Science: A sniff of a cure for flu

Scientists are on the attack against influenza's ability to mutate into lethal new varieties.
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For those of us who have struggled through the new year with a hacking cough, aching sinews and a runny nose, it is small comfort to learn that - officially at least - Britain is not in the midst of a flu epidemic. Doctors need to report about twice as many cases as they have in recent weeks for an epidemic to be declared. This lack of official recognition, however, has not stopped the spread of one of the most potent viruses in the catalogue of human disease.

Influenza, named in 14th-century Florence when an unusual conjunction of planets was thought to "influence" an outbreak of coughs and fever, has dogged humankind for generations. It caused the single biggest pandemic this century when a particularly virulent strain killed between 20 million and 40 million people in the winter of 1918-19. Even in non-epidemic years, flu routinely kills thousands of Britons, mostly the very old and infirm.

Although flu is a common infection, it has proved uncommonly difficult for scientists to tackle. The virus has an in-built variation mechanism to ensure that, with every successive replication, many different kinds of viral progeny are spawned.

This chameleon-like ability to change its appearance accounts for the way it bobs and weaves its way past our immune defences. Flu seems to have evolved a foolproof way of moving efficiently through a population to ensure that there are plenty of viruses floating in the vicinity of a chance cough, a sudden sneeze or an inadvertent yawn.

Hope is on the way, however, in the form of two new drugs being tested. Both attack a part of the virus which scientists believe will prove to be its Achilles heel.

The viral protein in question is called neuraminidase, and plays a vital role in the life cycle of the flu agent by cutting the "umbilical cord" that keeps the newborn viruses from attacking uninfected cells.

What makes neuraminidase such an attractive target for drug designers is that the protein contains a region that seems to be common to all flu viruses. This "conserved site" is crucial for carrying out the protein's job of cleaving the virus as it emerges from the membrane of the human cell where it was created. The rationale is that if a drug can be made to block this site, the virus can be prevented from freeing itself, so stopping the infection of further cells. And as all flu viruses possess the same conserved site on their neuraminidase protein, it should work against all strains of virus.

Graeme Laver, professor of biochemistry and molecular biology at the Australian National University in Canberra, was the first scientist to grow crystals of neuraminidase, which led to the discovery of the 3-D structure of the protein's conserved site by Peter Colman of the Commonwealth Scientific Research Organisation, in Australia. Since then, drug companies have been racing to find drugs that can slot into the conserved site of neuraminidase, as a key fits a lock.

Two such contenders have emerged, although neither is yet licensed. One, called zanamivir and backed by Glaxo-Wellcome, began its first human trials in 1994 and is applied via an inhaler. The other, dubbed GS 4071 and developed by Gilead, a Californian company, with backing from Roche, is given in tablet form.

Both neuraminidase inhibitors, however, will work only if they are given in the earliest stages of infection, often long before people realise they have flu. Scientists believe that this means the drugs will offer practical help only if a simple test can be devised for people to see whether they are in the first stages of disease - before obvious symptoms have appeared.

Treating flu with drugs, therefore, is still some years away, which means that the main defence against a deadly new pandemic is constant surveillance for the emergence of new strains and the development of specific vaccines to combat their spread. It is, of course, the variability of the influenza virus that has made it so difficult to develop a vaccine that can work against all versions of the disease.

There are three main types of flu virus - A, B and C. Within the A type, which can infect both human beings and other animals and has been responsible for the most deadly epidemics, virologists have identified a number of sub-types based on versions of the two key proteins found on the virus's surface, neuraminidase and haemagglutinin, which serves the function of locking on to the cell membrane prior to the virus infecting its host cell.

So far scientists have identified 15 haemagglutinin sub-types and nine neuraminidases. Combinations of these two protein are used to classify A-type flu viruses, along the lines of sub-type H1N1, H1N2 or H2N2, and so on. Scientists believe it was the H1N1 sub-type that caused the 1918- 19 pandemic. The 1957 Asian flu outbreak which killed 1 million people was caused by H2N2, and sub-type H3N2 killed 700,000 in the 1968 pandemic of Hong Kong flu.

Flu experts believe that the worst pandemics are caused when new forms of the virus emerge, and are able to overwhelm the body's immune defences. It is also possible that some flu viruses are more lethal than others because their haemagglutinin protein somehow enables them to infect a wider range of tissues, rather than just the cells lining the respiratory tract.

Is it possible that the most deadly pandemics are caused by changes to the haemagglutinin protein? Attempts to extract flu virus from the corpses of 1918 victims preserved in the permafrost of Alaska and the Norwegian island of Spitsbergen have so far failed to resolve this problem. "What we don't yet know is what determines the virulence of the virus," says Alan Hay, director of the World Health Organisation's World Influenza Centre at the National Institute of Medical Research, at Mill Hill in north London, where the flu virus was first isolated in 1933.

Although viruses can "drift" from one replication to another, they can occasionally experience a more radical "shift" which involves the shuffling or recombination of genetic material during the viral version of sex. Type A virus, which also infects wild birds, domestic fowl and pigs, is a skilful exponent of the phenomenon, which accounts for its pandemic potential.

When strains of type A flu from different species come together in one individual, the conditions are perfect for a shift to take place. Pigs are thought to be the most likely mixing vessels for different flu viruses, allowing the free exchange of genetic material. The result is a new strain of flu that can then cause havoc in the human population by being so unusual. Virologists believe that China is the place most likely place for this to occur, because of the large numbers of people, pigs and ducks living in close proximity. This could account for so many epidemics starting in the East.

But pigs are not the only suspect animals. A year ago a new strain of flu emerged in the chicken population of Hong Kong. More than 1.5 chickens were slaughtered, but not before the virus had jumped the species barrier to infect 18 people, six of whom died. Fortunately, although the virus was deadly, it did not seem to possess the ability to move easily from one person to another. If it had done, it would almost certainly have developed into the next pandemic.

Surveillance has been intense since last year to try to find out whether this Hong Kong virus has managed to escape into the human population, or to infect other animals. "There is no evidence that it's out there in the population. It seems that the majority of those who were infected had direct contact with chickens," says Dr Hay. "But there is concern about a recombination with another virus to make it more easily transmissible."

Even if this did not happen with the Hong Kong chicken virus, there will be plenty of opportunities in the future for it to occur with another flu virus, Dr Hay says. "What we know is that a pandemic will happen. What we don't know is when."

Pete Davies's book, `Catching Cold', is to be published by Michael Joseph in August