Avian Flu

Influenza A viruses are not unique to humans. Certain types of influenza A are specific to various different mammals (e.g. humans, pigs, sea mammals and horses) and to birds (avian influenza). Unlike mammals, however, birds can harbor all types of influenza A; that is those that infect mammals and those specific just to birds. Pigs can also harbor human and avian influenza A and produce hybrid viruses since they have receptors on their respiratory tract cells that can bind both human and avian influenza A. It was a thought that pigs were an obligate intermediary host in which these human-avian hybrid viruses were formed but in 1997 the direct infection of humans by a bird flu virus was documented. This virus was of the H5N1 types (see below) and infection resulted in a high mortality rate as a result of primary viral pneumonia. Normally, human infections by bird influenza A is extremely rare.

Influenza A sub-types

The virus binds to cells of the infected animal via two virus surface proteins called the hemagglutinin (HA) and the neuraminidase (NA). There are currently 15 sub-types of HA and 9 sub-types of NA circulating worldwide. Some of these occur in humans and some in other animals. For example, the influenza A viruses that have recently infected the human population are of the sub-types H1N1, H1N2, H2N2 and H3N2. H2N2 is not currently circulating in humans but the others are. In horses, we find H7N7 and H3N8 while in birds, H5N1, H9N2, H7N2, H7N7 and H7N3 are present.

Although wild bird populations can be infected by all types of influenza A, they usually do not show disease symptoms: i.e. the virus exhibits no or low pathogenicity. However, some avian influenza A strains can be very pathogenic, especially when  they spread into domestic poultry. These are the influenza A strains that have the H5 and H7 hemagglutinin. When low pathogenic viruses spread from wild birds to poultry, they can rapidly mutate to become highly virulent. This may occur within a matter of months and can decimate poultry flocks.  

Acquisition of increased virulence in domestic birds

Why should avian influenza A become highly pathogenic when it spreads from wild birds to domesticated birds? As will be discussed further below, flu viruses are always mutating and there are many forms that are slightly different within the virus population. This slow change in properties is called antigenic drift. As the virus population drifts there are likely to be variations in virulence: some will have higher pathogenicity and some will have lower. In the wild bird population, there is a selective advantage to low pathogenicity since wild birds are not usually in very close contact (at least not as close as in poultry farms). Clearly, if a highly pathogenic strain arises that kills its host very rapidly, it will not spread unless it reaches another bird before the host bird dies. The longer that the infected bird remains alive, the more likely is the virus to infect another bird. This means that there is a selective advantage in having low pathogenicity. However, this does not apply in the crowded conditions of poultry farms in which viral infections can move through the flock with great speed. Thus, when a pathogenic strain arises it spreads rapidly. Although it is true that highly pathogenic strains of H5 and H7 flu can arise in wild birds, they usually seem to die out before they can spread very far; in fact, when occasionally highly pathogenic H5 and H7 influenza A have been found in dead wild birds, it seems that the wild birds have usually caught the highly pathogenic form from domestic poultry. 

Influenza virus mutation and immunity – drift and shift

Our immunity to influenza A results largely from our raising antibodies to the two surface proteins of the virus - the HA and the NA proteins (these are the neutralizing antigens). However, as a result of the constant mutation of influenza viruses that are circulating in the human population, we see a change in the properties of the virus that is called antigenic drift. This drift occurs because influenza viruses are RNA viruses and the enzyme that copies their genomes has no proof-reading capabilities. After a few years, enough changes have accumulated in the HA protein and, to a lesser extent the NA protein, of circulating human influenza A that the virus cannot be recognized by the antibodies already possessed by the human population. Thus, we have less immunity to the drifted viruses and this leads to sporadic seasonal influenza outbreaks and limited epidemics. Since the viruses are drifting all the time as mutation is continuous, we need to develop new vaccines every year. 

Because of their genomes are broken up into eight segments, influenza viruses can swap segments of their RNA when two different viruses co-infect a single cell. Thus, if two different antigenic types, for example, H1N1 and H3N2, co-infect a cell, we can get H3N1 and H1N2 produced as well; all four of these have been circulating recently in humans. When human influenza A infects the same person or animal as a non-human influenza, reassortment can occur between the animal and human viruses so that a human influenza virus swaps one of its genomic segments for a homologous segment from the animal virus to form a hybrid virus. This often occurs in pigs which can harbor human, bird and pig influenza viruses simultaneously.  South East Asia is the area in which this frequently happens because humans and animals, especially pigs, live in close proximity and bird flu circulates in wild birds in this part of the world. Thus, pigs can acquire bird and human influenza viruses leading to reassortment. Bird flu does not normally infect humans directly (but see below). Reassortment can also happen in wild birds but humans are not in as close contact with wild birds as they are with pigs. 

Because of this reassortment, one might get a human influenza virus that has the HA or NA or both from bird flu or pig flu. If that happens, the surface antigens are likely to be new to the human population and humans will have no immunity since HA and NA are the proteins to which we raise neutralizing antibodies. Thus, we get an abrupt change in the antigenicity of the circulating viruses. If the internal proteins are those of a virulent human influenza virus, the new virus will spread rapidly and a major epidemic or pandemic results.  This survival strategy is of great advantage to the virus since there is the sudden appearance of a sub-type that is new to the human population and consequently a large number of susceptible hosts.

Sometimes, recombination is not necessary and the virus can simply jump from one species to another as it drifts. This is what has happened in South East Asia in 2004 when a bird influenza virus passed to some humans. This H5N1 virus is very virulent in people (has a high mortality rate) but is not easily spread from human to human (because it has surface antigens that are selected for transmission from bird to bird). It is likely, however, that it will reassort in a human with a human flu virus so that the H5N1 antigens are associated in a reassorted virus with internal proteins of a human influenza. This is likely to make it more easily spread by human to human contact. Alternatively, the H5N1 may simply mutate in humans without reassortment and some mutant viruses may spread more easily from human to human. 

Pandemics

Periodically a flu pandemic occurs. During the twentieth century, there were three pandemics in 1918, 1957 and 1968. In each case the important factor was the emergence of a virus that could be spread in the human population because it had a novel HA to which the population had not been exposed and therefore had no immunity (1918: H1; 1957: H2; 1968: H3)

Some pandemics, such as the Spanish flu of 1918-1919, killed millions of people but others resulted in much lower mortality. The Spanish flu virus was of the H1N1 influenza A type and we now know that it did not recombine with a human virus but bird H1N1 simply became infective for humans. In the early part of the 20^th century this virus killed more than 50 million people worldwide and at least half a million in the United States (the mortality rate was just 2.5%). This large number of deaths was partly because of the more unhealthy conditions that people lived in then and probably also because of crowded condition that resulted in some parts of the world from the First World War. Today, we have better sanitary conditions (at least in more developed countries) but we also have more rapid travel making it likely that a new influenza strain will spread much more rapidly than it did almost a century ago. 

Normally, flu kills the young because they have no immunity to the virus and the old because of their compromised immune system but in the case of the Spanish flu, many victims were young and otherwise healthy. The H1N1 influenza strain still circulates in people today, having crossed into humans again in the 1970’s, but now we have antibodies against it. Other famous pandemics that have occurred recently are the 1957/58 Asian flu (influenza A type H2N2) that killed hundreds of thousands and the 1968/69 Hong Kong flu (influenza A H3N2) that killed 700,000 people. Unlike the Spanish flu, these viruses emerged as a result of reassortment between human and bird flu.

Current avian flu

As noted above, avian influenza A viruses do not normally infect people but recently there have been sporadic cases in which humans have caught several of the circulating bird flu viruses. This has usually occurred when humans come in close contact with poultry flocks. Normally, wild birds spread their types of influenza A via the oral fecal route but they usually show no symptoms. They can, however, spread the virus to domesticated poultry. Avian flu, even in poultry, is often mild but when the HA is of the H7 or H5 type, the virus can rapidly become highly pathogenic, killing more than 90% of infected chickens within two days. Infected water birds (ducks, geese) frequently migrate large distances annually spreading avian flu worldwide.  

In 1997, the H5N1 strain of avian influenza A infected domestic poultry in Hong Kong and was transmitted to humans (no reassortment was involved). Six people out of eighteen infected died and it appeared that some of the infected humans got the virus from another person. To control this outbreak the Hong Kong authorities slaughtered 1.5 million chickens. H9N2 avian influenza A also appeared in humans in China and Hong Kong in 1999. There were no deaths. There have been sporadic outbreaks of other avian flu in poultry in recent years and isolated cases of transmission to humans. In humans H5N1 leads to the usual respiratory symptoms of flu and in some people acute respiratory distress, pneumonia and its complications including multiple organ failure.  

Why concern about H5N1?

Currently the strain of avian flu that is of greatest concern is H5N1. During 2003/04 there were a number of outbreaks of this strain in South East Asia in poultry in which a high virulence form developed; moreover, a small number of people have been infected and mortality has been high. Human to human infection has also been reported.   

The concern results from the possibility that this highly virulent H5N1 strain, which now appears to infect humans from birds, will mutate further so that human to human infection will be as easy as with human influenza A viruses. If this occurs a pandemic will result because H5 has not circulated in humans in the past century (thus we have no immunity) and this virus leads to high human mortality (50%).

So what are the risks? At present the virus does not spread easily to humans, as shown by the fact that about 100 people have so far contracted the virus (as far as is known) and in many H5N1 outbreaks in the past few years, no human transmission was evident at all. The World Health Organization notes that there are three conditions to be met for a pandemic to start:

• A new influenza A sub type emerges to which we have no immunity. This is the case with bird H5N1.
• This virus can infect humans, resulting in serious illness. This is also presently the case with H5N1 but it is rare.
• Human to human transmission is efficient.

So the two first conditions have been met in that H5N1 is a bird virus that has not circulated among people. When it does infect people, it is highly pathogenic. Thus, what presently stops a pandemic is the fact that the virus spreads from one person to another very inefficiently. But as long as human infections by H5N1 continue, the possibility of easily transmissible mutants arising by mutation is strong. This could be sudden as a result of reassortment or slow as a result of drift of H5N1 in infected humans. 

The World Health Organization (WHO) list several other causes for concern.

• Domestic ducks are now secreting H5N1 that is highly pathogenic to poultry yet the ducks show no symptoms. This means that there is a “silent reservoir” that is difficult to detect and control but is spreading the disease to other birds.
• The circulating strains of H5N1 found in birds have recently been found to be more pathogenic in laboratory mammalian models.
• Current H5N1 strains survive longer, allowing them to infect humans who come in contact with bird feces etc.
• Most mammals are resistant to bird flu but the mammalian host range is expanding as the virus drifts.
• Normally, wild birds are resistant to H5N1 bird flu. They carry the virus but show few symptoms. This seems to be changing. In 2005, about 6000 wild migratory birds died in one are of China. The WHO notes that there have been two other recent instances of high mortality in wild migratory birds.

Vaccines

Once we have identified a type of influenza A that can spread rapidly in humans, it should be possible to make a vaccine but we do not yet know the antigenic properties of such a virus since it has not appeared. Because we shall have to await the arrival of the new H5N1 virus, it will take up to six months after the start of the pandemic for the vaccine to begin to be available. 

The information above comes from the Centers for Disease Control (Atlanta, USA) and the World Health Organization (Geneva, Switzerland)