23 October 2002 19:00 GMT

by Julie Clayton

Malta - Researchers are closing in on the genes responsible for enabling flu viruses to leap straight from birds to humans, reported virologists at the First European Influenza Conference here. Identifying those genes could aid vaccine development and protect against killer infections such as the 1997 Hong Kong flu outbreak, which shocked virologists because it showed, for the first time, that flu could jump directly from birds to humans, without infecting an intermediate host, such as pigs.

Avian influenza viruses of the H5N1 type, which were circulating in live bird markets and poultry farms around Hong Kong between May and December 1997, infected 18 people and killed six. Fortunately for the contacts of the victims, the viruses could not spread from person to person: each case involved direct transmission from birds to humans.

But it may only be a matter of time before an avian virus evolves the capacity to spread from person to person, particularly if the infected individuals also harbor human influenza viruses with which the avian strains could reassort. The people infected in 1997 had no protective immunity against the viruses.

These events have given rise to two new lines of research. The first is to understand the genes responsible, and the second, to produce vaccines that could serve as prototypes for the protection of people against future infection.

Jaqueline Katz, section chief at the Center for Disease Control and Prevention (CDC) in Atlanta, today revealed the identity of at least one of the genes - coding for an internal virus protein, PB2- that might have been responsible for the severity of the 1997 Hong Kong outbreak.

Katz compared the action of two different strains of the 1997 virus. The first strain, HK483, was found in a 13-year old girl who had died, and in whom an autopsy revealed that the virus had spread to many organs, including her brain. The second strain, HK486, came from a five-year old girl who had suffered a milder form of disease and recovered.

By reverse genetics, Katz's team used plasmids to isolate and capture individual viral genes, and swap these between the two strains. Inserting the PB2 gene from the "high-pathogenicity" strain HK483, into the background of the "low-pathogenicity" strain HK486, produced a recombinant virus with the same features as the wild-type parent HK483 strain, at least in mice. Notably, the recombinant virus spread easily to multiple organs. By contrast, placing the PB2 gene from strain HK486 into strain HK483, yielded a hybrid virus that did not spread beyond the place where it was inoculated - whether the lungs or elsewhere.

Meanwhile, Katz's colleague Kanta Subbarao, chief of the Molecular Genetics section at CDC, is producing the first vaccines against avian flu strains that continue to circulate among birds in Hong Kong and China, including the H5N1 type.

Using human viruses as backbones, Subbarao's team has created hybrids by substituting in avian counterparts of the genes for hemagglutinin and neuraminidase. As surface glycoproteins, these form the targets for protective antibodies.

Following inoculation into mice, the hybrid viruses not only triggered good antibody responses, but also protected the mice against challenge with the wild-type avian viruses, suggesting that avian-derived strains have good potential as future vaccines.

Subbarao told delegates that she was keen to begin collaborating with industrial partners to exploit the potential of the vaccine "seeds." Her vaccine-development strategy is moving away from previous approaches, she says, because the rapidly changing antigenicity of flu viruses makes it pointless to prepare a vaccine until an outbreak occurs.

"What we have learnt since 1997 is that it's taken a very long time to even have vaccine candidates," said Subbarao. "We also know that it's going to probably take two doses per person to immunize."

From now on, she said, the approach will be to say: "Let's get some experience, let's make some vaccine so that maybe the first dose can be with something of the right subtype, maybe it's not the exact strain, and by the time of the second dose we might have the right strain.

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