Re: Where does the flue come from every year?

Question: Where does the flu come from every year? Is it a new flu every 
time or is it just changing a little bit?
 
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. 

Structure
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. 

Classification
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 V 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: 
„h Flu Viruses at the Centers for Disease Control 
„h Influenza (National Foundation for Infectious Diseases) 
„h Influenza Information at the World Health Organization 
„h Flu News and Info 
„h Influenzanews 
„h Flu101 


Ed Balkovic, PhD 

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