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Mar 28, 2012 (CIDRAP News) – In a set of articles published today in Nature, influenza experts say global flu surveillance—especially in poultry and swine—is sorely lacking and needs a major overhaul to make it more sustained, timely, and representative.

In an editorial, a news report, and two commentaries, experts make the case that current surveillance efforts are far too sparse, erratic, and crisis-driven and that they suffer from a geographic imbalance.

"Imagine a global weather and climate forecasting system that collects data regularly in just a handful of countries, and takes measurements elsewhere only during extreme weather events," says the editorial. "That is what today's global flu-surveillance system mostly looks like."

The gaps in flu surveillance are well known, but they are getting renewed attention following the creation in labs of H5N1 strains that can spread in mammals, the editors said in a reference to unpublished studies by teams at Erasmus Medical Center in the Netherlands and the University of Wisconsin. A US biosecurity advisory board recommended in December that the full details of the studies not be published.

The centerpiece of the Nature articles is an analysis piece by reporter Declan Butler. He notes that flu surveillance is important not only for detecting pandemic threats, but also for spotting outbreaks, monitoring viral evolution, understanding factors that enable viruses to spread, and maintaining the effectiveness of animal vaccines and diagnostics.

Looking for trends, Butler examined the records of all non-identical sequences from all types of avian and swine flu deposited in the US National Center for Biotechnology Information's Influenza Virus Sequence Database between 2003 and 2011.

To summarize the "dire state" of animal flu surveillance, Butler writes that the world had 21 billion poultry in 2010, but only about 1,000 flu sequences from 400 avian virus isolates were collected, and many countries that have billions of poultry contributed few or none of those sequences.

The number of avian sequences deposited in the database generally rose between 2003 and 2010, but then sagged, he found. Meanwhile, the number of pig sequences stayed fairly flat from 2003 to 2010 before surging last year.

An additional problem is that years can pass between the collection and sequencing of isolates, Sylvie van der Werf, PhD, of the Pasteur Institute in Paris told Nature. Reasons include lack of funding and the disinclination of many researchers to share their sequences before publishing their findings.

Butler also found that almost all sequences come from "a handful" of countries, led by the United States and China.

Summing up the findings, the editorial states, "From 2003 to 2011, most countries collected few or no sequences, and genetic surveillance of flu in pigs was and is almost non-existent."

Flu experts say the situation could be rapidly improved by setting up, in the countries and regions at highest risk, a network of sentinel sites to collect viruses and sequence them quickly, according to Butler's report. But international leadership is needed, and no global body has overall responsibility for flu surveillance, he says.

In a commentary, Jeremy Farrar, DPhil, who works at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, contends that one way to improve flu surveillance is to move a share of the relevant expertise and technology from the developed world to the developing countries that are most threatened by H5N1 and other emerging diseases.

"I believe that we have to bring some of the huge investment by the developed world in genomics, technology and training to affected countries in Asia and elsewhere," writes Farrar, who is in the Oxford University Clinical Research Unit at the hospital. "In this way, surveillance, analysis, of samples, and—crucially—the public health and clinical research response can be conducted in the same place, making the process faster and more flexible in dealing with rapid developments.

"It would require a transfer of technology, prolonged exchange of scientists and a sustained commitment to investment and training locally—along with an equitable sharing of the benefits of the research," he adds.

Farrar remarks that today, 8 years after Vietnam's first human H5N1 case, too few H5N1-endemic countries have access to vaccines or intravenous antiviral drugs. And in a reference to the reports of lab-modified H5N1 viruses that can spread in mammals, he adds that "scientists like us in endemic areas" are still waiting to learn about the mutations that led to increased transmissibility.

In a fourth article, four experts from four different countries offer brief suggestions about ways to improve monitoring of H5N1 viruses. For example:

Yi Guan, MD, PhD, of Shantou University and Medical College and the University of Hong Kong in China, calls for more active surveillance of ducks in affected areas, since 70% of the world's ducks are raised where H5N1 is endemic.

Richard Webby, PhD, of St. Jude Children's Research Hospital in Memphis, says a good first step to improve swine surveillance—now scattered among universities, industry, and government agencies—would be to increase coordination by establishing a centralized database.

Butler D. Flu surveillance lacking. Nature 2012 Mar 29;483(7391):520-2 [Story]

Farrar J. H5N1 surveillance: shift expertise to where it matters. (Commentary) Nature 2012 Mar 29;483(7391):534-5 [Article]

Guan Y, Webby R, Capua I, Waldenstrom J. How to track a flu virus: four experts pinpoint ways to improve monitoring of H5N1 influenza in the field. (Commentary) Nature 2012 Mar 29;483(7391):535-6 [Article]

Nature editors. Must try harder. (Editorial) Nature 2012 Mar 29;483(7391):509-10 [Article]
http://www.cidrap.umn.edu/cidrap/conten ... 2surv.html

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Flu surveillance lacking


Nature analysis highlights need for international strategy to watch for pandemic threats.
Declan Butler

28 March 2012


When researchers created strains of the H5N1 avian influenza virus that could spread easily between mammals, they argued that their work would aid in surveillance, by identifying mutations to watch for in the wild.

But an analysis by Nature paints a dire picture of how animal flu viruses are being monitored. In 2010, the world’s poultry population was estimated at 21 billion, yet only around 1,000 flu sequences from 400 avian virus isolates were collected — and many countries that are home to billions of farmed chickens, ducks and pigs contributed few or none.

In addition, the surveillance is typically not sustained, but instead is ad hoc and reactive, and is largely in response to disease outbreaks or temporary research projects. But a flu virus that emerges anywhere, at any time, can threaten the entire planet. The Nature analysis “highlights a global problem: lack of data”, says Ian Brown, head of avian virology and mammalian influenza at the Animal Health and Veterinary Laboratories Agency lab in Weybridge, UK.

Timely global surveillance of animal flu viruses is crucial not just for identifying pandemic threats, but also for detecting outbreaks, monitoring how viruses are evolving, understanding risk factors that enable them to spread and keeping animal vaccines and diagnostics up to date.

To assess trends in global genetic surveillance, Nature analysed the records of non-identical sequences from all subtypes of avian and pig flu deposited in the US National Center for Biotechnology Information’s Influenza Virus Sequence Database between 2003 and 2011. The database contains sequences from GenBank and several large flu sequencing projects, including the Influenza Genome Sequencing Project — a major initiative run by the National Institute of Allergy and Infectious Diseases (NIAID) to boost the sequencing of existing isolates. The analysis covered all subtypes of flu virus, not just H5N1. That’s important, says Malik Peiris, a flu virologist and surveillance expert at the University of Hong Kong, because “H5N1 is not the sole pandemic candidate, and low pathogenic viruses are just as likely, if not more likely, to become pandemic”.

The number of avian flu sequences deposited in the database skyrocketed between 2003 and 2010, before dropping off in 2011. The number of pig sequences deposited remained relatively flat from 2003 to 2010, before jumping dramatically in 2011.



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However, few contemporary data are available. The number of avian flu sequences from isolates collected in each year peaks in 2007 and plummets thereafter. The jump in the number of pig sequences also disappears (see ‘Delayed sequencing’).

Roughly 30% of the sequences are from isolates collected before 2003. The 2007 peak in avian viral sampling was largely the result of surveys of more than 100,000 wild birds to monitor for the arrival of H5N1 in the Americas1, 2. Also contributing was the sequencing of the H5N1 viral flare that moved from Asia into Europe and Africa in 2005 and 20063, 4. The older sequences can inform surveillance by showing how the viruses have evolved, says Peiris, but contemporary data are important “for real-time surveillance”, such as spotting changes that might herald dangerous strains.

Many years can pass between the collection and sequencing of isolates, says Sylvie van der Werf, head of the Molecular Genetics of RNA Viruses lab at the Pasteur Institute in Paris. One reason is that many of the virus samples are sequenced in retrospective research studies. Another is a lack of funding for sequencing, although falling sequencing costs are easing this bottleneck. The Influenza Genome Sequencing Project is also helping by generating vast quantities of sequences — it now accounts for half of all avian and pig sequences — but it is aimed at increasing the genomic knowledge base, rather than real-time surveillance.


Researchers, too, are contributing to the lag, because many do not share their sequences until after the data have been published. An exception is the Centers of Excellence for Influenza Research and Surveillance — a network created by the NIAID in 2007 to boost flu surveillance — which has a policy of releasing all sequence data within 45 days of its collection.

The two agencies responsible for monitoring disease outbreaks in animals — the Food and Agriculture Organization (FAO) of the United Nations and the World Organisation for Animal Health (OIE) — stipulate that sequences of potentially zoonotic viruses should be deposited in public databases within 3 months, but few researchers do so, says Ilaria Capua an avian-flu researcher at the Veterinary Public Health Institute in Legnaro, Italy, who champions greater availability of sequences5.

Nature also looked at where the sequences come from (see ‘The geography of sampling’). The picture that emerges is worse than some experts had thought. Almost all come from just a handful of countries — most countries have little or no genetic surveillance in place.

Just 7 of the 39 countries with more than 100 million poultry in 2010 collected more than 1,000 avian flu samples between 2003 and 2011. Eight countries — Brazil, Morocco, the Philippines, Colombia, Ecuador, Algeria, Venezuela and the Dominican Republic — collected none at all; 13 collected between 1 and 100; and 11 collected between 100 and 1,000. Even fewer pig sequences were collected, with one-third of the countries that are home to more than 4 million pigs depositing none at all (see ‘The pig in the room’).



The pig in the room

Surveillance of avian flu viruses is bad, but that of pig viruses is worse. Yet pigs are a serious pandemic risk: they can be co-infected with both human and avian flu strains, which means that they provide ample opportunity for gene swapping and, thereby, the emergence of pandemic strains such as the 2009 H1N1 pandemic virus.

The world is home to some 1 billion domestic pigs, almost half of which are in China, yet only 7,679 pig flu sequences were collected between 2003 and 2011. Just three countries — the United States, China and Hong Kong — collected more than 1,000 swine flu sequences each, and around 200 countries collected none at all. Five of those countries – Russia, Poland, the Philippines, Denmark and the Netherlands — are each home to more than 10 million pigs.

In pigs, flu tends to be mild, so there is little economic incentive for surveillance. Moreover, the pork industry often doesn’t want the negative image of having swine flu detected in its farms.

Research teams at Hong Kong University, including one led by virologist Malik Peiris, are compiling one of the world's single largest sources of pig sequences. They get their viral isolates from abattoirs, which means that data can be collected for routine surveillance while leaving the source farm anonymous. Because more than 90% of the pigs slaughtered in Hong Kong come from ten provinces in mainland China, the reach and utility of these data extend far beyond Hong Kong.

The pandemic risk posed by pigs has also risen since 2009. The 2009 pandemic H1N1 virus, which is now endemic in pigs, is unusual in that it contains the triple reassortant internal gene (TRIG) cassette, a highly conserved set of six genes that allows the virus to swap genes with flu viruses from other species much more freely than the seasonal H1N1 that circulated before 2009 (see ‘Pandemic 2009 H1N1 virus gives wings to avian flu’). Seasonal H1N1 reassorted sparingly, but “we are noting lots of reassortment between the pandemic virus and endemic swine viruses”, says Peiris.

Another pig virus that has the TRIG cassette, H3N2, infected 12 people in the United States in 2011. “I think that this is just the tip of the iceberg and such reassortments are surely going on worldwide, globally changing the swine influenza virus landscape,” says Peiris. “This certainly is a source of concern for public health.”

More

The size of a country’s poultry population is no predictor of how many samples that country will generate (see ‘Many birds, few samples’). Countries that have well-developed veterinary services and a well-structured and hygienic farming industry inevitably have fewer flu sequences to report, as disease levels tend to be low, says Brown. However, many of the countries that have contributed few or no sequences have poor veterinary systems and flu-prone farming systems, such as backyard farms and mixed poultry and pig farms, which are often close to wild ducks and other flu reservoirs.



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“Proper geographic representation is lacking,” says van der Werf, as is sustained surveillance. This results in large gaps in data, she says, because “many consecutive years of surveillance are needed to see trends” (see page 535). Poorer countries tend to have inadequate surveillance resources, and farmers often have little incentive to report outbreaks because they will not receive any compensation for culled livestock. Countries sometimes also fail to look for, or report, outbreaks so that they can claim they are free of infection and so avoid trade problems.

Flu experts say that the dire state of surveillance could be rapidly turned around by, for example, creating a network of sentinel sites, focusing on the countries and regions most at risk, that would collect isolates and sequence them in real time. Such a network would probably even cost less than the fragmented and uncoordinated surveillance efforts in place today, says Jeremy Farrar, director of the Oxford University Clinical Research Unit in Ho Chi Minh City, Vietnam (see page 534).

The problem is that no global body has overall responsibility for flu surveillance. The World Health Organization (WHO) runs a global network of labs for human flu surveillance and selects human strains to be included in vaccines for seasonal flu. Monitoring animals falls to the FAO, which tends to focus on food security, and the OIE, which looks mostly at animal health and trade.

What is needed is international leadership, says Farrar. “If, say, the WHO and the FAO were to construct an advisory framework, surveillance could probably be done much more systematically and efficiently.”
Nature483,520–522(29 March 2012)doi:10.1038/483520aSee Editorial page 509


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http://www.nature.com/news/flu-surveill ... ng-1.10301

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H5N1 surveillance: Shift expertise to where it matters
Jeremy Farrar
Nature 483,534–535(29 March 2012)doi:10.1038/483534aPublished online 28 March 2012



Tools and training for responding to diseases such as avian flu must relocate to countries where infections are most likely to emerge, says Jeremy Farrar.

Every day on my way to the hospital, I pass streets lined with poultry. The birds disappeared a few years ago, but have gradually returned. This would be of little concern if I was in Europe or North America — but I work in Vietnam studying emerging pathogens, including the avian influenza virus (H5N1). There is a patient with H5N1 in the hospital as I write. This is a region where the H5N1 virus has killed millions of birds and several people, where SARS and Nipah virus emerged and where the threat of antibiotic and antimalarial drug resistance is growing. Because of this, we have become acutely aware of the continued danger of infectious diseases, and the inadequacies of our current systems for tracking them and responding in a timely fashion.



JULIET BRYANT


Investing in the monitoring of new infections in Asia would speed public-health and clinical responses.

Too often, surveillance is crisis-driven, ad hoc and reactive; it is incorporated into overextended and under-resourced systems. It frequently relies on outside experts, who arrive with little understanding or appreciation of the country, local infrastructure or culture. Inevitably, a lot of time and resources get wasted — a purchased PCR machine ends up collecting dust in an empty lab, commitments to supply consumables are not honoured and there are too few trained people to service and run things after short-term projects end. Much donor funding is wasted on meetings, teleconferences, workshops and flying in consultants.

This disconnect between the people and places involved continues to create problems. In 2007, Indonesia put on hold the sharing of H5N1 samples with the World Health Organization, out of a concern that they would be used to create vaccines and other therapies that only wealthy countries could afford. No one can condone refusing to share information of such public-health importance, but today, eight years after Vietnam's first human case of H5N1, too few endemic countries have access to the vaccines or intravenous antiviral drugs that continue to be stockpiled in richer parts of the world. Recent research has pinpointed specific mutations in the H5N1 virus that may render it more transmissible in mammals — but scientists like us in endemic areas are still waiting to learn what those mutations are.

On the spot

With moderate investment, we could be conducting surveillance for H5N1 and other emerging infections much more effectively, and could link that surveillance with immediate action. Surveillance on its own without a public-health need or clinical response is of questionable value, and unlikely to be sustained. I believe that we have to bring some of the huge investment by the developed world in genomics, technology and training to affected countries in Asia and elsewhere. In this way, surveillance, analysis of samples, and — crucially — the public-health and clinical-research response can be conducted in the same place, making the process faster and more flexible in dealing with rapid developments. It would require a transfer of technology, prolonged exchange of scientists and a sustained commitment to investment and training locally — along with an equitable sharing of the benefits of the research.

The unit in which I work in Vietnam shows that this type of project is possible. Over the past 21 years, we — alongside our sister programme in Thailand and with partnerships across Asia — have helped to train thousands of regional scientists in clinical medicine, epidemiology, microbiology, bioinformatics and other disciplines crucial to monitoring, controlling and understanding infectious diseases and outbreaks. We are small and flexible, which keeps bureaucracy and costs down — we employ only a few hundred staff across several countries, but collaborate with many more. Thanks to funding from the Vietnamese government, the UK Wellcome Trust, the US National Institutes of Health and the Li Ka Shing Foundation in Hong Kong, we have some of the capacity and flexibility needed to respond immediately to the rapidly changing dynamic of infectious diseases such as H5N1, enterovirus 71 or artemisinin-resistant malaria, and can make results available in real time. Such an approach is impossible when the work requires individuals to fly in and out and to analyse samples in another country.

Small but powerful

There are other great examples of long-term research partnerships between national and international organizations, but they are all too few. These infrastructures are easier to build than many believe — you need only a small group of committed people, a shared vision and ethos, flexible funding that encourages local decision-making, and a focus on excellence. There can be great power in such small institutions — which may need as little as a few hundred thousand dollars a year to operate — if only we made better use of them (G. T. Keusch and C. A. Medlin Nature 422, 561–562; 2003).

Because our research unit is based in the region where the story is unfolding, we can appreciate the social issues that can stymie even the best scientific endeavour. For instance, small-scale backyard poultry farms (often family farms with mixed chickens, ducks and pigs) remain a crucial livelihood and the main source of protein for many households in rural Asia. Because no adequate compensation schemes have been developed to encourage reporting of sick poultry and livestock, the usual responses are to cull all local poultry and apportion blame. Such activities can ruin small farmers and their families.



“There is now a window of opportunity to build global scientific capacity before another crisis hits.”

There is now a window of opportunity to build global scientific capacity before another crisis — such as a new pandemic — hits. This means collaborating with the people who share a vested interest in using the money efficiently and effectively to prevent outbreaks and address daily public-health and clinical issues in their own countries. After living in Vietnam for more than 16 years and raising my family here, I can understand the feeling of urgency. Everyone I work with who sees chickens each day on their way to work, hears about local outbreaks in the news or treats patients is united in the effort to stay one step ahead of H5N1 and other potentially deadly outbreaks. We must share the available knowledge and the tools to make it possible — an undertaking that will require us to shift the centre of gravity for such research to where the needs are greatest.


Author information



Affiliations

Jeremy Farrar is at the Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.



Corresponding author

Correspondence to:
Jeremy Farrar
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