The H5N1 Influenza Variant In China

In the November 7, 2006 issue of the Proceedings of the National Academy of Sciences, the following article appears:

G. J. D. Smith, X. H. Fan, J. Wang, K. S. Li, K. Qin, J. X. Zhang, D. Vijaykrishna, C. L. Cheung, K. Huang, J. M. Rayner, J. S. M. Peiris, H. Chen, R. G. Webster, and Y. Guan
Emergence and predominance of an H5N1 influenza variant in China
PNAS 2006 103: 16936-16941.

This has led to a rebuke from the Ministry of Agriculture.  Such public spats over technical issues are never in the favor of the official body, because any errors in analysis will subtract hugely from the credibility and stature.  This may also be the first opportunity to test whether Margaret Chan, the recently appointed director-general of the World Health Organisation, can be really as "country-neutral" as she insists.

(Ming Pao)

The State Council's Information Office held a press conference yesterday on the matter of Hong Kong University professor Guan Yi's article "Emergence and predominance of an H5N1 influenza variant in China" published in the "Proceedings of the National Academy of Sciences."  The Ministry of Agriculture's Veterinarian Department director Jia Youling criticized Guan Yi strongly and pointed out that his article cited incorrect data, the methodology was unscientific and the inferences were unsupported by the facts.  He emphasized that China has an effective vaccine that is widely used against avian influenza.  He said that China is willing to cooperate with the World Health Organisation and provide virus samples according to specifications.

We believe that the rights and wrongs of this article are not just about the reputation of Guan Yi and a few other Chinese experts.  It also concerns whether there are gaps in how China monitors and controls avian influenza and whether the broadly used vaccines are effective.  Will the Fujian variant of the avian flu virus quickly spread to cause a fatal epidemic?  The World Health Organisation should follow the hints given in the article and send people to southern China to collect new avian samples and conduct independent tests.  This would be the correct away to dispel international doubts.

Yesterday, Guan Yi did not respond to the criticisms from the Ministry of Agriculture.  But according to the interviewing done by our reporter before and after the publication of the article, Guan Yi's research method (including the collection and analysis of the samples) is similar to how Hong Kong University has studied avian influenza in the past and meets international medical research standards.  The Proceedings of the National Academy of Sciences is also a top medical  journal and will publish papers only after rigorous review.  The Ministry of Agriculture officials have staked their reputation on the line by rejecting Guan Yi's article wholesale, but since their counter-arguments are unconvincing, this is a dangerous approach.

For example, the Chinese officials questioned how Guan Yi collected more than 50,000 samples of avian secretions.  They said that he collected 1,000 to 2,000 samples on each occasion, and this is objectively difficult.  The chickens and ducks are about to be sold, so their owners will not easily permit strangers to poke around the throats and cloacal chambers of the chickens, ducks and geese.  Therefore, the officials believe that Guan Yi must be collecting feces specimens at the avian markets.  Since the chickens, ducks and geese are mixed together, it is not possible to come up with accurate data.

Yet, according to what the reporter found, Guan Yi was able to obtain sizeable research funding from the Hong Kong University Medical School.  His research team paid the owners at the avian markets for consent to collect samples directly from the chicken, ducks and geese.  The process was documented by texts and photographs.  The Chinese officials may question whether private data collection is legal, but they cannot overturn the scientific value.

As another example, Guan Yi's article mentioned that there were 76 samples of chicken anti-body serum that were effective against the typical avian flu viruses but ineffective against the Fujian variant.  The Chinese officials questioned whether 76 samples were too few for the purpose of evaluating a vaccine and determining that the Chinese campaign is failing.  To them, this was rash, irresponsible and unforgivable.

Yet, Guan Yi's team actually collected 1,113 samples of chicken serum for the purpose of testing the effectiveness of the vaccine.  Between November 2005 and April 2006, these were collected in Guangdong and Guiyang.  Of these, 180 (or 16% of the total) showed that anti-bodies were present and therefore the number of samples that can be used to test the anti-bodies against various types of avian flu variants was small.  But the problem reflected here was that the Chinese government has compelled all chicken farms to vaccinate all their chickens since September, 2005.  So how come the number of samples with the anti-body was less than 20%?  Is this a case that you can issue orders from above and the people below will find ways not to implement them, thus leaving a huge gap in the avian flu prevention system?  Or are evil businesses selling fake vaccines?  The officials claimed to have collected 4 million serum samples in the past year and innumerable tests showed that the vaccine was effective.  But if the WHO experts are to conduct independent tests and analyses, will the results be the same?

At this point, this is no longer a debate among scholars and experts.  It concerns the reliability of the entire avian flu prevention system in China.  Guan Yi's viewpoints may not be completely correct, but the Chinese officials have not yet provided sufficient proof that overturns his research.  Instead, more doubts have been raised.  Since the Ministry of Agriculture has agreed to cooperate with the World Health Organisation, the only solution is for the World Health Organisation to send its experts into the field.  This will be the first big test for Margaret Chan after taking over the helm at the World Health Organisation.

(China Daily)  New US bird flu report lacks evidence base.  November 10, 2006.

Editor's note: The Proceedings of the National Academy of Sciences of the United States of America published "Emergence and predominance of an H5N1 influenza variant in China" last week.

The paper contains "ungrounded statements," Chen Hualan, director of the National Avian Influenza Reference Laboratory, and Shu Yuelong, director of the National Influenza Centre under the Chinese Centre for Disease Control and Prevention, told China Daily in an interview. The following is the transcript of the interview.

Q: The article, "Emergence and predominance of an H5N1 influenza variant in China," claims there is a "previously unidentified H5N1 virus sub-lineage" - the Fujian-like strain in China. Is that true?

Chen: I have read the article and found its viewpoints and conclusion regarding the so-called "Fujian variant" lacks scientific evidence.

The authors alleged that the prototype virus of the "Fujian-like (FJ-like) variant" was first detected in March 2005, and that viruses from this sub-lineage have replaced the multiple sub-lineages of the H5N1 virus in southern China and emerged among live-poultry markets in Fujian, Guangdong, Yunnan, Guizhou and Hunan provinces and the Guangxi Zhuang Autonomous Region.

The article further asserted the virus had already been transmitted to Hong Kong, Laos, Malaysia and Thailand, resulting in a new transmission and outbreak wave.

But in fact, the so-called "Fujian-like variant" was by no means a new variant. Its gene sequence is highly more than 99 per cent similar to the H5N1 subtype virus isolated in Hunan and other provinces during the bird flu outbreak in early 2004.

China's Ministry of Agriculture has prescribed that the samples of all suspected cases of highly pathogenic avian influenza should be delivered to the National Avian Influenza Reference Laboratory for virus isolation and gene sequence analysis.

Over the past two years, our laboratory has isolated some viruses from the waterfowl in southern China, and reported the results to such international organizations as the Food and Agriculture Organization (FAO) of the United Nations and the World Organization for Animal Health (OIE).

The genotype of these viruses was fairly stable, showing no big variance in antigenicity (the ability to trigger an immune response).

The Ministry of Agriculture isolated only one new mutant virus of avian influenza during a surveillance campaign early this year in Shanxi Province and the Ningxia Hui Autonomous Region in North China. But no new virus was discovered in southern China.

We have already posted the sequence of the newly-found virus to the GenBank - international public genetic database, and the ministry has also notified the case to the FAO and the OIE.

Experiments showed that the virus strain was of low pathogenicity to mammals. My laboratory has already developed diagnostic reagents and vaccines against the strain, and new vaccines have been applied in Shanxi and Ningxia, which has put infections under effective control.

Q: The article claims that the vaccine is less effective to the "Fujian-like variant," which emerged due to the massive vaccination in poultry in China.  As an inventor of China's avian influenza vaccine, what are your comments on that claim?

Chen: Our laboratory has investigated the vaccine efficacy to all representative isolates in different places at different times, and confirmed that the vaccine currently in use is effective.

The antibody tests conducted by the Ministry of Agriculture on 3 million to 4 million samples each year have shown that the antibody level has reached the internationally accepted protection level.  In line with international common practice for evaluating vaccine efficacy, we first vaccinate the animals before testing them and observing for symptoms, deaths and virus shedding.

We have been carrying out virus tests on animals for our vaccines, which have provided sound protection to vaccinated poultry and proven effective in controlling all the viruses isolated in southern China in recent years.  Furthermore, judging from the outcome of present immunization efforts in China, it is evident that all the vaccine products in use are effective.

As indicated in the article, the authors, conducting tests on 76 poultry sera collected from live-poultry markets in southern China it was unclear what kind of vaccination these birds had been given discovered that these sera are less effective in neutralizing the so-called "Fujian-like variant" than in neutralizing other H5N1 viruses.  They concluded that the poultry vaccine currently used in China is less effective in preventing the "Fujian-like strain."

It is unscientific to evaluate a vaccine in such a way, which is flawed both in testing materials and methods.  What's more, the testing results described in the article do not support its conclusion that China's massive vaccination has caused mutation of the virus and impaired the effectiveness of the vaccines.  Because even though these serum samples were collected randomly, they still have quite high neutralizing titers against the so-called "Fujian-like strain."

Q: What is the effect of the measure for prevention and control of bird flu by "vaccination plus culling" that has been adopted here in the country?

Chen: Poultry vaccination commenced in some key areas in China right after the outbreak of bird flu in parts of the country in 2004. A compulsory programme for the vaccination of all poultry began in the second half of 2005, along with culling of all the infected birds and the flocks at risk to eradicate the epidemic sources.

Vaccination density was maintained at more than 95 per cent between January and October this year, according to Ministry of Agriculture statistics.  It appears that along with the increased density of vaccination, the number of cases has reduced significantly.

For example, China reported only 10 outbreaks of H5N1 bird flu in the January-October period this year, compared with 50 cases in 2004 and 31 in 2005, a testimony that the "vaccination plus culling" strategy is effective.  This strategy has received the acknowledgement of many international organizations, including the FAO and the OIE.

Q: The article states viruses from this "Fujian-like" sub-lineage caused the five recent human H5N1 infections in southern China. Is that true?

Shu: The Chinese mainland has confirmed 20 human infection cases since October 2005. The infections, seven in 2005 and 13 in 2006, are all separate cases involving 12 provinces, regions and municipalities. The majority of the contagion, or 18 cases, were discovered in southern China, while only two were reported in the north.  The disease usually breaks out in the winter and spring when there is a high incidence of respiratory diseases.

The gene sequence analysis of 16 H5N1 strains isolated from samples collected from all cases indicated that the 15 strains isolated from southern China cases belong to the same group. There is no ground for five of the human cases to be caused by so-called mutated strains in southern China.

The remaining strain isolated from the human case in northern China (the Xinjiang Uygur Autonomous Region) belongs to the same virus group as the strain isolated from domestic poultry in Heishan of Liaoning Province and the strain isolated from migratory birds in Qinghai Province.  In comparison, viruses isolated from the cases in the south are quite different from those in the north, and also from the cases in Viet Nam and Thailand.  As the entire gene segments of the 16 strains isolated from cases in the mainland are from poultry sources, there has not been a biological basis for human-to-human transmission.

For the purpose of strengthening international exchange and co-operation, the Chinese Centre for Disease Control and Prevention provided the WHO with two strains of human bird flu viruses in December 2005 and four in May 2006.  This centre has also delivered some part of gene sequence of human bird flu viruses to the GenBank.

Q: The article claims that "Fujian-like variant" has already initiated a third wave of transmission throughout Southeast Asia. What's your comment?

Chen: I've noticed that the article has repeatedly said that the "Fujian-like" H5N1 influenza virus sub-lineage has resulted in a new transmission wave in Southeast Asia. However, the data in the article itself does not support this claim.  Some authors of the paper claimed two years ago that the so-called "genotype Z virus" might lead to a worldwide pandemic. Their claims and predictions have turned out to be all subjective and groundless.

Predictions about major animal diseases, especially those related to the development of avian influenza, often exert a dramatic impact on society and people's minds.  Therefore, a responsible scientist must adopt a very cautious attitude when making any predictions about the development tendency of any diseases. Such predictions should be based upon extensive scientific research and actual and reliable data.

Although the "genotype Z virus" claim of the authors was hyped by the media, in the academic circle, however, it was not accepted.

Just as an official of the WHO said, the "genotype Z virus" is rather bewildering because during the avian influenza outbreak of 2004, it was not identified in countries in Southeast Asia or in China.  Recently, one expert participating in the research of this article told the media that there was no data indicating the "Fujian-like" virus maintains a higher virulence, or poses higher threat to trigger avian influenza pandemic compared with other genotype viruses.

Related Link:  禽流感福建变种根本不存在  Beijing News