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The once pervasive fear of the H5N1 virus, a bird flu subtype, has been fading along with declining public attention.

Except for reports of an outbreak among the migratory birds in the Qinghai Lake area nearly a month ago, no new rashes of the H5N1 virus have struck villages or chicken and duck farms recently.

But Liu Wenjun, a leading scientist at the Institute of Microbiology, the Chinese Academy of Sciences, believes there is still reason to fear attacks in the future, and particularly new strains that may hit humans.

"Many scientists around the world are working hard to trace (the virus) and hope to catch the mutation of the virus before its changes cause human-to-human infection," said Liu.

The research being carried out is far from systematic and co-ordinated enough to reach that goal, he said, and information sharing is still needed.

Unknown sources

Like most other scientists, Liu's anxiety comes from too many unknown factors about the H5N1 virus, especially how it infects people.

H5N1 is considered the most lethal form of the avian influenza virus so far among birds. First reported in Hong Kong in 1997, it is now considered by the World Health Organization as the potential source for the next human pandemic.

There were three human flu pandemics in the 20th century. The Spanish Flu pandemic of 1918 was believed to have killed as many as 50 million people worldwide. The other two pandemics, in 1957 and 1968, killed between 1 and 2 million individuals.

Between last October and February this year, China reported 35 bird flu outbreaks among domesticated chicken and ducks, which killed a total of 186,000. To curb its spread, 22.8 million birds were culled.

Jia Youling, the State's chief veterinary officer, said in March that the H5N1 bird flu is unlikely to break out massively in China this year, thanks to the country's intensified vaccination efforts.

Since the first case of human infection was reported in Viet Nam in 2003, scientists believed humans could only be infected by having close contact with H5N1-infected poultry.

However, Jia admitted that of 15 confirmed human infections of the H5N1 bird flu in China between last October and March of this year, 11 became seriously ill in areas where no poultry bird flu outbreak had been recorded.

In the past two months, three new human infections were reported respectively in Sichuan Province, Guangzhou and Wuhan. Among the 18 total human infections in China, 12 lost their lives.

Jia explained that people may actually get infected by inhaling the air or saliva polluted with the H5N1 virus, drinking contaminated water or contacting the pollutants.

But the infections in metropolis areas further increase the mystery about the H5N1 virus, said Liu.

"How did the pollutants or H5N1-polluted water travel to cities from the epidemic outbreaks?

"It is not impossible that some poultry sold in the markets could still carry the virus without having shown any symptoms," Liu said.

His hypothesis seems to be confirmed by the finding of Guan Yi, a microbiologist at Hong Kong University.

Guan's research shows that in the six months leading to April, the H5N1 virus could be found in around 1 per cent of birds randomly seized in the markets in South China, even though they appeared healthy.

There may be a few factors causing this, such as insufficient vaccination, poor administration and low quality of vaccines, Guan explained.

Poultry vaccination

Due to economic reasons, it is difficult to guarantee that every home-grown chicken, duck or other bird is vaccinated in China's remote villages, Jia said.

Chen Hualan, chief scientist of China's poultry-administered H5N1 vaccines, believes that her vaccine is not a factor.

"Our vaccine has been widely used in China and Viet Nam, and massive testing shows that in the protection period, the (H5N1) virus will not replicate in the vaccinated poultries, and they would not remit the virus to outside environment," said Chen of Harbin Veterinary Research Institute.

Another debate on poultry vaccination is that the vaccination might promote adaptation and mutation.

Although more and more countries tend to vaccinate their poultry, Thailand, a country seriously hit by the H5N1 bird flu, has not done so.

Chen said that, so far, there is no observed mutation of the H5N1 virus against her vaccine.

"Our vaccine has offered an ideal protection against all viral strains isolated domestically," Chen said.

Despite Chen's confidence, other scientists point out that researchers from a full range of academic institutions - other than Chen and her colleagues - should be able to review and double-check the results, to confirm the effects of the vaccine.

More scientists should be able to test randomly seized healthy poultry from the markets and farms to see if the vaccinated poultry has produced antibodies or whether H5N1 could still be isolated, said a scientist who asked to remain anonymous.

Once any virus is isolated from poultry, their infection sources should be immediately traced, he added.

"I think the Ministry of Agriculture should have done it, but so far we have read very few reports of it in open academic publications," the scientist said.

Holding mutating virus

Although how H5N1 is transmitted between birds still remains unknown, scientists are concerned that H5N1 may mutate to cause human-to-human transmission. They are also worried whether current drugs and vaccines will be effective to curb its replication in human cells if that should occur.

A study headed by Thijs Kuiken of the Erasmus Medical Centre in the Netherlands indicated that human infection of H5N1 virus is currently low.

According to the study, H5N1 could begin to destroy human cells only when it reaches the lower parts of the lungs, but it is difficult for the virus to travel that far in the human respiratory system.

But James Stevens of Scripps University in the United States found that ther is a protein called HA on the virus's outer surface mutates, it will enable the H5N1 to easily bind itself to human cells, making it easier for poultry to transmit the virus to humans, and perhaps for humans to transmit to other humans.

So far, oseltamivir, branded as Tamiflu, has been considered the most powerful drug against the virus. WHO and governments have been stockpiling it and more than a dozen of pharmaceuticals worldwide have obtained licences from its original manufacturer, the Swiss firm Roche, to produce it.

Yet a study published in the New England Journal of Medicine last December shows that two Vietnamese people died of H5N1 bird flu in 2005 because the virus developed some resistance to Tamiflu.

"So far, the only solution is that there should be a variety of drugs available to treat the virus," said Liu of CAS.

Drugs useful to treat H5N1 mainly target the protein of the virus that binds animal cells. Yet this is the part that is most likely to mutate.

Liu's solution is different. He has focused on curbing the human proteins that receive and help the virus replicate. "By the end of this year, there might be some very positive results published," he said.

Yet it may take a long time before the research evolves and a drug is developed.

Human vaccines

Beijing-based biotech firm Sinovac, among 28 vaccine developers worldwide, has been approved to launch the clinical trial of a H5N1 vaccine for humans. It is the only Chinese institution to have obtained the green light to do so.

Yet, like all vaccine developers, the primary difficulty for Sinovac is whether its vaccine can match the mutated H5N1 virus. It has to take into consideration that any new vaccine may not be effective when the virus loses its genetic traits originally targeted by the vaccine.

Yin Weidong, president of Sinovac, told that once a key mutation takes place, WHO will be able to sequence the genome of the new virus and send the new viral strain to vaccine developers worldwide within 48 days.

Early this month, a study published in Lancet shows that a bird flu vaccine developed by French firm Sanofi Pasteur can protect up to 67 per cent people from the H5N1 infection.

Yet the vaccine can play such a role only in a 30-microgram dose, several times of the allotted dose for the regular flu vaccine. This means if a pandemic attacks, there might be not enough production capacities to meet the world's demands.

Traditionally, researchers mass-produce the viral component of vaccines by injecting the virus into chicken eggs, where it replicates within the embryo.

Sinovac's vaccine development is based on this method.

However, the process often means production of vaccines is very slow.

China should increase the production capacity of common seasonal flu vaccines, Yin said. Once a pandemic breaks out, the production capacity can be rapidly shifted to H5N1 vaccines, said Yin, adding that his company is also exploring ways other than using eggs to develop vaccines.

"The governments should encourage and support more citizens to vaccinate common flu vaccines, expanding the domestic demands and thus boost the production capacity of manufacturers," said Yin.

(China Daily May 24, 2006)