A shot in the arm

Hong Kong's scientists are accustomed to being thrust onto the frontline in the battle to control disease. They helped crack the mystery surrounding the cause of Sars, and before that they helped trace the evolution of bird flu.

Now, a fresh crop of scientists and medics is on another mission to unlock more of the mysteries surrounding influenza, and make the city an international research centre for a disease that remains one of the main threats to world health.

Backed by HK$136 million in funding, a collaborative effort is being undertaken by researchers from the University of Hong Kong, Chinese University, Hong Kong University of Science and Technology and Baptist University.

The scale of their mission is unprecedented in Hong Kong. The eight-year project hopes to tap into international efforts to prepare for and control the next flu pandemic, which experts warn is overdue.

Scientists have said for some time that the H5N1 bird flu virus could mutate into a form that spreads easily among people, sparking a pandemic. The virus began plaguing Asian poultry stocks in late 2003. At least 223 people have died worldwide, with Indonesia accounting for 101 of them.

The team began its quest after being awarded HK$76 million last September, the biggest allocation by the University Grants Committee under its Areas of Excellence scheme. The project, titled Control of Pandemic and Inter-pandemic Influenza, is backed by another HK$60 million from other sources.

The team comprises eight group leaders, 18 co-investigators, 15 research collaborators from Hong Kong and the mainland, and 23 international collaborators.

An international scientific board includes Peter Doherty, a Nobel Prize-winning immunologist; flu virologist John Skehel; Roy Anderson, who developed mathematical modelling for epidemiology in Britain; renowned flu and Sars researcher Albert Osterhaus; Simon Gordon of Oxford University, an expert in the field of innate immunity; Eddie Holmes, an expert on viral evolution; and Zhong Nanshan, director of the Guangzhou Institute of Respiratory Diseases.

'We have clearly shown that Hong Kong has contributed significantly to knowledge in the past. We are very confident with this additional resource and with this core group we will really enhance the contribution of Hong Kong to global research,' said project co-ordinator and director, Malik Peiris, who is also chair professor in microbiology at the University of Hong Kong. 'This is really our vision, to basically enhance public and animal health by developing a synergistic multidisciplinary influenza research programme.'

The first data on the impact of seasonal flu in tropical places came from the local universities.

'Influenza is not only important in pandemics. We have shown that in seasonal flu, over 1,000 people die within Hong Kong itself, mainly in the over-65 age group,' said Professor Peiris, Hong Kong's

bird flu expert and a Fellow of the Royal Society.

His comments underscore concerns that while bird flu continues to wreak havoc on the poultry industry, there is growing lethargy about flu pandemic preparedness.

Last week, a leading US specialist on infectious diseases said much of the world, including governments, business and the news media, was 'asleep at the switch'.

Michael Osterholm, director of the Centre for Infectious Disease Research and Policy at the University of Minnesota, and a frequent writer on such topics as avian flu and bioterrorism, said planning was poor. 'People just assume business will run as normal - which it won't. And no one, including the media, is paying attention.'

The fallout from a flu pandemic, he said, could include massive energy shortages around the world, a surge in other deadly infectious diseases, and uncountable associated deaths due to shortage of medical supplies and treatment.

Dr Osterholm made his comments at a media conference sponsored by the East-West Centre of Honolulu and co-hosted by the National Press Council of Thailand.

The controller of Hong Kong's Centre for Health Protection, Thomas Tsang Ho-fai, said his agency considered the project 'very valuable'.

'The project involves many aspects of influenza, including virology, epidemiology and clinical management. By understanding more about the evolution of virus, pathogenesis, transmission, infection control, anti-virals and vaccine during the inter-pandemic period, we will be able to contribute knowledge to the world to better deal with influenza and the next pandemic influenza,' Dr Tsang said.

Researchers at Hong Kong University have been studying H5N1 since it jumped the species barrier in 1997 and infected 18 people, killing six of them. They worked with seed money of HK$1 million, and the project grew into a multi-disciplinary research.

The same team also put their heads together to solve this century's plague: Sars, which was detected in a Hong Kong hotel and spread globally in March 2003. The team found a novel coronavirus was causing the disease, which infected 1,755 people across the city and caused 300 deaths.

'The good research that came out of Hong Kong on Sars, apart from other places, is because we have this ability to take this multidisciplinary approach, combining basic research with clinical research and epidemiology,' Professor Peiris said.

He said the new project would look at what caused the disease in humans, how it was transmitted, ways to block transmission, and how diagnostic tests, drugs, and vaccines can be improved.

The research would combine basic science, clinical research and epidemiology. 'This programme tries to pull all this together. Pandemics arise from animals, we are interested in the animal and human interface,' Professor Peiris said.

Hong Kong appears a natural base for the project. It is the second most widely cited research group on avian influenza, and has published 18 high-impact articles in the past seven years in medical journals. It has provided half of all H5N1 virus gene sequences that are publicly available, with the University of Hong Kong serving as a World Health Organisation H5 reference centre.

Within the next eight years, the project aims to identify flu viruses of potential risk to humans, have these key viruses characterised and have reagents for them so that if any of these become important the viruses and reagents would be available to the international community.

It will also identify the viral and host factors that are responsible for allowing viruses to jump species from birds to humans and cause disease in humans. Another aim is to devise options for diagnosis, treatment and vaccines. 'We are not saying that we can solve all these problems, if we do, we would have solved all the problems of influenza. We certainly hope to make significant contributions in each of these areas,' Professor Peiris said.

'We do have a global niche advantage, because this area has been studied since the 1970s, from Ken Shortridge's time,' he said, referring to work that names Asia as the influenza centre.

'If you want to study the virus over time, the fact that we have these viruses from the 1970s up to now allows us to make very detailed studies of how the viruses have been changing.'

Another laboratory with a long-term collection of animal flu viruses is that of Tennessee-based scientist Robert Webster, who is also a collaborator in the new project.

Professor Peiris said several researchers were already studying flu, but this project had a wider emphasis. 'Generally speaking, most groups working on influenza are working on a very specific area, for example, detailed viral replication, or somebody may be working on viral evolution,' he said.

There is another world-class research project Professor Peiris cited as undertaking similar work was Albert Osterhaus' 100-strong laboratory team at Erasmus MC in University of Rotterdam.

Dr Osterhaus gained prominence when his group identified a Hong Kong flu strain, which killed a three-year-old boy in 1997, was an H5N1 strain.

Hong Kong also has been working with scientists on the mainland and in Indonesia, Malaysia, Vietnam, Thailand, Sri Lanka, and India through the university's Pasteur network.

Paris-based Institut Pasteur has teamed up with HKU to create the HKU-Pasteur Research Centre as a long-term project in Hong Kong.

'We can be fully confident there will be a pandemic but we do not know when,' Professor Peiris said. 'The reason for the present focus on H5N1 is because if that virus becomes pandemic, the severity of that pandemic is probably going to be really bad.'

Professor Peiris said it was possible to make predictions on flu. In mid-2005, an HKU paper warned that after the outbreak in Qinghai Lake on the mainland there was a danger that the virus would spread to the South Asian sub-continent and to Europe. 'Many people did not really believe that this would happen,' he said. 'But as you know this prediction was perfectly true. It spread all the way to Europe and, more than this, to Africa and India.'

On pathogenesis, or the mechanism by which viruses cause disease, a key question would be what allowed an avian flu virus to infect human cells.

'Normally most of them don't. The second one is when this virus infects humans, especially H5N1, why is the disease so severe?'

On epidemiology, the team would like to look at how the human virus transmits, what are the exact mechanisms by which the virus transmits from one person to another, and what can you do to block the transmission.

'For example, will hand washing or wearing a mask help? If you take the global view, some of the richer countries, such as Hong Kong, will be able to afford antivirals and vaccines to minimise the impact of the pandemic,' he said.

'For most of the rest of the world, they would probably not have access to these.'

An international scientific board will provide directions for the team. 'These are the top people all over the world,' Professor Peiris said. 'That in itself is a testament to how highly the existing work already is regarded internationally.'

Another feature of the project is that it will help train the future generation of senior scientists in Hong Kong. 'When you train someone in science, it does not mean he has to work only in influenza. That training can be applied to any discipline,' he said.

If a pandemic hits in the near future, he said, 'we will be well set up to investigate what's happening and to provide information to cope with such a pandemic in terms of what's happening with the virus and to human patients, what are the treatment options, and what can we do to prevent infection'.