A NEW strain of H5N1 bird flu has emerged in China and is poised to start yet another global wave of infection. The human pandemic vaccines now being developed will not protect against it. Worse still, nearly three times as many Chinese poultry are infected with H5N1 now as last year, meaning there is a greater chance of human infections 鈥� despite China鈥檚 insistence that all poultry be vaccinated against it. In fact, vaccination may be to blame for the new strain.
鈥淭he human pandemic vaccine now being developed would not work against a virus descended from the new strain鈥�
Yi Guan and colleagues at the University of Hong Kong have been testing poultry in markets across southern China for bird flu for years. In 2004, 0.9 per cent of market poultry tested positive for H5N1, including 2 per cent of ducks, a major carrier of the virus. But between the middle of 2005 and June this year the virus turned up in 2.4 per cent of market poultry 鈥� a nearly threefold increase 鈥� and 3.3 per cent of ducks. The virus is also showing up in chickens for 11 months of the year, up from only four months previously.
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The reason, says Guan, is a new 鈥淔ujian-like鈥� strain of the virus, descended from one first seen in a duck in Fujian, China, in 2005. It caused 3 per cent of poultry infections in September 2005 but was responsible for 95 per cent of infections by June 2006. 鈥淭he predominance of Fujian-like virus appears to be responsible for the increased prevalence of H5N1 in poultry,鈥� write Guan and colleagues in a study published in the Proceedings of the National Academy of Sciences this week (DOI: 10.1073/pnas.0608157103).
鈥淭he new 鈥楩ujian-like鈥� strain caused 3 per cent of poultry infections in September 2005 and 95 per cent by June 2006鈥�
A higher number of infected but apparently healthy birds in Chinese markets for more of the year means a greater risk for humans, says Guan. All but one of China鈥檚 21 officially reported human cases of H5N1 have occurred since November 2005 鈥� after the Fujian strain started its rise. Some of these people lived far away from any known outbreak in poultry, but close to urban poultry markets, suggesting the new strain is spreading silently in some of the world鈥檚 most crowded cities.
That means there could be many more unrecognised human cases. In China and elsewhere, people with serious cases of flu are only tested for H5N1 if poultry have suddenly died nearby. If seemingly healthy birds are infected with H5N1 and spreading it, they could also be passing it to humans without anyone knowing. 鈥淚f death of poultry is used as the only indication of H5N1 infection, but the emergence of human cases is ignored, the consequence will be increased transmission of the virus in poultry,鈥� says Guan, who believes surveillance needs to be stepped up to include routine testing of birds throughout areas infected with H5N1.
Based on what previous H5N1 viruses have done in China, Fujian now seems poised to start a third epidemic wave, potentially worldwide, following the first in 2004 and H5N1鈥檚 spread across Eurasia in 2005. So far the Fujian virus has reached Thailand, Malaysia and Laos.
Its sudden emergence suggests that a selection pressure is acting on the virus. In November 2005 China ordered compulsory vaccination of all poultry. The law has been imperfectly applied, however: Guan and colleagues found vaccine-induced antibodies in only 16 per cent of birds tested. What鈥檚 more, they found these antibodies do not recognise the Fujian virus, even though they attack the previous strains of H5N1. 鈥淭his novel variant may have become dominant because it was not as easily affected as other strains by the current avian vaccine,鈥� Guan says.
In 2004, an investigation by 麻豆传媒 concluded that vaccinating poultry against bird flu can lead to the emergence of novel strains that can circulate undetected in vaccinated birds unless there are scrupulous controls (麻豆传媒, 27 March 2004, p 6). The risk is that whatever strain emerges might have unexpected features, such as an ability to kill humans.
While Guan鈥檚 team has no evidence to suggest that the Fujian strain is more virulent or likely to transmit between humans than previous strains, so far it has killed one person in Thailand and caused five of the Chinese cases for which the team has virus samples. 鈥淎s far as I know all (20) human cases since November 2005 were caused by this virus,鈥� Guan told 麻豆传媒.
The discovery is a warning bell to researchers working on human vaccines for H5N1. The pandemic vaccine now being developed by pharmaceutical companies is based on strains of H5N1 isolated from Vietnam in 2004 and Indonesia last year 鈥� but antibodies to these strains do not recognise the Fujian strain. This means the vaccine would not work against any pandemic virus carrying surface proteins from the Fujian strain.
Guan and colleagues say comprehensive influenza surveillance is needed in both people and animals throughout the region affected by H5N1, both to track the real spread of the virus and to provide updates for vaccine developers.
Behind enemy lines
THE sudden emergence of a 鈥渟uper-strain鈥� of H5N1 that sweeps away all other strains may seem unsettling, but it is something we could have predicted. Human flu does this all the time. The reason people get flu year after year is because the virus evolves slightly different surface proteins that our immune systems don鈥檛 recognise from the last time we had flu.
Researchers had thought this was a continual process, with individual mutations being selected for if they give the virus an advantage over the others. Now David Lipman and colleagues at the National Institutes of Health in Bethesda, Maryland, have shown that the process is far more sporadic.
Using a large collection of recent flu strains, they showed that H3N2, the most common human strain, generally floats in evolutionary limbo accumulating random mutations, none of which gives any virus an advantage over the rest. As more and more people become immune, flu seasons become milder.
Then every few years, one virus happens to collect a winning combination of these individually useless changes that enables it to avoid recognition by human flu antibodies. It out-competes other H3N2 viruses and rapidly becomes the dominant strain that sweeps the world (Biology Direct, DOI: 10.1186/1745-6150-1-34).
In 1998, for instance, one strain from Australia acquired a novel surface change, but it wasn鈥檛 until 2003, after a few more key mutations, that it suddenly emerged as the most murderous H3N2 of recent years.
Lipman鈥檚 team suggests that by monitoring these random mutations, we might learn to predict what dominant strain is about to emerge, giving vaccine makers more warning.
