influenza A. Finally, a third antigenically distinct virus, influenza C virus, was isolated in 1949. We will concentrate on influenza A & B viruses in this lecture.


The influenza viruses are characterized by a segmented genome, that is located within a helical nucleocapsid. The nucleocapsid and matrix proteins are surrounded by an envelope that is composed of a lipid bilayer. Protruding from the envelope are the antigenic viral surface glycoproteins: the hemaglutinin (HA) and neuraminidase (NA). The genome of the influenza A & B viruses is composed of 8 segments of RNA. Each of the segments code for at least one polypeptide. The structural proteins of the virion are encoded by separate gene segments and include: 3 viral RNA polymerases, nucleoprotein, matrix, and the HA and NA surface glycoproteins. Another segment codes for 2 non-structural proteins, whose functions are not well known.


Influenza viruses are placed within their proper type (A, B, or C) by antigenic similarities among their internal nucleocapsid and matrix proteins. Within the type A viruses, subtypes can be distinguished by antigenic differences among their HA & NA glycoproteins. New influenza subtypes are detected by major antigenic changes within the HA and/or NA glycoprotein subtypes (“antigenic shift”). These changes are believed to occur due to re-assortment with animal influenza A viruses. Finally, within the type A subtypes, variants can be detected by antigenic divergence of the HA & NA proteins (“antigenic drift”). These new variants are generated by an accumulation of point mutations in these proteins. Viral subtypes have not been seen in type B virus, but antigenic variants have been detected. The lack of major antigenic change in type B is probably due to the lack of its circulation in animal species.

Generation of new influenza viruses infectious for humans

As mentioned above, the influenza viruses are divided into three types (A, B, and C) based on reactogenicity of their internal antigens. I will limit the remainder of my answer to influenza type A viruses, since they show the most genetic variation.

Influenza A viruses are classified and divided into subtypes based on their surface glycoprotein antigens: 14 subtypes of hemagglutinin (HA or H) H1-H14 and 9 types of neuraminidase (NA or N) N1-N9. These influenza type A viruses are able to infect a number of different species including: humans, swine, horses birds, and aquatic mammals. All 14 subtypes of HA have been isolated from birds, 3 of them in humans, two in pigs, horses, seals and whales, and one in mink. The NA antigens show a similar species distribution. Therefore, a large number of non-crossreactive influenza antigens are always circulating in nature. Antibodies produced against HA and NA antigens are responsible for protection against re-infection by the identical virus subtype.

Major evolutionary changes (emergence of new viruses) in the influenza type A viruses occur by the mixing or re-assorting of their genetic material causing changes in their external surface HA and NA antigens. This phenomenon is known as “antigenic shift.” The genetic material or genomes of influenza viruses occur in eight separate molecules or segments. If two different subtypes of influenza A virus infect the same cell, their genetic segments are able to reassort and produce a new influenza virus with segments from both infecting viruses. As an example, if a H3N5 virus and a H2N2 virus infect the same cell the following offspring viruses can be produced: H3N5, H2N2, H3N2, and H2N5. This re- assortment can occur between human and animal isolates. Therefore, new viruses can be produced which can replicate in humans, but have new subtypes of animal HA and NA antigens. There are no protective antibodies to these antigens in the human population, so the new virus can spread very rapidly around the world.

The virus subtypes that have been so far been known to infect humans are H1N1, H2N2, and H3N2. The H1N1 viruses circulated from the beginning of the century through the 1950’s. In 1957, a new H2N2 virus appeared, known as the “Asian Flu”, and rapidly spread around the world. This virus had both a new HA and a new NA. In 1968, another new virus appeared – a H3N2 virus, known as the “Hong Kong Flu.” This virus was not as severe as the H2N2 virus, since it only varied in the HA antigen. The H1N1 virus also reappeared in 1977. Currently, both the H3N2 and H1N1 viruses are circulating through the human population. The major question is what new virus (H?N?) will emerge in the future and cause the next major world-wide epidemic.

You may then ask, “Why then do people get sick with the flu every couple of years, when there has been no major change in the HA or NA antigens?”

Well, between major changes in the HA and NA antigens, point mutations can occur on the HA and NA molecules and these mutations may help the virus to avoid the protective antibodies and produce an illness. This phenomenon is known as “antigenic drift.” The H3N2 virus has been able to successfully drift from its initial appearance in 1968 and still produce infections in 1999.

Additional information about influenza viruses and their evolution can be found at the following websites:

Ed Balkovic, PhD

The views and opinions expressed here are my own and may not reflect those of my employer.

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