Bird-FlU: IS IT A HUMAN PANDEMIC THREAT?

Professor George G Brownlee, FMedSci, FRS

The potential for bird flu - avian influenza, to cause a human pandemic is now undeniable, since more than 200 people have been infected worldwide and over 100 have died, since the first human deaths were reported from Hong Kong in 1997. The mortality figure, - over 50% of infected people will die, makes this disease potentially one of the most dangerous known pathogens for Mankind. Deaths occur mainly in people who have been in close contact with infected poultry. Fortunately, bird flu has not, so far, adapted to become easily transmitted between humans. I, and most other influenza experts, agree that it is only a matter of time before this adaptation occurs. More strenuous Government action, and significantly more funds for influenza research are needed to prepare for, and hopefully overcome, this threat.

“Is it safe to eat a chicken that could have been infected with bird flu” is the first question I am always asked about bird flu. My answer is “yes, unless you eat is Sushi- style, uncooked.” This is invariable followed by the second question. “What is the risk of bird flu becoming a human pandemic like the infamous Spanish influenza of 1918 or the “Black Death” of the Middle Ages”. My answer is “I do not know, but I think it will occur sometime, although the time scale is uncertain”.

The acronym, H5N1, is not yet as far as I know an entry in the Oxford English Dictionary but I predict it soon will be. It describes the haemagglutinin (H5) and neuraminidase (N1) subtype of a particular group of bird flu viruses of the influenza A type, (to distinguish them from influenza B and the rarer C type viruses) that we have heard so much about recently. Virologists classify influenza A type viruses according to the different haemagglutinins and neuraminidase glycoproteins that exist in Nature. There are, in fact, 15 haemagglutinins and 9 neuraminidases, known to have infected birds, pigs, horses or seals.  These glycoproteins form the spikes on the surface of influenza virus (Fig. 1). H5N1 bird flu is no different in overall structure from a conventional influenza virus.  Only 3 of the influenza A subtypes, i.e. H1N1, H1N2 and H3N2, are normally associated with conventional flu in Man.

But all this changed in 1997, when the first case of an infection and death of a person from bird flu was recorded. The subtype was H5N1. H5 strains had previously been detected in poultry, for example in Scotland in chickens in 1959 (influenza A/chicken/Scotland/59). This virus killed many chickens but no human deaths were reported. By contrast, 224 people have so far been known to have been infected with H5N1 virus in 10 Old World countries with the highest number of deaths in Vietnam (see Table). 127 people - mainly those in close contact with H5N1 infected chickens, have died.  However the risk of infection is not restricted to poultry workers. Well-authenticated examples of human to human transmission have been reported in families after one member of the family has been infected. So far, in the UK, H5N1 has been reported only in a single swan from Scotland.

Based on prior knowledge of the avian origin of the H2N2 human pandemic in 1957 and the H3N2 human pandemic in 1968, and the likelihood that the 1918 Spanish flu was also of avian origin, it is probable that a human pandemic based on the H5N1 virus will arise sometime. It is likely that this will occur by a mixed infection of a person with a bird flu (H5N1) virus and a conventional, currently circulating human influenza of H3 or H1 subtype. I illustrated a theoretical and frightening scenario (Fig. 2) showing how this might occur in the year 2016! Further point mutations in a number of the gene segments of such a so-called, reassortant virus would probably be required to adapt a H5N1 bird flu virus to become a pandemic threat and transmit easily between people.

Many governments, including the UK government, have taken steps (pandemic planning) to protect their population against a potential bird flu pandemic by stockpiling antivirals and vaccines. The UK government is currently stockpiling about 14 million courses of the anti-neuraminidase inhibitor “Tamiflu”. But it is unclear, who in the UK population of 60 million or so people, would qualify for this antiviral in the event of a real pandemic!  I believe some people are already stockpiling antivirals in their own domestic fridges.  The UK Government has also authorized expenditure, somewhat belatedly, for the preparation, testing and stockpiling of several million doses of anti-H5N1 vaccines.  It is gratifying to me that Dr Fodor and I were able to contribute, in 1999, to the development of an important methodology of easily preparing influenza virus in the laboratory from DNA plasmids. This procedure is now the basis of the method for preparing H5N1 human vaccines, and also for preparing H5N1 vaccines for use in poultry. I have heard that 500 million doses of vaccines have already been administered to poultry in China to protect this valuable food resource and to protect against the spread of H5N1 bird flu.

Welcome as these initiatives are, there are problems with existing antivirals and with preparing anti-H5N1 vaccines. Existing antivirals have to be administered very soon after symptoms of infection are noticed otherwise they may be too late to markedly alter the course of the disease. Additionally, antiviral resistance to Tamiflu has now been reported.  Combination therapy with several antivirals of different specificity is required to overcome this problem. Moreover, vaccines will only be effective against the current circulating H5N1 strains of bird flu. When a pandemic arises  it is probable that the antigenicity of the haemagglutinin of the H5N1 bird flu  would  have undergone significant “antigenic drift”, due to the rapidly evolving nature of influenza viruses, thereby making vaccines prepared against strains of bird flu circulating 10 years before ineffective or of limited use. In summary, more research effort and more funds for basic research on bird flu are needed to tackle the bird flu threat and enable new therapies to be developed.

This article first appeared in Isis News Ediiton 48, Summer 2006