H7N9 Flu in the Asia-Pacific
Risks, Responses, and the Consequences of Better Surveillance
As of late April, China’s state-run Xinhua news agency had reported 126 human cases of H7N9, a novel strain of bird flu that has been the cause of 24 deaths nationwide. In light of the unfolding events, NBR spoke with Jeremy Farrar (Oxford University) about the context of, and responses to, the outbreak.
<On March 31, 2013, the Chinese government reported that 2 men from Shanghai had died from a novel strain of influenza virus, known as H7N9. On April 30, China's state-run Xinhua news agency reported a total of 126 human cases of H7N9 avian or bird flu, with 24 of those cases thus far proving fatal. Most forms of avian influenza do not infect humans, with notable exceptions like this H7N9 strain and the H5N1 strain, which caused approximately 300 deaths in Asia following an outbreak in 2003. The World Health Organization (WHO) reported on April 22 that it has not seen "evidence of sustained human-to-human transmission" although such a development remains in the realm of possibility because influenza viruses can mutate. NBR spoke with Jeremy Farrar about the context of, and responses to, the current H7N9 outbreak.
Professor Farrar is Professor of Tropical Medicine and Global Health at Oxford University, Global Scholar at Princeton University, and Director of the Oxford University Clinical Research Unit in Vietnam. He will become Director of the Wellcome Trust in October 2013. His research interests are infectious diseases and tropical health. He has contributed to over 450 peer-reviewed scientific papers and serves on several World Health Organization advisory committees. He was appointed Order of the British Empire (OBE) in 2005 for services to Tropical Medicine, and he has been awarded the Ho Chi Minh City Medal from the Government of Vietnam, the Oon International Award for his work on H5N1 avian flu, Frederick Murgatroyd Prize for Tropical Medicine by the Royal College Physicians, and the Bailey Ashford Award by the American Society for Tropical Medicine and Hygiene. He is a Fellow of the Academy of Medical Sciences and chairs the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), a global initiative to share data about emerging diseases that could become epidemics or pandemics.
How does what is known so far about today’s H7N9 flu virus and the way it is spreading compare to previous strains and outbreaks of avian flu such as the H5N1 strain that inspired similar headlines 2003?
Let’s start with H5N1, which has been circulating since 1997 when the first human cases were identified in Hong Kong. It reemerged in 2003 in Vietnam and has been endemic in Southeast Asia and Egypt ever since. Cambodia has had a large number of cases this year with continuing very high mortality. In Vietnam, just in the last month we have had two new cases. There are outbreaks and deaths among chickens on a regular basis across the region. Fortunately, since 2003 the number of human cases has remained relatively small, with virtually no human-to-human transmission. In each human case, however, the mortality is very high and very tragic.
The H7N9 strain that emerged in 2013 looks very different, even just four weeks into the outbreak of cases. Transmission between the avian population (presumably poultry) and humans has been high in a very short space of time, which suggests that this virus can jump from poultry into humans much more easily than H5N1 has ever done. And, of course, that makes H7 more worrying because each jump across species gives the virus the potential ability to adapt to humans, and then to go between humans. We have not seen any sustained human-to-human transmission in H5N1. We’ve not seen it yet in H7N9, but it is the number of times this virus has jumped across species that, I think, is very worrying.
Another difference between the two viruses is that it’s difficult to know which chickens are infected with H7N9-infected chickens appear healthy, showing no signs of illness. By contrast, H5N1-infected chickens get very sick and die, which makes it easy to follow outbreaks in the animal sector and ultimately to make decisions about culling chickens in order to prevent chicken-to-human transmission. There is a test that can diagnose H7N9 in chickens, but knowing which chickens to test is difficult since they all seem to live very happily with the virus, and we are not yet sure of the sensitivity of the tests. With more than ten billion chickens in China alone, it’s clear that we can’t test every one and, given how fast they breed, the ten billion chickens today are, of course, very different from the ten billion tomorrow. Keeping up with that in the animal sector is impossible. And that is just the chickens—there are many other domestic or wild birds and animals that could be potential reservoirs of the virus and that would be able to move it across large distances.
Are potentially very dangerous flu outbreaks occurring more frequently now than in the past? How worried should we be about H7N9, given that the severity and impact are still unknown?
There is now much more surveillance of illness than ever before and much better coordination of the human and animal sector, although much remains to be done. The surveillance techniques are much better and more widely available. As a result, we’re going to have to get used to finding things that ten years ago we probably would never have known about. It’s highly likely that we’re going to see this sort of thing being reported on a much more regular basis. And the events may be becoming more common as we change how we live and how we farm, as our environment changes, and as we travel much more than ever before and move animals in ways and over distances that were just not done twenty years ago. We’re going to have to get used to taking each event seriously in its own right—try to be logical in the way we think about it—without becoming cynical about yet more fearmongering. We have to admit that we do not know what’s going to happen to this H7N9 virus or indeed many of these novel viruses. Dealing with that uncertainty, the risk management, and communication with the public and the science community is extraordinarily difficult and ever more essential. Public engagement with this is absolutely crucial.
Thankfully, the severity of the 2009 H1N1 swine flu pandemic  was less than first feared. Nevertheless, at some point it’s highly likely that influenza—or something else—is going to cause a very big global event. SARS  had a devastating impact and yet was in itself relatively easily contained. We have to maintain our vigilance and take each event seriously without being alarmist and without saying every time something like this happens that we’re going to be in a scenario like the film “Contagion.”
How would you compare the response to H7N9 in China to the country’s responses to previous worrisome flu outbreaks?
Many people, myself and people in China included, would say that the Chinese response to SARS ten years ago was slow and cumbersome. In the early stages Chinese authorities were not completely open about what was happening. The response was damaging for healthcare in China and for China’s reputation. But since then there has been a complete sea change in the way that people work together. In the current outbreak, I think people who have not worked closely with China over the last few years have been surprised by China’s very positive, open approach. We have been privileged to work very closely with China’s Center for Disease Control and Prevention. and others over the last few years, and the approach they are taking now has been true for many years. It has been superb to work with them.
If you look at the response to H7N9, when the first cases were identified the Chinese authorities quickly made information available globally through the appropriate channels (the WHO and influenza coordinating centers around the world) as well as taking the time to reach out to personal and research networks to help other countries understand what was emerging and prepare for potential cross-border transmission.
The virology community in China has also done superbly. They’ve shared the sequences of new viruses so that others can prepare by making diagnostics and identifying cases. This information helps us understand the epidemiology and do mathematical modeling about the way that the virus strains spread. They have also integrated their epidemiology with the response in the clinical sector (looking after patients) and on the animal side, along with political support from the affected cities and at a national level. In many ways it has been a case study in how to integrate human health and animal health with the needed political support. Many countries could learn from how this has been handled.
To what do you attribute the tremendous improvement in China’s and the international community’s commendable response thus far to H7N9?
In addition to a sea change in China’s surveillance capabilities and transparency about H7N9, I think Mexico and the United States deserve great credit for setting the standard globally for how countries should, and increasingly do, respond to these outbreaks. During the pandemic of 2009 the Mexican authorities and the U.S. Centers for Disease Control and Prevention, Department of Health and Human Services, and so on, were incredibly open about the pandemic. They shared resources, made information available, and communicated with the scientific community and lay public quickly and in a considered way. Mexico and the United States gained enormous respect from everybody for the way they handled that. That doesn’t get said often, but it was a hugely positive event and I think has changed the way we all do things around the world.
People are very quick, obviously, to criticize countries like America and China. America is now the dominant force in the world and China is obviously a rising force globally, and it’s very easy to criticize places like that. But I think it’s very important to give praise where it’s due. America played a superb role during the 2009 pandemic, and I think China is doing so now. There is also a trust that is growing between countries, and the WHO deserves credit for the way they have brokered that and contributed in often very, very difficult circumstances.
Vietnam and Malaysia recently banned imports of Chinese poultry. What are your thoughts on the way China’s neighbors are responding?
I think the response has been more measured than it has perhaps been in the past. Vietnam has been very active in terms of setting up pass points and preparing for the virus to arrive in the chicken industry or in humans, as has every neighboring country. But it’s notable that these preparations have not been front-page news, and they have not been panic-driven.
On the clinical side, Vietnam was the first country to approve the WHO-ISARIC protocol  so that if a human case of H7H9 were to occur here in Vietnam tomorrow we would have a pre-approved way to do research so that we could understand how best to treat people. That represents enormous progress. I think ISARIC and Vietnam have played a really fantastic role by making these protocols available publicly and freely to anybody who wants to use them via the Internet, thus sharing their clinical approaches to looking after patients. In this way, they are leading efforts to understand what treatments really work, and hence save lives, and to share that information openly and publicly with everyone immediately.
What about the response, readiness, and global coordination of the clinical research community?
I remain critical of my own community, the clinical research community: we (and I am part of that criticism) have not yet established how to gather information in the quickest way possible to work out what treatment works at an individual patient level and how that can effect transmission in the community. Focusing for the moment on influenza and looking back to the swine flu pandemic of 2009, if we ask very, very simple questions—like what doses of drugs to use and for how long during the pandemic, how to treat a very, very young child, whether or not to use combinations of antiviral drugs or to use antivirals at all, how to treat a pregnant woman or an obese individual, what non-clinical interventions work (closing schools, masks, hand washing), etc.—we cannot answer any of them. Our current mechanisms and structures around the world make it extraordinarily difficult to mount very basic clinical observational study, let alone conduct clinical trials of new interventions or improve the utility of existing interventions at anything like the speed that is needed. I don’t think we have come anywhere near where we need to be in terms of getting that right, although I hope with WHO and through organizations like ISARIC and InFACT  we are starting to change the paradigms.
Most of the reported H7N9 bird flu cases today—and H5N1 cases back in 2003—have been in Asia, and in China specifically. Is China ground zero for flu? Might there be similar incidences of infection and death in other areas with less sophisticated disease surveillance?
China has a good disease surveillance system now in place, and it has been very open about reporting cases of flu recently. I think one of the most important things to remember is how very big China is—as home to 1.3 billion people as well as to a huge number of chickens, ducks, and other poultry. Importantly, in Asia the link between human beings and chickens and ducks is obviously very different to the relationship you have in North America with your chickens and ducks. Many in rural China and Asia keep chickens and ducks in their homes or in very close proximity to their homes. And so, therefore, the ecology—the environment in which humans and chickens and ducks and other poultry live—is very different. Understanding the social and ecological factors, as well as the biological ones, that drive how viruses cross species is crucial. Part of the reason for these outbreaks—H5N1, H7N9, and other influenza viruses—starting in this part of the world is inevitably just a population numbers game. There are more people living in this part of the world than anywhere else, and therefore the chances of these things happening are higher in Asia than they would be in other parts of the world with fewer people and poultry.
But we should not get fixated on these things. The whole world prepared for an H5N1 epidemic in 2003 that would start somewhere in Asia and then spread around the world, but of course what happened in 2009 is that a completely different virus caused the epidemic. And the first human cases came out of Mexico and the United States and then spread from the West to the East. We also should not forget that H5N1 remains endemic in parts of Egypt.
So we can’t just put systems in place that have prepared us for the last event. That will only lead to us being surprised and not being able to respond properly to a new event, which will inevitably be different. And yes, China, Vietnam—Asia in general—is an epicenter because of the population size (human, poultry, and pigs), but these events could happen anywhere. I think we need to accept that these events are global—not regional or associated with specific countries. Flu and other viruses can spread around the world in 24 hours by air travel and other means.
In 2011 two teams of scientists announced that they had found a way to make certain flu strains more transmissible between mammals.  Fears of bioterrorism or accidental release of a massively destructive virus led them to implement a self-imposed, year-long moratorium on that work. How is that research, which was resumed with new guidelines after the ban was lifted in 2013, informing the response to, and understanding of, the H7N9 strain?
I fully understand why people have had major concerns about that work. My personal view is that the work was essential to do, but the key element is that the work is appropriately regulated and goes on in absolutely secure laboratories. I think it’s crucial that we understand the biological basis for human-to-human transmission of influenza viruses and what drives viruses crossing the species barrier. And I think that can only come as a result of very carefully controlled research, as in these two examples.
We know so little about influenza and what drives it to cross from a chicken, pig, or duck into a human being, what it is that stops that from happening, and what it is that would lead it to spread from person to person and hence cause an epidemic or pandemic. What I think the research tells us is that a virus does not need to undergo that many changes in order to move from being not passable to passable between mammals. Four or five changes in the animal models used in those two experiments were enough to allow influenza to go between animals. That is important information. If we were to find those mutations occurring in nature and in human cases, then that would raise our concern because it may suggest that those viruses could pass between people in a way that they’ve not done to date. Of course, these may not be the important mutations in humans, and we should not get fixed just on these mutations. But I think the work was absolutely crucial. We need to communicate with all stakeholders to ensure everyone knows about the work, and we should welcome the debate that takes place. We scientists work within a community, and we need the support of that community in order to do our work.
The fact is that I live in a country where H5N1 is circulating in chickens. Thankfully, we rarely see human cases, but we’ve had two in the last month both of whom died. We do sequence those viruses and we make that information available globally. And since this work we do look for those mutations that the research you mentioned identified. In other words, the information from that research is actually being used in endemic countries now. I think it’s very important for people to appreciate that this is not just research done in labs the United States and the Netherlands; it actually has an importance for the country right where I live (Vietnam), where we use it on a regular basis.
How soon can a vaccine for H7N9 be made available?
The good news is that global vaccine manufacturing capacity has undoubtedly increased since 2003.  I think the bad news is that, with current technology, it will inevitably always take too long between the event occurring and a new vaccine being available. And by “available” I mean available to all the parts of the world that need it—not just to countries with sophisticated production and delivery infrastructure.
The fastest we could technically produce a new vaccine is four to six months. That timetable is true for the country or the city that’s producing it, but it’s not true at a global level. We could not produce in sufficient quantities a new influenza vaccine that is available to, delivered to, and used by the entire world within a year of identifying the threatening strain. And, of course, epidemics happen more quickly than that.
Why can’t we just take the infrastructure already in place for manufacturing seasonal flu vaccines and use it for H7N9 vaccines instead?
Influenza strains are always changing. An influenza vaccine developed two years ago may not protect you fully this year against current strains. We have not yet developed the technology to give you an influenza shot today that would protect you from all future strains of the virus. That makes it difficult when a new virus like H7N9 appears. We just don’t have the capacity to quickly respond, and we don’t have any protection from prior vaccination against this new strain.
China shared the H7N9 virus very quickly with WHO coordinating centers around the world. The United States, China, and Japan—all of those centers are now making stocks of the virus that they can share with manufacturing companies to potentially make vaccines. But if you wanted to change today from seasonal influenza vaccine production to H7N9 production, that would be a huge decision. We can’t do both in sufficient quantity—it’s partially either/or. And even then, we just don’t have that spare capacity to swap from seasonal vaccine and suddenly produce hundreds of millions or billions of doses of an entirely new vaccine. That takes time.
And so the decision is very, very difficult. If we decide that H7N9 is going to be a global event and to produce a vaccine for it, we must acknowledge the full consequences. If we go forward with large-scale production of H7N9 vaccine, then we will have to reduce the number of seasonal vaccines that are available, which inevitably will mean more deaths—particularly among the elderly and the very young —from seasonal flu, so these are very complicated calls. And what we have to do—again this comes back to why research is so important—is to have a mechanism by which we can produce influenza vaccines that protect against more strains so they don’t need to be updated as regularly as they do now, and produce them much, much quicker. We also have to learn what other interventions can work to reduce the spread of such epidemics, whether social distancing, masks, hand washing, or therapeutics. And this means involving a much wider group of scientists in these debates, including social scientists, epidemiologists, and clinicians.
Do some populations take vaccines for granted, perhaps not appreciating the complexities involved in making them available or the potential consequences of limited vaccine coverage?
In many parts of the world—in North America, in Japan, and particularly in Europe at the moment—there is, sadly, growing public cynicism about vaccines. And I appreciate where this comes from. The West has done such a remarkable job of reducing infectious diseases as daily events—largely as a result of effective vaccination and public health measures—that those diseases seem to have virtually disappeared. As a result, people are much less aware of the diseases that are out there, which were common in the West just one or two generations ago when everyone would have known someone who had died of measles, polio, or tetanus.
By contrast, in developing countries where vaccines are not nearly as accessible—for financial and logistical reasons—communities routinely face the horrific, often fatal diseases that some in the West perceive to be nonexistent. That’s as true for influenza as it is for so many other diseases. The fact is that vaccination has made them seem virtually nonexistent in many places; but once you get communities making the decision not to vaccinate these diseases re-emerge, as we’re seeing with a massive measles outbreak in Wales in the United Kingdom at the moment.
People have the right to express their views and concerns that vaccines may cause harm, and understanding that is very, very important. But the good that vaccines do so massively outweighs any potential harm that we must encourage people to continue to use the vaccines that are available and make more of them available, particularly to the developing world. As I have said many times throughout this interview, this comes down to improving the two-way flow of communication between the scientific world and the public. This is one of the greatest challenges of our time, but it is essential if we are to make the most of what is a golden age of science with the potential for so much benefit. But we have to communicate better, and organizations such as yours can do so much to help that. Thank you.
 For background, see Wikipedia: Swine influenza, http://en.wikipedia.org/wiki/Swine_influenza. First termed as an outbreak, the 2009 H1N1 swine flu emerged in the state of Veracruz, Mexico. The Mexican government closed most of Mexico City’s public and private facilities in an attempt to contain the spread of the virus; however, it continued to spread globally, and clinics in some areas were overwhelmed by infected people. In June 2009, the WHO and U.S. Centers for Disease Control and Prevention (CDC) stopped counting cases and declared the outbreak a pandemic. The number of cases declined significantly by May of the following year, and in August 2010, WHO Director-General Margaret Chan declared the end of the H1N1 pandemic. While the virus has killed more than 18,000 people since it emerged, critics claimed the WHO exaggerated the danger.
 Severe acute respiratory syndrome (SARS), first reported in southern China in February 2003, spread to more than two dozen countries in North America, South America, Europe, and Asia within a few months. According to the WHO, more than 8,000 people worldwide became sick with SARS during the 2003 outbreak. Of these, 774 died.
 ISARIC (the International Severe Acute Respiratory and Emerging Infection Consortium) is a global initiative that aims to change the way in which research is carried out during and between epidemics. It does this by ensuring open access protocols and data-sharing processes for clinical researchers in order to facilitate a rapid response to emerging diseases that may turn into epidemics or pandemics. This open access means researchers from high- to low-income countries can either work to or adapt the same protocols while sharing compatible data sets. Jeremy Farrar is ISARIC’s founding chairman.
 InFACT is a global collaboration of clinicians and researchers working in intensive care units around the world. InFACT has launched a comprehensive research program consisting of a global clinical registry; clinical trials of widely available and inexpensive interventions that might minimize the sequelae of severe H1N1 infection; a biobank to characterize genetic risk factors and the clinical biology of severe infection; and an initiative to attenuate severe H1N1 disease in the developing world where its toll will be greatest.
 Two groups of scientists, one at the Erasmus Medical Center in the Netherlands and another at the University of Wisconsin, independently managed to create strains of H5N1 in their labs that could pass between mammals. For more about this research, see Alexandra Sifferlin, “Scientists Push to Resume Research On Virulent Man-Made Flu Virus,” Time Magazine, January 23, 2013, http://healthland.time.com/2013/01/23/scientists-push-to-resume-research-on-virulent-man-made-flu-virus/#ixzz2Ru4F0K1k.
 See the report from a workshop co-presented by NBR with the China CDC on pre-pandemic vaccines and global manufacturing capacity: The National Bureau of Asian Research, “Pandemic Influenza Vaccines Workshop: Building a Platform for Global Collaboration,” January 2007, http://pacifichealthsummit.org/downloads/PanVax/PandemicVaccinesWorkshopReport.pdf.
This interview was conducted by Claire Topal, Senior Advisor for International Health, and Sandra Ward, Director for Communications and Brand Development at NBR.