New study points to possible 'flu firewall'

An Australian-US study has shown it may be possible to develop a 'firewall' vaccine against the world's most dangerous human pathogen, the influenza virus.

The collaborative study, published in Proceedings of the National Academy of Science this week, suggests that a recombinant vaccine designed to induce cell-mediated immunity, could provide broad-spectrum protection against the changeling virus.

Teams led by Nobel laureate immunologist Prof Peter Doherty and Dr Steve Turner, of the University of Melbourne, and Dr Robert Webster of St Jude Children's Research Hospital in Memphis, Tennessee, found that laboratory mice retained a limited but "not negligible" T-cell memory of an infection by one strain of the influenza virus, that conferred a degree of protection against infection by other strains.

Because the influenza virus' coat proteins change frequently and unpredictably, conventional influenza vaccines protect only against currently circulating strains. It takes around six months to develop a vaccine after a new strain is detected.

International health authorities fear the first major 'flu pandemic of the 21st century is long overdue, and inevitable, and the world is as vulnerable as it was during of the 20th century's biggest pandemic. The deadly Spanish 'flu of 1918-19 killed an estimated 20 million people on six continents; as many as 20 million more died of secondary pneumonia.

Influenza is more highly contagious than the SARS virus, because it is spread by sneezing. The world's great cities are less than a day's jet travel from south-east China, the epicentre of past pandemics, and a lethal new 'flu virus would take a devastating human and economic toll long before a vaccine could be developed.

In the 1990s, the small Australian biotech company Biota Holdings developed a drug that prevents influenza, and alleviates an established 'flu infection, but a vaccine that protected against all current and future strains would be humankind's best defence against any new pandemic.

Attempts to develop a vaccine cross-protect against multiple influenza strains have all failed -- the immune system's antibody 'memory' of past infections is ineffective, because it cannot anticipate how the virus' coat proteins will change in emerging strains.

But Melbourne University's Steve Turner said certain segments of the virus' internal proteins are highly conserved between strains. They offer a relatively fixed target for a vaccine that would induce a killer T-cell response.

T-cell memory

The Melbourne and Memphis researchers have confirmed the existence of durable and stable T-cell 'memory' of a previous infection, directed against highly conserved domains of two of the virus' internal proteins -- nucleoprotein and acid polymerase.

Turner said that when he and his colleagues mutated the virus to eliminate these lacking these target domains, the mice were more susceptible to infection. This indicated that the T-cell response to internal proteins normally complements the primary, antibody response to the virus.

Using reverse genetics, the researchers developed recombinant virus strains in which the internal proteins incorporated peptides from other sources -- mice exposed to these strains developed a T-cell memory that subsequently protected them against other recombinant strains.

But Turner said the response varied according to the combination of genes, or haplotype, in the mouse's major histocompatibility complex, which coordinates the immune response.

One inbred mouse strain with a particular MHC haplotype responded to specific domains of the internal proteins, but mice with a different MHC haplotype did not.

Turner said it may be necessary to custom-design vaccines to protect people with different MHC haplotypes, or to develop combination vaccines that would span the diversity of haplotypes in the population.

"But our experiments suggest that a lot of people who have been exposed to influenza may already have a persistent, stable T-cell memory that could be boosted by a vaccine," he said.

Turner said the findings had implications beyond influenza. It might be possible to use a similar strategy to develop vaccines to induce cell-mediated immunity to intracellular pathogens like the tuberculosis bacterium or even the malaria parasite, that are also able to evade the immune system's antibody defences.