Could understanding the evolution of flu protect us from the next pandemic?

We spoke to Professor Wendy Barclay about her research into the influenza virus, and how it could safeguard us against future outbreaks.

What drew you to researching respiratory viruses, in particular influenza?

I started out doing my PhD at the Common Cold Unit, which was a human volunteer centre. It was really timely, because common cold viruses at the time had just had their X-ray crystal structure solved. For the first time you could actually see what the virus really looked like, and the parts of the virus that antibodies might be directed against.

While I was doing my PhD, I got a glimpse of molecular virology research and the genetic engineering of viruses, and decided that that was what I was interested in. Viruses are so simple that you can actually create them de novo. You can do real hypothesis-driven stuff. For instance, you might say: “I hypothesise that this gene, or this part of the protein of the virus, is really important for a certain feature, like being able to spread through the air or being able to replicate in a certain cell type”. In the lab you can create two identical viruses that only differ in that one feature, and then go ahead and test it. You can’t really do that with other things that are alive.

Are you ever concerned that, in the process of engineering new viruses for the purposes of research, this information may become misappropriated or mismanaged in some way?

I’ve been very much involved in the public debate about the gain-of-function controversy. These discussions came to a head in around 2012, when two labs announced that they had created an H5N1 strain of influenza that could transmit through the air between ferrets, and that sparked a lot of concern. It’s important for us to ask question about where the limits of science come. Should scientists be allowed to create new viruses from scratch? What if one of them is more dangerous than anything we’ve seen before, and how should we contain that knowledge?

However, I think it’s important to understand that scientists have been doing this sort of research for a very long time. We’ve been able to create a virus from scratch since the 1970s. People have thought long and hard about the merits and the difficulties, and there is a lot of oversight both in this country and all over the world about that sort of work.

There are many things that we do in science that have the potential for misuse and danger. However, if we don’t do them, then we lose out on gaining new knowledge. Provided that the next generation of scientists in the field are aware of the pros and cons of doing it, and Principal Investigators are aware of the rules and proper procedures, then it’s all fine. We do worry about this kind of thing, we worry about every single experiment we do, and we risk assess each one. Here at Imperial, we have a fantastic safety team that help us to do that. As long as channels are open and people are talking about it openly, then I don’t think you have any problems. The danger comes from banning it, and people going underground, which would make things a lot more difficult to control.

Can you explain a bit more about what you are currently researching, and the focus of your Wellcome Trust Collaborative Award?

The main focus of my lab is to understand how influenza pandemics emerge. We want to know which evolutionary processes take the virus from the animal (e.g. wild birds) and into humans, and into a virus that can transmit through the air between humans.

The Wellcome Trust Collaborative Award is about how the virus learns to become transmissible between humans. In the grant, we use ferrets because they are an excellent model for human influenza. It turns out that if you infect a ferret with a human transmissible strain, then the ferrets become mildly sick themselves, but they also breathe out the virus and it passes through the air from one animal to the other.

We want to re-enact the evolution of the influenza virus by infecting the ferrets with an avian flu, which we hypothesise gave rise to the Hong Kong flu pandemic of 1968. What we’re doing is tracing back historically to find viruses that were probably the precursors of the pandemic. They will be used to infect ferrets, and then we will monitor the evolution of the virus within the animals, by using deep sequencing (overseen by Professor Paul Kellam), to see what changes are required and how those changes are acquired. What we’re really interested in is the circumstances under which such changes could be selected for within one animal, and then be passed through the air and spark a bigger outbreak. So, we’re setting up chains of transmission to study that.

My group is working alongside evolutionary biologists (Dr Colin Russell, University of Cambridge) and mathematical modellers (Professor Steven Riley) to bring together all of those different approaches, to really understand in great depth how this evolutionary process occurs and on what scale it happens.

The final aspect of the Collaborative Award is to take it forward to the modern day. The seasonal flu viruses that come around every winter evolve subtly year-on-year, undergoing what we call “antigenic drift”. That’s why we have to update the vaccine. In the lab, we’re going to recreate that antigenic drift again in ferrets, and watch the virus evolve in response to ferrets being vaccinated or infected with a strain of flu. In doing this, we hope to be able to be much better at predicting how the virus will evolve in the future, and therefore which vaccines strains we should be using.

Professor Wendy Barclay

From a public health perspective, what would the impact of a typical flu pandemic be in a UK context?

When the World Health Organization judges the pandemic preparedness of different countries around the world, the UK is high up on the list. We do a very good job of having a plan of action in how to deal with pandemics, because we have a National Health Service and an integrated healthcare system. I think we are as prepared as any country really could be.

I think the biggest problem that we’ve got in terms of public health planning is the unpredictability of both seasonal flu and pandemic flu. A lot of the research that I’m involved in is trying to improve our ability to understand how the virus is evolving, so that predicting what might happen next becomes a little bit more reliable.

In terms of pandemic emergence, there are ongoing debates about whether we can stockpile drugs, and how much money we should invest in preparing for the next outbreak. Many people feel very uncomfortable about money being invested in this way, because of the unpredictability. You can’t really stockpile a vaccine against one particular strain, because it might be another strain that comes through. There is this difficult balance to strike between how prepared you want to be, and how much money you are prepared to spend on an event that might not happen for the next 10 or 20 years.

It is a really difficult thing for the health authority, the Department of Health and governments to make decisions on. As a scientist, all I can do is try to offer a better understanding of the processes by which all of this happens, so that these seemingly unpredictable outbreaks become more predictable, and people can be more informed about spending this kind of money.

Do you think there is a need for greater governance in the way that the media reports on thte emergence of pandemics?

I sit on the board of the Science Media Centre, and I do a fair bit of work talking to the media and journalists. The better journalists in this country are very concerned to get their information from the right place, and to reflect a story that is scientifically accurate. So, I think we should pay credit to them. The problem is that certain scientists have not yet taken on board that it is part of their professional duty to talk to the media, and to reassure the public when an outbreak is emerging. If nobody else is telling the media what the real truth is, then journalists almost can’t be blamed for going to less reliable sources. I think if we encourage scientists to work more with the media, we don’t need any further governance. We should just encourage a positive attitude from both sides.

The problems that I often come across are to do with headline writing. Many journalists do a very good and accurate job when writing an article. However, there are writers whose job it is to create a headline in order to sell the newspaper. Quite frequently, the headline is not very accurate in terms of what the content of the article is, and that’s unfortunate. People glance at it and perhaps don’t bother delving deeper, and they get this misleading bullet point message. I do think it’s a real problem. Some governance in that respect I think would be welcomed both by science journalists and scientists in general. There is always that fear as a scientist when talking to the media – you do your best to get the detail across in the article, but who knows what headline is going to come out on top of that?

What common misconceptions are there around the flu vaccine that you think need to be challenged?

Firstly, not enough doctors and nurses take their flu vaccine, and in general not enough people who are on the at-risk list get it. People think that they will get a mild bout of flu if they get the vaccine, and that is absolutely wrong. The vaccine that is given to adults is an inactivated prep; it’s a completely inert protein that looks like the surface of a flu virus, but it isn’t infectious. There is absolutely no way that you can catch flu by having your flu vaccine.

A lot of nurses are under the misconception that they are going to get sick from the vaccine for a couple of days, and that therefore they shouldn’t have it because it will take them away from nursing their patients. I would argue quite the opposite: if you are coming into contact with vulnerable patients and you don’t have your vaccine, you are in danger of passing on a very deadly virus to individuals who can’t deal with it. Another thing that people say is that they wouldn’t go to work if they had the flu, and therefore wouldn’t pass it on. What became apparent during the swine flu pandemic is that at least 75% of the people who got infected by the virus were completely asymptomatic, but still capable of spreading their virus on. We know this from our ferret studies as well. It isn’t adequate for medically-trained people to say, “I’m not going to have my flu vaccine because I won’t pass it on” – they will do. It is absolutely a priority for anyone who is in contact with someone vulnerable to go and get their flu jab. They can’t get flu from doing so, and if they don’t do it then they really are being quite irresponsible.

What developments have there been recently in terms of how people are vaccinated?

What’s interesting is that there is a new vaccine for children that is being rolled out in the UK, which is a live virus. It’s a nasal spray, and a lot of people aren’t yet aware of it. This is a new idea based on findings that indicate that the majority of flu spread in the community is spread by children in nurseries and in schools. There’s a concept that if we can control that spread, we can help more vulnerable people at home who sometimes don’t respond very well to their own flu jabs.

The idea is that we vaccinate these children with a spray up the nose – it’s not a needle and they don’t mind having it. It gives them a very short-lived and local nasal infection; the virus is crippled so that it can’t penetrate to the core body temperature, but it can replicate in the very cold area of the nose. The children don’t even know they’ve got it, and a day later the virus is all gone. In this time, their immune system has been kicked into action and generates a good antibody response. It’s working brilliantly well. The UK are going for this, and we just have to wait and see how effective it will be in terms of the knock-on effects in helping everybody in the community.

It’s very interesting, because here in the UK we’ve had all sorts of debates about vaccines over the past couple of decades, and I think there’s a great fear among policy makers that introducing new vaccines is difficult. I think it’s quite sad really, given that this particular vaccine is of huge benefit to the children themselves who get it, and it is also of massive benefit to everybody else in the community. I think children are quite capable of understanding that they can do something altruistic, that their little spray is not hurting them and that they are doing their bit for their community. I think that’s a missed opportunity in today’s world where everyone is so selfish about life. Children are not inherently selfish, and I think that if you tell them that it’s a good thing that they’re doing, they would feel rather proud of it.

Professor Wendy Barclay is Chair in Influenza Virology, and is based within the Division of Infectious Diseases in the Department of Medicine. For further information about Professor Barclay's research, visit her Professional Web Page.