Oral evidence: Science in emergencies: UK lessons from Ebola, HC 469Tuesday 20 October 2015

Oral evidence, 20 October 2015.

Witnesses

Dr Ripley Ballou, Vice President and Head, GSK Vaccines Research and Development Centre, Rockville, Maryland, Professor Adrian Hill, Director, The Jenner Institute, University of Oxford, and Professor Trudie Lang, Head, The Global Health Network, University of Oxford, gave evidence.

Chair

Can I welcome the second panel? I apologise for my lateness; it was unavoidable and it is no indication of the importance of this inquiry, which I think the evidence has already shown has very important lessons for all of us to learn. I am going to dive right in and put to all of you some comments made by the British Society of Immunology. It has submitted written evidence to the Committee that in its view, “With the exception of influenza, we lack a truly effective and co‑ordinated platform for the research, development, and manufacturing of new vaccines and treatments against novel or emerging disease threats, such as Ebola”. Does that concur with your views? What do you think needs to be done to address those concerns? Could I start with Professor Hill?

Professor Hill

Broadly, I agree. I am Adrian Hill, director of the Jenner Institute, which is based at the University of Oxford. We are involved purely in vaccine design and early stage development. We partner with the Pirbright Institute, which is involved in veterinary vaccine development. We were very engaged in testing new Ebola vaccines. In the last year we have tested a total of five of those so far, some in collaboration with Dr Ballou from GSK. The British Society of Immunology is correct, in that we do not have a complete platform going from vaccine design and discovery, if you like, to animal studies, early stage clinical trials and larger-scale manufacturing and deployment, but then again hardly any country does. Vaccinology is a very broad discipline that requires a whole range of skill sets and facilities, and we need to be able to link labs like our own, which do very early stage research, early clinical trials and some manufacturing, with large companies that are in a position to manufacture large amounts—millions of doses—of vaccine. The central challenge on Ebola and other outbreak pathogens is that the business case for large pharma becoming involved in marketing or developing those vaccines is very weak. Take Ebola, which we have known about since 1976. There have been maybe 20 or 30 outbreaks, all in central Africa, over that period of 40 years. All were well contained until the outbreak in West Africa at the beginning of last year. What is the business case for making a vaccine that is unlikely to be used in any of those outbreaks? We need a system whereby public and foundation money is used to work with academics and industry to develop Ebola vaccines and other vaccines for which the business case is weak. This is not a new problem. We have identified the solutions before. For malaria, on which I work a lot, HIV and TB there are public-private partnerships that are pretty well financed by foundations and by Government to develop vaccines for those very difficult diseases. To me, the irony with Ebola is that it was not a disease where it turned out to be difficult to make a vaccine. We could have done it five years ago and had the vaccines ready. I suspect that many other vaccines we need—for MERS or Marburg, which were mentioned earlier; I could give you a list of 15—are probably relatively easy to make. We need to get on with those, but somebody has to finance it. It is very difficult to look to large industry and say, “Do all of these,” because vaccine development is expensive. The society is right; we need a solution to answer this issue.

Chair

Before I was Chair, I heard excellent presentations from the Jenner Institute previously, and I have visited the Oxford vaccine centre and know of the very important work that went on at Oxford to try to accelerate progress towards a vaccine. Professor Lang, what are your reflections on the comments made by Professor Hill, particularly his point that we could have come up with a vaccine five years earlier? Do you think that prior to the outbreak the UK did not have processes in place to identify and develop vaccines against the most serious disease risks facing the UK?

Professor Lang

I come to this from the therapeutic side. Your comment about the immunology paper talked about drugs and vaccines. On the panel there is vaccine development on either side of me, and I can talk about the drug situation. I agree with everything Adrian says, and it is exactly true of therapeutics as well. By way of introduction, I work for the Centre for Tropical Medicine in Oxford and have spent 20 years running clinical trials in their root source settings. We run an organisation called the Global Health Network which tries to strengthen research capacity in those settings. It is exactly the same story. We lack treatments and evidence-based treatment care for all sorts of neglected diseases. It is the 90/10 gap. Most of the research that happens in the world is concerned with diseases that are not diseases of poverty; they happen in places in the world where we work. I come to this from a tropical medicine background. Many of us in the room and on the panels today know each other because we all come from tropical medicine and work in that area. We have faced the same thing for years. You are working against the background of no commercial viability, but there are also fantastic examples of public-private partnerships and corporate social responsibility activities that many pharmaceutical companies are engaged in. That has led us to develop quite a strong research capacity and the ability to develop products like this in those settings, which we have been doing for years. Not many of us working in this area had any Ebola expertise before last year, and we were called up to the plate. Based on our experience, we were asked by the Wellcome Trust, and awarded a grant, to set up a clinical trial platform to evaluate potential therapeutics. Against the backdrop of disease outbreaks like this, there has never before been a clinical trial to evaluate a drug for Ebola; nor for MERS, which Tom mentioned earlier, or for H1N1 or the respiratory viruses that are emerging. There are never any clinical trials, and you have a very narrow window to set up a trial, get it going and get your answer, which is an extremely tall order. It usually takes 18 months to set up a clinical trial; we managed to do it within six weeks for this, but that was everybody pulling out all the stops and making it incredibly agile and streamlined. We have learned a lot. Those are the cumulative reasons why we do not have therapeutic agents or vaccines in this situation. You are on the same spectrum of it not being necessarily commercially viable and the odd setting for the disease outbreak. It is a very challenging space to work in, because it is usually impossible to set up a trial at that speed.

Chair

Dr Ballou, Professor Lang has made a number of points: the length of time it normally takes to set up a trial—I think on average it is 621 days in the UK; and the lack of commercial viability in general when normally you have such a small cohort who would be exposed to a disease, until there is an outbreak on the scale we saw with Ebola. She mentioned that there had been some success with public-private partnerships. What is your answer to the point about how to prevent this and needing a big outbreak in the future, given some of the other challenges we are facing at the moment, because we know Ebola is not the only disease on the horizon?

Dr Ballou

I am Ripley Ballou and I represent GSK, which is a global pharmaceutical vaccine and consumer products company headquartered in the UK. I am currently the head of the research and development centre based in Rockville, Maryland. A year ago I was responsible for clinical programmes in GSK Vaccines Belgium, and it was in that context that I played a leadership role in the development of GSK’s candidate vaccine. Before getting involved in Ebola, I spent most of the last 30 years working on malaria with my colleagues here. One of the reasons we were able to respond very quickly was that there was a network in place built largely around malaria, HIV and TB. We were able to pick up the phone and call colleagues, and within days have, essentially, a group of willing participants who could check down: “We need to do this, this and this, and these are the people we are going to call. We need funding. We need access to trial sites.” It evolved very quickly, but that is an ad hoc situation; it is not really a plan. We were able to respond very quickly when WHO said, “Can you help us?” It took them a long time to ask for help, but when they did we were able to respond quickly. The comments you have heard are absolutely spot-on. I would like to put one nuance on why we do not have Ebola vaccines, beyond the obvious fact that there is a small market. An interesting fact is that there has been Ebola vaccine development for the last 15 years, driven largely by researchers in the United States who were funded by the US Government worrying about Ebola being weaponised, so for a very different purpose there was vaccine development. We understood pretty much how to make an Ebola vaccine at the time. GSK happened into a situation, through the acquisition of a biotech, where one of the candidate vaccines landed in our portfolio. It was in my portfolio in the company. When I became aware of the data and then was aware that we had an outbreak, it was easy to put two and two together and say, “Should we potentially advance this in the context of potentially assisting in the control of this outbreak?” One of the problems that led to slow development of vaccines like the Ebola vaccines, which for more than a decade have been under research, is the fact that there is not a clear path to licensure. If you cannot license a vaccine, you cannot commercialise it. This is true of a number of the other disease threats we are worried about. They are very rare events. When they occur they may do so explosively but in a very short period of time. To be able to put together clinical trials designed to gather the kind of evidence base that regulators require to register vaccines or drugs as being safe and effective is not compatible with an outbreak setting. On top of that, this occurred in a very resource-poor environment where essentially social government was dissolving in front of our eyes. There was nobody to talk to about getting authorisation for a clinical trial. If it was not for WHO, Public Health England, and Sierra Leone and others coming in and helping to shore up those institutions, it would have been even more difficult.

Dr Mathias

Our previous panel commented on some problems of WHO. What is your opinion of WHO and its advantages and disadvantages in the recent outbreak?

Dr Ballou

From the vaccine side, to me the major problem was that they had no policy that even contemplated the use of a vaccine in an Ebola outbreak. On 23 March, when I read on the internet that there was an outbreak in Monrovia, as an infectious disease physician my immediate response was that this was very unusual. It was clear that there was a big impact on healthcare workers. I called the WHO and spoke to colleagues there I knew from malaria. I said, “We’ve got a vaccine. It’s not been in the clinic yet. How could we accelerate it?” Essentially, the response was, “We manage Ebola through contact tracing, isolation and taking care of patients. We don’t have any policy for how we might use a vaccine.”

Dr Mathias

That was in March.

Dr Ballou

Yes. I called back in June and in July, and finally in August they came back and said, “We have a major problem. Can you do something?”

Dr Mathias

They weren’t looking at the news, were they?

Dr Ballou

I do not mean to be critical of WHO. What was missing was a proactive policy that vaccines, which might not be licensed and ready in the pharmacy today but are in development in some place, might be used as a tool in these kinds of outbreaks. Thinking along those lines was simply not there.

Professor Hill

I fully agree. The key word we need to focus on is “stockpile”—stockpiles of vaccines. We do this on the veterinary side. The UK has a stockpile in case there is a foot and mouth outbreak. Why doesn’t the world have a stockpile in case there is an Ebola outbreak? We have no licensed vaccine; we have one vaccine that has been shown to work, but it has not been licensed yet. It will take a little time for this and for GSK’s and other vaccines to be licensed. What do you do then? Who has the stockpile, and who controls it? We have done this before in Africa for meningitis A. There was a stockpile and it was flown out to wherever outbreaks happened. What I am advocating is a halfway house to full licensure of vaccines for all these threats. There are more than a dozen. Typically, vaccine development costs hundreds of millions of pounds. Where are we going to get the billions to do all of that? You may not need that in the short term if you can make investigational stockpiles, which is after all what we did for Ebola. We did not know that the vaccines would work until we tried them. The one that was tried was 100% effective, so the science underlying that was good. Can we do the same for Marburg and for MERS? I am in an institute where we make these vaccines very routinely. The challenge is to take them forward and have them ready in a stockpile, manufactured not to millions of doses but tens of thousands. Once there is an outbreak, not only do you have the opportunity to control it when it is tens of people, not thousands, but you also get a chance to test your vaccine and show that it is efficacious. That needs to be co‑ordinated globally. The UK has made a good start by beginning the UK vaccine network—a £20 million investment from the Government. There are other international partners who have to come together and come up with an agreed plan. I do not think that is happening fast enough. It is all doable, but we have to decide to do it and execute it. That is urgent. It would look extremely bad if next month there is a Marburg outbreak and we are in the same situation, with a vaccine made but not tested.

Dr Mathias

As Jenner led the way, is the UK still leading the way? I mean Jenner the physician.

Professor Hill

We were in an unusually fortunate position to test the Ebola vaccine, because we have tested vaccines of that type and we have a strong working relationship with several partners, including GSK. We had fantastic support from the chief medical officer, the Government and the regulators to get trials started quickly. That was why we were able to take a vaccine into the clinic in weeks rather than months. That situation could happen again, but I am not advocating that. We should not have been rushing to catch up; we should have done this a few years beforehand, and had the vaccine stockpiled and ready to test, knowing that it was fairly safe in hundreds of people and knowing the dose of the vaccine and how many doses we needed to give. All of that can be done now before the next outbreak, and we would be prepared. It is not happening, because it is nobody’s clear responsibility internationally to do that.

Chair

Emerging infectious diseases have been on the national risk register since 2008 when it started, but Ebola appeared on it only in 2015 after the outbreak. You are advocating stockpiles. Who would identify which diseases to stockpile for and making sure that we have the right stockpiles and are not expending lots of money on stockpiles for the wrong diseases?

Professor Hill

That is a key question. Remember that the WHO and other international bodies had diseases of poverty—HIV, malaria and TB kill lots of people; and they had neglected tropical diseases, and many elements in others. Ebola and the outbreak pathogens did not even make the list of neglected, so they were not even in the bottom division; they were being ignored. That will not happen, fortunately, any more after Ebola, so something will have to be done. The UK is very strong in surveillance internationally and in mathematical modelling and imaging of where diseases are, using satellite imaging and so on. I do not think it will be difficult to get consensus about what the top five or 10 target diseases should be. Those discussions are ongoing. That is not the difficult bit; you can get a committee to do that. The difficult part is the next bit: make the vaccines, manufacture them, test them and have them in stockpiles, and that needs funding.

Professor Lang

Obviously, it is really important to have vaccines, but we need to remember that we need drugs to treat these diseases, especially in outbreaks, and vaccines to prevent them. Our experience with WHO in trying to establish whether there were any therapeutics that could treat this disease was that they did a remarkable job at pulling us all together and holding key meetings to discuss things like the ethics of running clinical trials in these situations, and how to design the trials and operate them. Where the WHO needs a significant amount of support and strengthening is in the ability to take a leadership role and co‑ordinate us. There were probably four or five key groups running clinical trials in this outbreak: our group, funded by the Wellcome Trust to set up a clinical trial platform; groups looking at convalescent plasma; and other groups elsewhere in Europe and the US looking at other therapeutics. There were four or five of us. We all communicated very well and the WHO facilitated that effectively, but we were left to lead our own charge in talking to the aid agencies who were setting up medical relief, and in where and how we worked with local organisations. There could have been much, much better co‑ordination and leadership from WHO, but they do not have the mandate, the strength and probably the finance to do that. That is a significant gap. The other side was selecting the products that went into trials, making sure the right products went in and we were not competing for sites, and having a very co‑ordinated approach that needed an international neutral leadership that was not there.

Derek Thomas

Professor Lang, you said in the past that there was no on-the-ground research seen as needed in the emergency response. Why do you think that was? How would that research have helped to develop the vaccine?

Professor Lang

What I meant by the bit you are quoting is that there was a strong medical and humanitarian response to Ebola at the beginning to put in treatment. That was absolutely needed and perfectly correct. We were able to add research later, so we were fitting that into the care-giving setting that was already established. Where we could do better next time, which we are already working on quite effectively with lots of groups, is to work much better with the humanitarian and medical aid organisations to put research into their thinking, co‑ordination and planning. Research should not be an afterthought. We need drugs and vaccines and we need to be able to implement research. Research is really different. A good question was raised earlier about data-sharing. Of course we need to share data. The data should come right at the beginning as soon as you are beginning to understand what is happening to the virus in the patient, when patients are dying, who is dying, and what is happening. Those are observational data. Then we need trials to evaluate interventions. That is protocol-driven research, which needs to be questioned in an ethics committee. That is a very different step and it needs to be thought about in a different way. People need to be taught and to learn how to do that. There is an amazing amount of research capacity in these regions—this is where we have all worked for years—but we do not share it and harness it. We need to put in place systems to harness it effectively in these outbreaks.

Derek Thomas

When the Ebola epidemic was on our TV screens and there was enormous pressure from the world’s media about how people were responding and what was happening, what assessment do you think the Government were making about where the gaps were in research, taking the horse has bolted approach and looking at the gaps and how we could quickly plug them?

Professor Lang

I can only answer that from my experience. There was an amazing amount of press coverage. I have worked on malaria and things like diarrhoeal disease for years and years and I have never been on “Newsnight” or the “Today” programme, wheeled out, as we were, but for us it was a good opportunity to explain why we needed clinical trials in that setting. There was a lot of concern, quite rightly, about the risk of ill people coming back to the UK, quite rightly, as there is now concern about Pauline. We were able to say that this was very difficult and challenging in the UK, but unless we could run the research in those settings and find out what therapies and vaccines worked we would never get anywhere. We used that as an opportunity to explain the difference between managing an individual in the UK, as we were, and assessing therapeutics in the rigour of a clinical trial and the importance of research. I hope we were plugging the knowledge gaps on why we need research in these settings.

Carol Monaghan

Professor Lang, in your article in Nature you talked about “a chaotic land-grab for…patients” when you were carrying out clinical trials. In what way did the competition for patients affect the research that has been carried out?

Professor Lang

It is what I alluded to earlier. If you are doing a clinical trial in an infectious disease, it is different from working in, say, hypertension where you can go through a list of patients and have 100 patients eligible for a clinical trial. In an infectious disease, which is our background, you have to wait for patients to walk in the door, so that is even worse. In this very narrow window of disease outbreak we did not know how long it was going to last, or how many patients would be available for the studies. With the huge benefit of hindsight, that is where we could have done with better co‑ordination, because it probably was not an overly sensible approach to have five different groups testing five different things and splitting it. It was left to Médicins sans Frontières, Save the Children and other organisations that had the sites to say, “You work here, you work here and you work here,” when actually we should have decided where the best intervention was and gone for it to answer that question, because you can do vaccine trials in the general population, but for testing therapeutics we need ill patients. We did not know how many we had or how long we would have them for. We need to do that better next time, and that is where we need neutral international leadership to help it happen.

Carol Monaghan

We are hopefully getting to a situation where Ebola has been eradicated, but that creates other challenges because there are fewer patients available for clinical trials. Has that been an issue as well?

Professor Lang

Absolutely. We only got our trial started at the end of the epidemic curve. You can see when patient numbers went up, and we were starting our trials as those numbers were coming down. This is why there have never been trials in an outbreak before, because you have a very narrow window within which to answer your question. Research should be built in, embedded in the immediate response. We should have systems ready to go and we need to strengthen local research capacity. We worked with amazing local partners; it was very much a partnership with African scientists, but we need to strengthen that local research capacity so that we can use the expertise on the ground and start trials earlier next time. We did an amazing job in getting trials set up in weeks rather than months, but it needs to be in days.

Carol Monaghan

To ask the panel generally, were any particular trials prioritised, and were data shared among the other trials that were going on?

Professor Hill

I believe a total of seven vaccines were tested over the last year for Ebola. Two of those were available early in the first stage. Data became pretty widely available initially at scientific meetings at WHO. Some journals published those data very quickly. I think that was pretty good in terms of making safety and immunological data on how the vaccine was performing available to the community. What was not in place—I would like to see this as a learning point—was a mechanism for independently comparing the immune responses the vaccines were producing. Given that we ended up with only one country where a vaccine could effectively be tested by the time we were ready to test, did we choose the best vaccine to test? You could argue that it was very effective and therefore we did, but you do not know that. The other ones could have been safer, at least as effective and so on, but there was not a system in place that was widely known, with a reference laboratory. One was identified but it did not have all the samples. I would like to see that much more rigorously and neutrally regulated in a future situation. To be fair to WHO, which has had a lot of criticism, they were very active and committed to co‑ordinating vaccine development in particular once they got started in August, and did a very good job from there on. They were led by a very experienced vaccinologist at the helm who did a good job. They were in a situation that they were relatively unfamiliar with, trying to develop a vaccine to control an outbreak. It has never been done before. It happened this time right at the end of the outbreak, so that was an achievement.

Professor Lang

I can add to that from the point of view of drug trials. This was something we did well. In the WHO meetings everybody who was running trials got together. We talked about making sure we were all collecting data in the same way. Everybody talks about data-sharing, but unless you have standards for what you are measuring and how you are recording it, it is very difficult to share data later. We shared all our data record forms and talked about how we were going to do that. An initiative is now being set up for a single platform where all of us put the trial data we gather. That will be open and available for people to share. I think we did that quite well for therapeutics.

Dr Ballou

From my perspective, the data-sharing went as smoothly as it could, given the limits we had. In order to get data from vaccine trials you have to immunise and wait to collect the samples and then they have to be run in some kind of standardised process. None of these assays was set up beforehand. Within the limits of what we were working with, there has been pretty good transparency. Relative to other programmes which do not have that kind of urgency this went very fast.

Chris Green

Professor Hill, during the outbreak the necessary clinical trial protocols were expedited for the University of Oxford vaccine trials. Can you talk us through how that rapid response was made and give a bit more detail?

Professor Hill

We were contacted by WHO in early August and at about the same time by the Wellcome Trust, who expressed an interest in supporting clinical trials. We were very lucky to have access to a vaccine from the NIH in the United States, which had been working with GSK on the development of that vaccine for bio-defence, as you heard. It had been designed for that purpose, so a mixture of strains was being prepared. Lots of pre-clinical work and excellent data were published showing efficacy in animal models of Ebola, so that was a great starting point. The problem was that it had not been given to any human being, so it was waiting there in a very large bag having been manufactured. What do you need to start a clinical trial? You need lots of approvals. The University of Oxford took on the job of being the clinical trials governance agency and sponsor for that particular trial in partnership with GSK, NIH, WHO and others. An application was made to the regulator in London, the Medicines and Healthcare Products Regulatory Agency, who turned this around in four business days. It is usually pretty good; it takes two or three weeks to review our applications—in other countries it is much longer—but four days is absolutely exceptional. The ethical committee met specially to review the application, and I think it made a decision that day. There was lots of work on formulating the vaccine, transporting it, relabelling it and so on, all of which happened in a few weeks, and we were able to start about a month after that telephone call, which is quite exceptional.

Chris Green

It seems to have been an incredibly rapid process. Are there any further improvements that can be made now you have that experience and you know what to do and what processes to follow? Could that time be brought down significantly further?

Professor Hill

I would like every trial that we do to take that short period of time, but given how many trials happen in the UK every year, the regulators will explain to you why that is not possible. There may be a case for further investment so that trials happen faster. I think it is relatively good; you can only improve it by a few weeks, if you think about it. The problems are greater beyond that. For example, why was this trial being done in the UK rather than West Africa? We managed to start a trial only three weeks after Oxford in Mali with collaborators at the Centre for Vaccine Development there. That was a very important trial to show safety in West African populations and that the immune response the vaccine was making was as good in West Africa as it was in UK volunteers. That turned out to be the case. The real challenge is how you set up an efficacy trial in-country in a setting where there is a horrendous outbreak going on, where the infrastructure for doing research did not exist beforehand, and where much of the medical, nursing and other public health capacity is fire-fighting to deal with the outbreak. Who is going to review the clinical trial protocols, and why should that be a priority for them? It is the same problem as Trudie outlined. My own view is that it is a lot to ask in Africa to have 53 authorities capable of doing that in an outbreak. You would like to have regional ethical committees and capacity. We work with some fantastic clinical trial teams in West Africa on malaria: in Burkina Faso and Gambia and an MRC unit in Senegal. Those were the wrong places. They had no obvious role working in Guinea, but they did come in to help. We do not know where the next outbreak is going to be. The real delay is in getting permission to do the phase 3 efficacy trial, not getting the phase 1 trial started, which can happen in weeks, as you saw.

Chris Green

We heard from the previous panel about concerns local people had that the measures to control Ebola were being done to people and there was a reaction against that, so having more local trials and working with people locally should help to overcome those problems.

Professor Hill

That is always the case. We always work with local people, as my colleagues will explain, but we were unfortunate in that there were no established vaccine trial teams in-country that we could immediately link to, whereas that would have been the case if the outbreak had been in, say, Burkina Faso, Mali or Senegal, so that was unlucky.

Professor Lang

Without question, there is remarkable research capacity in Africa in countries neighbouring those we have worked with for many years, and in other regions of Africa. We could definitely do better at harnessing them and thinking about what we could do next time about transferring the expertise that exists following the amazing efforts that have been made over the years in malaria, TB, HIV and all the other trials that have gone on. The regulatory capacity exists; it is unfortunate that where the disease outbreaks are likely to occur there is often lower research capacity. I think we can work really closely with DFID and other groups to think about how we can do much better. One of the ideas we have is to put a system in place where those experienced clinical researchers are kept on standby for use in disease outbreaks. They are working on existing trials, maybe malaria, onchocerciasis, or something else, but they are on standby to deploy within the region in the advent of the next disease outbreak. That is something we could look at, rather than having to move people from Europe to Africa.

Chris Green

Dr Ballou, we heard about the difficulties of corporations and pharmaceutical companies engaging in developments and having those vaccines prepared. There is concern about big data and who controls and owns it, and having vaccines stored. If the patent runs out you cannot make any money on it. Has any progress been made to overcome those or other problems?

Dr Ballou

This epidemic has been a huge eye-opener for GSK. Sir Andrew Witty has made this a big area of focus within the company. This outbreak has had tremendous ramifications for our own internal R and D. We have had to stop major programmes in order to focus literally hundreds of people to work on Ebola, and we do not think this is a viable approach going into the future. If I could just elaborate on the concept Adrian mentioned earlier, we think there needs to be a new model. GSK has quite extensively elaborated its ideas about how that might be done. We have spoken with the UK Government, the US Government and others and prepared a White Paper on this. We have referred to an organisation called the bio-preparedness organisation—BPO—with the idea of leveraging key technical platforms that the company believes would be suitable for addressing emerging outbreak threats, including one of the platforms that was used for this particular one, but we have others, and providing them to a stand-alone organisation that would be very closely supported, by GSK in this case, but other industries could use the same model. You would have a group with the wherewithal, knowledge, capabilities and capacity to develop vaccines to the point where they can be tested for safety, to understand the dose, the schedule and their likelihood of working, based probably on animal models, and then manufacture them to a quality that would allow them to be stockpiled in the hundreds of thousands of doses. This BPO concept is now fairly well evolved. We are in the process of looking for support for it. This is something that Governments need to be behind. This kind of investment is to protect populations from emerging outbreaks. We look for a governance model that would allow decisions about how to prioritise, what projects to work on, how the work is being done and who has access to the vaccine stock, and for this to be done in an independent and transparent way. This does not imply manufacture. The solution to manufacturing for large-scale stockpiling is a separate question, but it is integral to the concept and we would be very open to tech transfer, to allow on a regional basis, for example, manufacturers to develop and maintain large stockpiles of vaccines that are thought to be potentially useful. Implicit in this is that, first, these are likely to be vaccines that have no commercial value; otherwise, industry would already be working on them and we would have those vaccines. Secondly, it is likely that they will be products that will be very difficult to register. We are talking about stockpiling for emergency use what would still be investigational vaccines. The framework around how you would use them, who gives permissions and what data you collect when you need to test, essentially, investigational products, as we did with Ebola—all of them were investigational vaccines and drugs—needs much more elaboration and strengthening.

Graham Stringer

Dr Ballou, you said that the regulators wanted randomised control trials but by and large they did not take place; just one took place. Who objected? Why did they object, and on what basis?

Dr Ballou

A meeting was held by WHO on both drugs and vaccines to discuss what should be done in terms of trials that would be used to generate efficacy data that would allow regulators to register vaccines. To have vaccines available in countries they need to be registered at some point. The regulators were very clear that if it is at all possible we should capture data using the most rigorous methods of data collection, data analysis and trial design. At the top of the prioritisation of data quality are randomised control trials. Of course, we proposed several designs, including randomised control trials, but also alternatives, recognising that to do randomised control trials is sometimes not possible. Clearly, in the study where the Merck and NewLink VSV vaccine was tested in Guinea, the decision was taken not to use a randomised control trial; it is weaker in terms of the quality of evidence and data efficacy, but when the signal is very clear, as it was in that study, it was very informative. Non-randomised control trials have their place, but I do not think they should be the first choice out of the starting gate.

Graham Stringer

My final question may or may not have an answer. Is there a ballpark figure for the cost of stockpiling 10 vaccines for 10 possible outbreaks?

Dr Ballou

There is a ballpark figure for what it would take to have a facility that would be able to do this. To generate and stockpile 10 vaccines will probably take a decade; it is not something that happens overnight. One of the real challenges is that if you are going to do it you need long-term funding. It is not a three-year grant and then you have 10 vaccines. It would require sustained funding over a decade or more to allow you to get to the point where you could work your way down the prioritisation list and have candidate vaccines stockpiled.

Graham Stringer

Is there a ballpark figure?

Dr Ballou

The ballpark figure is probably of the order of £50 million a year.

Chair

Dr Ballou, I want to take you back to your first answer to Mr Stringer. You gave us written evidence in which you referred to the meeting about what kind of trial would proceed. You said: “The message was, essentially: ‘If it goes the way we are seeing, we are talking about depopulation of West Africa by April 2015’. It was incredibly sobering…This scenario contributed to a sense of desperation which I believe impeded normal scientific debate, especially around study designs.” That was not the sense of the answer I got from you just then.

Dr Ballou

That is correct. What I am referring to in that discussion is the fact that at the time we were debating optimal trial designs there were very impassioned arguments coming from parts of the community who felt that any study that involved the use of a placebo or a control vaccine or drug was inherently unethical. This completely dismisses the fact that we were talking about products whose safety profile we did not know and we had no evidence that they actually worked. As product developers, we come from the perspective that one always has to do the risk-benefit analysis, and there is not always the clear and obvious answer that of course it is going to work because it works in a monkey. We have seen many products that work fine in animal models but do not work in humans, and in fact can steer the discussion and development process in absolutely the wrong direction. I maintain that randomised control trials are clearly the optimal way to do this, but they are not always possible when you do not have the infrastructure and the willingness of the community to participate; we heard from the anthropological side earlier that the whole issue of engagement of communities is critical. In this particular setting, where there were three countries that had gone through decades of civil war, distrust of Government, foreigners and science was a major challenge.

Chair

Professor Lang, was it also your experience that among the community in the debate about study design there was resistance to certain types of study?

Professor Lang

It was exactly as Rip said. It was a very unusual situation to work in. Normally, you have the luxury of time and calm scientific discussion: here is the question you need to answer; here is the evidence that you can bring to support what design you choose; and then you come to a consensus in the scientific community about what the right design is. In this situation we had to act very fast and quite a lot of players were involved. The backdrop for the therapeutic trials was that we were trying to implement clinical trials in treatment centres where you had very sick, frightened people, and there was no other treatment to give, or nothing else to use as a comparison. We are always told, “Why did you not bring this experience earlier?” We have a huge amount of experience running very difficult trials in vulnerable populations where we are looking at mortality as the end point because it is in awful disease settings. We are used to working with the community to find out how they perceive it and what the risks would be, and working with local anthropologists and social scientists to understand that. In this situation it was very clear that there was no way you could sit down with a family group. Traditionally, we would randomise and say, “You get the drug, but you will get something else.” You would never be able to do that. Médicins sans Frontières and local ethics committees said, “We cannot let you sit there and say that the mother gets the drug and the daughter doesn’t.” That was a clear message; but that was okay, we could work within that, because very good scientific designs are used in clinical trials all the time, such as in oncology, where you have a similar situation. You have a desperate situation where no other drugs are available. When you are looking for a very clear outcome—died or didn’t die—and a very big difference in survivors, you can use a different type of design. I agree with Rip entirely that ideally we would like to use a randomised control trial where they get one or the other, but that is not always possible, and not always needed. What we need to think about is using the most appropriate design in the most appropriate setting that is scientifically justified. We need to be able to have that debate in a rational scientific way, which was not always the case.

Chair

It is that bit that is worrying me. It sounds like it was not possible to have a rational scientific debate and there was lots of pressure put on scientists in the process. In the development of any vaccine in an outbreak scenario this set of circumstances would be replicated, so how would you recommend trying to avoid such a fraught scenario in future?

Professor Hill

The easy answer to give is education, but it is not always possible in the short term.

Chair

You have to pinpoint the location.

Professor Hill

What I think we have learned and should emphasise is that ring vaccination, even though it is not the gold standard, was the design used in Guinea for the successful vaccine trial. It worked really well in that context and gave a very clear result. Ring vaccination had been forgotten about a bit. It was used in Nigeria in the 1970s, but then the gold standard came in and nobody did ring vaccination. I think we are going to see many more ring vaccination trials implemented to test outbreak vaccines. To return to the point about community buy-in, if you look at that trial, so many people, who were randomised to receive the vaccine immediately, declined vaccination that they formed an additional control group who got a significant incidence of Ebola. You can compare all the people who were randomised to get the vaccine and were vaccinated with those who chose not to be vaccinated and you see a significant difference. That illustrates two things. It is another way of looking at vaccine efficacy, but it also tells you that quite a lot of people—about 20%, I recall—declined vaccination, which illustrates that not everybody was going to buy into the idea of vaccination.

Victoria Borwick

To go back to Cobra, which we talked about in the earlier session, why do you think Cobra took so long to respond to the request for the Ebola SAGE committee to be formed? Do you have a view on that? It harks back to what we were talking about earlier.

Professor Hill

I don’t, no.

Professor Lang

As a research community it is outside our experience. The next panel might be able to answer that.

Chair

Thank you all for your evidence, which has been very helpful and thought-provoking. We are conducting an inquiry into a very serious matter. We may want to write back to you on a couple of points.

Professor Hill

Can I make a final point? There are two problems. We have talked about one a great deal. How do we get vaccines for these outbreak pathogens? What is the business case, and so on? The second one that I hope will be of interest is the problem of vaccine manufacturing capacity in the UK. It is not a great exaggeration to say that we do not have any. There was a survey at the time. We needed a lot of Ebola vaccine that worked and was available, but we did not have anywhere to make it. Many people are conscious of this. It is not a cheap solution to manufacture, and you cannot create it in weeks; you need years to build manufacturing plant. The UK is lacking in that capacity. It is a national security issue; it is a separate issue but it was very high profile at times during the Ebola outbreak.

Chair

Professor Hill, can you tell us where vaccines are currently made? I think it is in the Netherlands.

Professor Hill

Dr Ballou would be better able to answer this. Most of the vaccines that we give our children and everybody else are made by a relatively small number of very large pharmaceutical companies that have extensive manufacturing capacity and the experience and know-how to do it, which is slowly acquired. If we go back 25 years, most European countries had somewhere to manufacture their vaccines. Very few do. Private industry controls that today. A lot of new industries and small companies in Asia provide vaccines for the developing world, but what we have lost in many European countries is a national facility for vaccine biomanufacturing. We have some very small facilities; they are not a solution to providing 50 million doses of an Ebola vaccine for the UK population, if we needed that. We should be aware of that. It is not a new suggestion from me; people have looked at this, but it is not one to which we have a solution.

Chair

Although we had a very effective response, a barrier and so on, had that not been as effective as we hoped and we needed to access a large number of Ebola vaccines in the UK, would we have been able to do that?

Professor Hill

In this particular case GSK was manufacturing vaccines as fast as possible with a new manufacturing process that was rate-limiting. Dr Ballou can say more, but I think the short answer is no. If we had wanted 50 million doses in January we could not have had them.

Chair

Could you write to us about that, Professor Hill?

Professor Hill

Certainly.

Chair

Thank you so much for your time. Examination of Witnesses

Witnesses

Dr Jeremy Farrar, Director, Wellcome Trust, and Professor Chris Whitty, Professor of Public and International Health, London School of Hygiene and Tropical Medicine, gave evidence.

Chair

Dr Farrar and Professor Whitty, welcome to the panel. I hope you have been enjoying the afternoon. It has been fascinating. Professor Whitty, we saw you in a different capacity a while ago. I want to read a little of the written evidence we received from the Wellcome Trust. Dr Farrar, you described Ebola as an avoidable crisis and said that “a lack of real time data of infection rates and further understanding of the virus significantly impacted on both the ability to make decisions regarding treatment and prevention of spread of the disease,” and that “should there be a similar emergency, the availability of vaccines and treatments would still be a critical unmet need.” Do you stand by that written evidence today? Professor Whitty, do you agree with that? What do you think we should be doing to try to address those core issues? We have been exploring that a bit this afternoon, but what are your specific views?

Dr Farrar

I do stand by that statement. I think it came out a bit in the previous session, and it is true of every emerging infectious disease. I have been personally involved in most of them, going back to the Nipah and SARS in the last century. The key to intervening is to do it early. If you miss that opportunity, or you do not make the right decisions, things spiral out of control and you lose the ability to keep track of it. That was what we saw in West Africa in 2014. The period between December 2013 and March/April 2014 was when it went from probably a single individual in Guinea to urban transmission across three countries in both urban and rural settings. That is unprecedented in the 40 years since Ebola was discovered. The key is early intervention. In previous outbreaks, where intervention has come earlier and they have been largely rural outbreaks, you have been able to intervene with classic public health, and the numbers have been in the 10s and sometimes 100s, but 30,000 individuals with Ebola is totally unprecedented, and it was in the first six months—what I would call phase l—that the opportunities were missed. In phase 2 from August, when we got into gear, as Professor Hill said—I am sure Chris will talk about this in a minute—things were done that made a big difference. The focus has to be on the first six months in changing that intervention.

Professor Whitty

I broadly agree with that, and I think most people would as well. To be clear, there are some epidemics that you cannot break early on. If there is a big flu pandemic it is going to hit us; there is nothing we can do to nip it in the bud, but while this particular Ebola epidemic happened, several other smaller epidemics happened, including one of Ebola in the Congo area, and a plague outbreak, for example, in Madagascar, and were snuffed out effectively. In a sense, this was the one that wasn’t, despite the fact that, as Dr Mathias essentially implied in one of her comments, anyone reading the news could tell that it was not behaving in a normal way. I would say that from about March, a bit later than Dr Farrar, it was pretty clear that it was not behaving in the way you would normally expect, so there was a period between about March and the end of July when there was an opportunity to get on top of it quite quickly and it did not happen.

Chair

Why do you think it did not? There are examples of other outbreaks where there has been a quicker response. We can point to Cobra being convened in a three-month gap from the SAGE scientific advice being commissioned. It is not clear why there was such a slow response to this from different sources. We have just heard from Dr Ballou, who said he phoned three times to offer vaccine services and got no response until July. What do you think was behind this, Professor Whitty?

Professor Whitty

Let me separate the international response from the UK response, but not quite as starkly as some people do. The international response was extraordinarily slow in the round, but I do not want to go in for a WHO kicking session. We all have to accept that WHO is owned by all of us; it is the international community and, if there is a problem with it, it is our problem as much as anyone else’s. There is a danger of thinking it is someone else’s fault. One area where I would part company with Professor Leach on the first panel, before you arrived, Chair, was her comment that the UK could have got on top of this in a sense unilaterally, or at least she implied that. If you think it through logically, I do not think the UK was in a position to be able to do that as an individual country. This had to be either declared by the WHO as an emergency or the countries themselves had to declare their emergency and ask us for help. We cannot just march in and say, “You don’t think you’ve got a problem but you have got a problem, and we are going to sort it out.” I am a bit more cautious about the UK acting alone, but there is no doubt that we know how to get on top of Ebola outbreaks. Ebola is not a new disease. Had things been done at any point probably up to the end of April, we could have had good control. The first case recorded in Sierra Leone, which was the country we eventually worked in, was not reported until 25 May, quite a lot later, and if there had been more action at that point it probably could have been slowed right down. It did look as though it was going away at the end of May, and people took their foot off the gas. That was a big mistake, and it roared back again in June.

Dr Farrar

I would agree with that. I very much agree with Chris that WHO is owned by all of us. There was a failure of leadership at WHO, but there was a collective, global failure to respond to what I called the first phase. There must be some lessons learned from that phase. Maybe we will come back to ideas about WHO reform later in the conversation, but we have to change the way that is done. When you prevent something happening you often get no credit for it because it was not going to happen anyway. In my personal view, there was a hangover from the pandemic in 2009 and a sense in some quarters that there was an exaggerated response to it and it proved to be—not my words—a damp squib, and therefore there was an exaggerated global response. I did not believe that then and I do not believe it now. I would much rather we over-responded occasionally rather than under-responding and ending up with 30,000 Ebola cases. You will not always get it right, but it is much better to over-react occasionally than under-react every so often. Perhaps we will come back to WHO reform in a minute. We also have to look at Ebola in the context of the 21st century. We tended to look backwards. While I accept Chris’s comment that we know how to control Ebola, I am not sure we knew how to control it in the context of the society in which it happened in the 21st century, which was multiple country urban transmission where the dynamics of that society are very different. Professor Leach talked about that earlier. Outbreaks in the past have been mostly rural, and that is a different community to work with. It is crucial when thinking of these epidemics to look to the future rather than repeat what happened in the past. You will make mistakes if you do that.

Professor Whitty

I absolutely endorse the points Professor Leach made earlier about the importance of social science in this response. It was important in almost every aspect of what we did. The first experience I had in government of a crisis like this was the so-called Mexican flu pandemic. We did not get the social science properly engaged, and the other thing we did not get right was that we did not marry up the international and domestic sides. On this occasion I think we did that a lot better, but in particular social science was much more heavily embedded from the beginning.

Chair

Professor Whitty, to go back to your previous hat as a Government adviser, one piece of evidence we have received is from Professor Edmunds of the London School of Hygiene and Tropical Medicine. He said that one of the fundamental problems is that, if you respond early and well, what happens afterwards is that people say all the money spent was not well spent because you had only a few hundred cases, yet essentially you have prevented the cases that would have caused the outbreak. How do you deal with that in terms of convincing decision makers that it was well spent, because it is a Catch-22, isn’t it?

Professor Whitty

It is a Catch-22. The reality is that people like me in my previous role will appear in front of either your Committee, who are asking, “Why did you not respond earlier?” or the Public Accounts Committee, who are asking, “Why did you spend all this money when it clearly was not needed?” You are damned if you do and damned if you don’t, but I do not think that in this case anyone has any doubt that we responded too late. By “we” I do not mean the UK but the international community. I don’t think anyone doubts that.

Graham Stringer

We have heard some quite scientific discussion this afternoon. How important is it to engage the BBC and CNN in getting television cameras there? Is that a critical factor?

Professor Whitty

I will give my answer, but I suspect Jeremy will give a much better one. My answer would be that the media are potentially your greatest ally and your greatest threat. They are the greatest ally because they can get important messages out there and make people realise that this is genuinely serious, and the UK media did a very good job on this occasion. They are your greatest threat because they can hype the thing up and take the wrong things way out of control. Broadly, the UK coverage was pretty measured. I also think that the British political response was extremely measured compared with many other countries, and that made it possible to have a proper operating environment, but it was not a given. There were other countries where the media got seriously in the way of events by making hysterical claims about the risk to well‑developed public health systems like the UK and other northern countries.

Dr Mathias

This might not be appropriate for the time we have. My question is about improvements in the African medical profession, WHO and the UK on co‑ordinating and reforming. If you cannot answer it in a short time, we might have to deal with it after the meeting.

Dr Farrar

I think I can answer it, or at least start with WHO. Publicly, I have called for reform. I think Margaret Chan is in place for another 18 months to two years. As to who the next director general of WHO is, it is absolutely critical. Perhaps we can come back to that. She has a two-year window when it will not be possible to reform the whole of the WHO. That task could take many years, but building on Ebola and Margaret Chan’s personal background in H5N1 in Hong Kong, one could establish within WHO a semi-autonomous unit dedicated to the surveillance of and response to emerging infections. It should be properly funded and, to come back to Professor Whitty’s point, owned by all of us and it would function even in the inter-epidemic periods, because when you are trying to create such a structure and respond in a crisis you run into real problems. I would have a separate governing board which reported to the director of that entity, and he or she would report to the director general of WHO, but the advice would be transparent and open so we would not be having conversations about who said what to Margaret Chan in corridors in which month and on what date. As with the European CDC, discussions in the morning would be on the website in the afternoon and transparently advised. I think that can be set up in the time Margaret Chan has left at WHO, and it is critical that we do it. That was what came out of the Stocking report; it will come out in subsequent reports, and we need to act on it.

Professor Whitty

I have two points to add. One is on the science and training side. The UK has a very proud tradition of training scientists from Africa in Africa in science as well as in medicine. Building local capacity in all the relevant sciences is absolutely critical. It is more important than surveillance and anything else. On WHO, the only thing I would add is that its regional areas—WHO AFRO is the area where this is—do not always have a good relationship with WHO in the centre. If I could build the capacity of WHO AFRO scientifically, it would be a phenomenal achievement, but I am not sure how easy it would be.

Victoria Borwick

To go back to the timetable of what happened when, which was referred to earlier, why do you think Cobra took so long to request that the Ebola SAGE be formed?

Professor Whitty

I am not the right person to ask about when the decision formally to form SAGE was made, but I do not think it would be right to think that scientific advice, including formalised scientific advice, was not going in from a very early stage. For example, the SHED mechanism—science in humanitarian emergencies and disasters—was providing advice to the Government in March. I had very close discussions with leading scientists in the UK—social anthropologists, epidemiologists and so on—throughout all the period right up to and beyond the point when SAGE was there. We are very fortunate in the UK to have, in part because of MRC history and the Wellcome Trust in particular, a very large body of some of the world’s best tropical health scientists in many different disciplines. For example, the head of our national School of Public Health was one of the co‑discoverers of Ebola; the chair of the board of Public Health England was one of the people who worked early on Ebola. Dr Farrar himself comes from an emerging infections background, so we had a lot of the right skills in place. Although it was not formalised until the Cobra mechanism asked for it to be formalised, the advice was happening well in advance of that.

Victoria Borwick

Lessons learned?

Professor Whitty

I think the biggest positive lesson—the reason I repeat it over and over again is that it gets missed in almost every other pandemic—was that we got the social science in right at the beginning, along with the modelling, the epidemiology and the clinical. If we had not done that, we would very possibly have failed to get on top of things properly in Sierra Leone. I think we can learn a lot about that for our own domestic responses in the future.

Dr Farrar

In addition to that, similar to my comments about WHO just now, I think it can be replicated within our own system that there is a standing body. So much of this depends, when the proverbial hits the fan, on personal relationships and the fact that you have worked together. Chris and I have known each other for 25 years, so that really facilitated a flow of information, and DFID and the Wellcome Trust have done many things together. That was the mechanism by which we were the first to fund some of the vaccine trials you heard about earlier from Professor Hill. I would like to see that body standing and functional throughout time, so that it does not have to come together just at a crisis. Just as I talked about a semi-autonomous unit within WHO that would be tasked with that, so there would be a standing body doing this on a regular basis and meeting regularly, even in the absence of an epidemic happening today. That is the only way you do the groundwork to respond when something happens; otherwise, you are always trying to catch your tail and be responsive rather than proactive.

Victoria Borwick

What about the additional resources needed to support the work? What additional resources were needed, and were they provided in a timely manner?

Dr Farrar

Once things got going they were provided. Because DFID, the Wellcome Trust and MRC had been used to working together professionally, we were able to make things happen very quickly, but it depended on some personal contacts. You cannot underestimate how important that is in these chaotic situations. I would like to formalise that more, so that the UK had a standing body that people worked with, whether or not there was an epidemic happening today, similar to what I am asking for at WHO.

Victoria Borwick

When you talk about additional resources, is that what your recommendation would be?

Dr Farrar

It would be. Part of that structure exists already. There is a body called UKCDS. I cannot remember what CDS stands for, but I am sure Chris will know.

Professor Whitty

Collaborative on Development Sciences.

Dr Farrar

We host it within the Wellcome Trust. That needs to be beefed up and made to function, and it would be the cross-governmental body that could potentially deliver that. I do not think they delivered during Ebola, but potentially they could be the cross‑governmental body tasked with doing that.

Victoria Borwick

To go back to evidence-gathering, assessment and communication, you talked about the personal relationships that facilitated it on this occasion, but how effective was the Ebola SAGE in assessing and communicating information? What lessons can we learn?

Professor Whitty

Professor Leach, who was on it, said earlier that she thought it was very effective. I agree with that, but I reiterate that it was only one formal bit of the mechanism. It was much more long term and in-depth, with many scientists who worked on SAGE itself.[1] SAGE was really to help Cobra formally; it was not the only way in which Government was getting information.

Carol Monaghan

Professor Whitty, in the previous panel we were talking a lot about vaccine development and trials. You said that insufficient attention was directed towards the clinical response to Ebola. Can you explain what you mean by that?

Professor Whitty

I do not know when I said that, but I do think that, so you have obviously read my mind. There was a very good response on the vaccine; the speed of response on vaccines was admirable from the academic community, from WHO, where they did that well, and from other bodies. The problems on therapeutics were that there were some very simple things that it was clear we should be trying. They were primarily around fluids. How much fluid should you give people, and should you give them antibiotics? They were very simple questions. These were available. We did not need to wait for a drug company to produce them. They were unlicensed.[2] We did not need to do a licence trial; we just needed to test out how best to do it, and we did not do that. Having been out there in the first few months, the extraordinarily brave Sierra Leonean, international and particularly UK staff were absolutely on their knees, and the possibility that we could have loaded on even a small additional thing was probably not realistic, but once the outbreak had peaked, which was round about December, we could easily have done that and got big enough numbers to get a serious answer, and we did not. That is a collective failure of the academic system. I do not think that belongs to Government; it belongs to all of us in the academic sector. We did not get that right.

Carol Monaghan

Was that a lost opportunity?

Professor Whitty

It was an opportunity lost.

Dr Farrar

Having lived through very closely SARS, bird flu, MERS, Ebola and a number of other epidemics, we have missed that opportunity in every single epidemic of the last decade. If you go through the diseases I have just mentioned and ask yourself, “Have we pushed through those epidemics therapeutic, diagnostic or vaccine studies?”, the answer to all of them is no, with the exception now of Ebola. That is a missed opportunity in each and every epidemic. In 2012 or 2013, I set up, with funding from the MRC in my previous life, the Bill and Melinda Gates Foundation, the Wellcome Trust and the Li Ka Shing Foundation, something called ISARIC, which Trudie is now part of. It sought to change the paradigm by which clinical research is done in the context of epidemics. I think that still deserves support, and it is how we would change the nature of the way we respond to these epidemics. We must overcome the sense of separation within the response network on the part of those who think everything can be solved with classic public health measures that we might have implemented during John Snow’s time in London. I am a great fan of John Snow and those interventions, but diagnostics, therapeutics and vaccines are part of the 21st century public health response and they must be part of the way we think about these epidemics in the future. I do not believe we do that sufficiently today.

Professor Whitty

During the epidemic we in the UK decided that we had to focus on one single strategic goal, which was to get down the force of the transmission, which we call R0, and we would do any form of research, including vaccines, diagnostics, modelling and anthropology, that was around that goal, but we would leave anything that was not around that goal, including therapeutics, to other people, because we just did not have the bandwidth to do everything. Our view was that the epidemic was running out of control. That led to some positive things happening, but there was a deliberate choice made that this was something we did not have enough people to do at the same time. That was just in the nature of the response, but at least we thought about it and felt we did not have the capacity at that point in time.

Carol Monaghan

There are some fairly strong messages coming from both of you, so I hope we can take note of them. Who had responsibility for deciding which research was going to be undertaken during this outbreak, or any outbreaks, and co‑ordinating it?

Dr Farrar

Do you mean on a global scale?

Carol Monaghan

Yes.

Dr Farrar

Ultimately, whether things go forward or not comes down to decisions made in Sierra Leone, Liberia and Guinea, because the Ministries of Health and Governments in those countries have the final say in what happens there. I think that on this the WHO did a reasonable job. In September or August 2014 there was a series of meetings in which WHO sought to establish priorities for both therapeutics and vaccines and to work through the mechanism by which those would pass forward. They were not always listened to, and that is a problem in itself, but there was an attempt to prioritise and say where it would be done. As you know, the United States took on primary responsibility for Liberia, France took on partnership responsibility for Guinea, and the UK took on primary responsibility for Sierra Leone.

Professor Whitty

I agree.

Carol Monaghan

The Wellcome Trust has spent over £18 million funding Ebola-related research. What is your opinion of the UK’s response? Are we overly reliant on charitable funding, or should more funding be put in for such things?

Dr Farrar

I think you should take the figure with a slight pinch of salt, because it is considerably more than that when you add it all together. Almost none of that was done in isolation. That money was provided in partnership with DFID, the MRC, GSK, the NIH and the WHO. The Guinea trial, which was successful, was done in partnership between us, DFID, the WHO in Guinea and the Ministry of Health in Guinea. My own background is in emerging infections, so that may be one reason why the Wellcome Trust put money up very quickly, but it did not do it alone. Do the UK Government need to do more? Yes, of course. It is on the UK national risk register. I believe there needs to be better co‑ordination within the UK about how one thinks about and prepares for these diseases and responds to them. The UK needs to support a stronger WHO and allow it to lead, and give respect to that organisation when it does lead. I absolutely take the points made earlier about vaccine manufacturing. The UK is incredibly vulnerable to a nasty coming from somewhere. The UK has almost no vaccine manufacturing capacity and, if something dreadful happened on a regional or global scale, getting vaccines from other countries would be incredibly difficult. We would be on our own. That is a very worrying situation to be in.

Carol Monaghan

What steps do you think the UK has to take to make sure it is research ready for any future outbreaks we may experience, of Ebola or other diseases?

Dr Farrar

As I said earlier, I would establish a standing body similar to WHO. If WHO is to have a dedicated semi-autonomous unit with protected funding to look after those activities, I would establish that within the community in the UK. It would bring in industry, academia, Public Health England and the devolved nations, and would allow those structures and, ultimately, personal links to be developed in so-called peacetime, such that, when inevitably something happens that potentially either threatens this country or is somewhere else in the world but we feel the need to respond, we would not be trying to respond to that; we would have prepared properly for it. I would like to see the UK establish that in the inter-epidemic period. The UK does not have the equivalent of the Centers for Disease Control epidemiological surveillance officer training programme. That has fallen down the priorities in the UK and it should be re‑established. Lastly, compared with, say, 25 years ago the UK plays a lesser role in global health diplomacy. When I first started to interact with WHO 20 years ago, the number of people from the UK involved in WHO or in the now European CDC and so on, was more than it is today. That is a critical role to play in trying to influence the way global policies in health work.

Professor Whitty

I would take a slightly different tack, although I agree with all those points. I would divide things into the known unknowns and the unknown unknowns. The known unknowns are things like Ebola, Marburg and a variety of others. As was said in the previous panel, we need to list those and the global community needs to work out countermeasures, which may be vaccines, but I want to be clear: vaccines do not work for everything. We do not have a good vaccine for HIV, malaria or TB. People have been trying for a long time. Let’s not get hung up on the mechanism; let’s start with the problem and work backwards. Of equal importance is that at some point we will be hit by another unknown unknown where the disease comes out of nowhere, like HIV. The key thing is that what we know about it is that it will go down one of a relatively limited range of transmission routes. It will be faeco-oral, airborne or sexual; it will be vector-borne, broadly. We can think about countermeasures to those, which in a sense are non-specific to what the disease is and are much more about how we hit it at multiple points along its pathway, almost irrespective of what it is. That will get us a lot further forward in our response. We can then try to work specific countermeasures to the disease that comes up. We have not been terribly good at that, and we need to be a lot more systematic about it.

Dr Farrar

I absolutely agree with Chris that vaccines are not a magic bullet for everything, but to pick up what Rip said earlier, the GSK proposed the BPO support structure and I, along with Stanley Plotkin and Adel Mahmoud in the States, have proposed something similar that I hope will be complementary, which is a global vaccine development fund. Professor Hill and people on the academic side will do the research. Britain plays a critical leading world role in that, and the Jenner Centre and Adrian are in the lead on that, as is GSK. There is a problem in the middle, which is taking that academic work into the early phase development, where there is a gap—the valley of death. It is very difficult to get phase 1 and phase 2 clinical trial data, and I believe we need a global vaccine development fund that would bridge the academic sector and the industrial sector; otherwise, we are very vulnerable to unmet clinical needs where there is no commercial driver.

Professor Whitty

I do not want my comments to be understood as anti-vaccine; they are not at all. I chair the new UK vaccine network, and the reason it was put in place was that we perceived all those weaknesses, and we need to work out how the UK countries can get around them and try to address them.

Carol Monaghan

The valley of death has been mentioned a number of times in this Committee over a range of different subjects. We are hearing it again. It is very interesting.

Chair

Professor Whitty, given that the evidence we have received is that it is relatively simple to identify maybe the top 10 riskiest infectious diseases, and we have had the threat of emerging infectious diseases on our national risk register since 2008, can you explain why we have not had some protocol in place for responding to the top 10 diseases, and why there has not been at least a UK response plan in place?

Professor Whitty

I think that Ebola is the first time we have demonstrated—in a bad way—that one of the things we know can cause dangerous local epidemics could become generalised if it gets into the wrong place. That has been a wake-up call for lots of people. As one member of the first panel said, the reason we have Ebola vaccines is bio-defence concerns in the security sphere. The reason people were not concentrating on it was that we looked at Ebola and said, “Yes, this is a big problem, but we know how to deal with these small outbreaks. It is killing very few people. Let’s put our resources into malaria, TB and HIV.” I think that was a logical thing to do. What this has demonstrated is that some of those things can go beyond the point where they have been historically and start moving out, so that has led to a change in mindset. We need to respond to that and realise that Ebola is not the only disease that could get into the wrong environment and then take off. We need to be mindful of that.

Graham Stringer

Dr Farrar, I am getting a very confused picture of the state of science in this area and our strengths and weaknesses. We have been told that the manufacturing side is almost non-existent, and you said that the academic side is very good both in quality and quantity. Overall, how would you assess our science base in this country for looking into this area?

Dr Farrar

In terms of vaccines or emerging infections?

Graham Stringer

Across the board. I suppose I am referring to infectious tropical diseases.

Dr Farrar

I may not be the best person to answer that question because it is my background, so, if it is a failure, it is my own failure. In vaccinology, it is absolutely true that the UK is world-leading in the academic sense—no doubt about that. There is the Jenner Centre in Oxford, but there are other centres, Imperial, Edinburgh, Liverpool and so on, where it is incredibly strong. The academic base for understanding immunology and the world of vaccines is as strong in the UK as it is anywhere in the world, and the UK should be very proud of that. GSK is one of the four major players in terms of industrial support for vaccinology. We are incredibly lucky to have GSK here. The problem lies between those two; it is the valley of death, where we do not have the capacity, which I believe is public health, and therefore I think there is a public responsibility. We can call it a market failure. In my view, that is a misnomer; it is a public health failure. This is where philanthropy and Government will have to work with industry and academia to fill the gap, because you cannot expect industry to do things for charitable purposes. That is a role for Government and for philanthropy like myself. The manufacturing issue is crucial, though, particularly around all the vaccines we need. Britain is very vulnerable to that, particularly if there is an emerging crisis in almost any infectious disease, including flu. Britain would not have the capacity to manufacture what it needed for its own purposes.

Professor Whitty

To add to the areas where we are strong, our tropical epidemiology and tropical public health is among the best in the world, if not the best, in many diseases. That is for historical reasons. The Liverpool and London schools of tropical medicine, Oxford, Imperial and various other places have real strengths in this area. The UK is looked to technically for a response, even if we are not responding in other ways, almost invariably. The danger is that people say, “Why are we doing this? Why aren’t we concentrating just on domestic issues?” It is an area of huge strength, and what this demonstrates is that from time to time we really need it.

Graham Stringer

I am putting words into your mouth, because you did not actually say this, but you implied that we had become weaker in the World Health Organisation in terms of representation. Why has that happened when we have such a strong academic base?

Dr Farrar

That is a good question. There are other players and actors now. Perhaps 25 years ago someone like Professor Whitty would have gone to work in Geneva, maybe even myself. Who knows? I would not particularly want to work there now, and that may be a reflection of where we have collectively allowed WHO to go. Twenty-five years ago the Gates Foundation did not exist in terms of global health; now it is a major place where world-leading figures who want to make a difference to global health go. Dare I say that even the Wellcome Trust might be somewhere you would go now if you wanted to make a difference to global health? Less and less is WHO seen as an attractive place to work, which is a great shame. Morale is low, they are getting kicked all the time and funding is being limited. Perhaps there has been a lack of leadership. We have to reverse that, because if we did not have a WHO we would have to invent it. It was established in the 1940s. I do not think it is fit for purpose today, but we absolutely need a global body that brings together the world health community and takes collective action. While it is easy to criticise them—I have been very vocal in that—we need a very strong WHO.

Professor Whitty

I would add a partially more positive spin. The relative decline of influence in the UK is because other countries have become technically much stronger, much more powerful and much richer, and that that is good, but leads to a problem.. For a long time multilateral organisations essentially were controlled by a small number of countries and others just took part. Now that they are genuinely multilateral, it makes it very difficult to get progress in every single one of them. WHO suffers from this, but so does almost every other multilateral organisation I can think of.

Graham Stringer

I think you have already touched on the answer to this question, but I will ask it specifically. At the start of the outbreak Ebola vaccines had not gone through phase 1 early clinical safety studies. Professor Whitty, you said that was a mistake. Why was the mistake made?

Professor Whitty

The mistake was made for the reasons I gave earlier. It was seen very much in the context of a disease that we thought we could control, and a series of decisions was made entirely on defence and security lines. We were not really seeing it as a public health issue. It is one of those things where, had I been making the decision 10 or even five years ago, I probably would have made the same decision if I had been in the room, so it was a mistake in retrospect. What it has taught us is that, if we have other vaccines which are through animal models and look pretty good but are not through phase 1 studies, let’s not leave them there. If that is the situation you are in, when there is an epidemic, even if you go at a phenomenal rate—I take my hat off to everybody involved who tried to get the vaccines through—you will lose six months. If they are sitting there, through phase 1, you have some basic safety data and you can go straight into the clinical trials.

Graham Stringer

Is there anything you want to add about how we can avoid getting into a situation where there is critical unmet need for treatment and vaccines when the next emergency arises? What role should the pharmaceutical industry itself be playing in that?

Dr Farrar

I would reiterate what Chris has just said. Not taking things through to phase 1 was absolutely the fundamental error. If you had asked me two years ago, before this started, whether Ebola would be on that top list of 10, I would have put my hand up and said no; it would not have been on my list, and this is my own background, but now it would be. There is a list of diseases we know about, and there are some platforms we could develop to respond to the unknown unknowns. Getting through phase 1 is critical. As we heard from Professor Lang earlier, we need to have protocols in place that allow you to go immediately—within days rather than months—into assessment. That can be put in place, and there can be global consensus that would allow it to happen, but we need to remember the timelines for that. We talk about therapeutics and vaccine trials that might take a couple of years in gestation. In the modern world with modern travel, we have to bring that down to days rather than even months if we want to intervene at the early phases of an epidemic.

Derek Thomas

We have established this afternoon that the World Health Organisation and the international community were slow to respond to Ebola. Do you think that was caused largely by insufficient disease surveillance, or is that too simplistic?

Dr Farrar

No. I think surveillance is critical to this. I have often said that you must combine surveillance with the capacity to respond. Surveillance on its own without the capacity, willingness and leadership that allow you to respond is not stamp-collecting but it is not far from it. Surveillance is the key, and the UK Government and ourselves, along with the Gates Foundation, are working towards setting up much better surveillance around the world with real-time sharing of data to allow these things to be picked up earlier, but you have to combine surveillance and response; you cannot stop at just describing things.

Professor Whitty

On this particular point, I would agree only partially. I completely agree that surveillance is critical, but I do not think that lack of surveillance had any part to play in why we were slow in this epidemic. We all knew about it; we were reading about it. MSF were there. We knew about it right from the beginning. It was a failure to act. Although I am totally with Jeremy on the importance of surveillance in many areas—for example, tracking drug resistance would be a very good one—let’s not kid ourselves that that would have solved this problem. It would not.

Dr Farrar

I absolutely agree with that.

Derek Thomas

The Prime Minister has pledged to provide funds to establish a rapid reaction unit to act as disease detectives. Is that stamp-collecting?

Dr Farrar

I agree with it. I spent the last 20 years of my life living in Vietnam doing that sort of thing. We have a responsibility to do that. The idea is to establish a fund that would enhance local capacity. This can be about international response, but it will be the people working there day to day in the inter‑epidemic period who will make the difference. That capacity has to be built where the challenges are at their greatest. The name has come to me—the Fleming Fund. What the Fleming Fund, the Wellcome Trust and Gates are doing is absolutely critical, but it has to be built in the countries that are most vulnerable, and there has to be willingness of the international community to add to that where necessary.

Chris Green

Dr Farrar, the Wellcome Trust raised concerns about the reason behind voluntary screening at airports and how it was communicated to the public. How could the communication have been improved?

Dr Farrar

One hopes that policies are made on the basis of strong evidence. I do not believe that in this case screening at airports would have made a difference. I also accept that policies need to take evidence into account but sometimes have to do things where there are other pressures. We saw this during SARS, where there was screening at airports, which I would argue had a greater impact than during Ebola. We also saw it during the pandemic of 2009. I do not think it was necessary during the Ebola outbreaks of 2014-15.

Chris Green

What do you think prompted the Government to reverse their policy and go against WHO advice?

Dr Farrar

I am not a politician, but sometimes there is a need for politicians to act and be seen to be acting. It was a public statement of how concerned the country was about the outbreak. I do not think that it was epidemiologically and scientifically justified, but I appreciate that there is scientific evidence that politicians then need to take into account when making those policy recommendations.

Chris Green

It was asserted at the time that it was based on expert advice. Sometimes a profusion of expert advice can cause confusion. How do we avoid this scenario happening again?

Dr Farrar

Just ask one expert.

Chair

Would that be you, Dr Farrar?

Dr Farrar

No, it would not be me. Airport infection control is not my strong area, but you are absolutely right. If you get 20 scientists in a room you will get a number of different opinions, and it is your job to try to filter those and make the right policy decisions. It comes back to having a standing group that is respected, is used to working together and comes to conclusions in a calmer, more rational way than in a response mode where you are pushing people together at the last minute.

Chris Green

So you know to which body to ask the question.

Dr Farrar

Yes.

Chair

That brings us to the end of our questions today. Thank you for all your answers, which have been very helpful. I think I am not wrong in saying that this has been the deadliest outbreak of its kind; over 11,000 people died. I think we can be quite proud of the UK’s response in many ways. We averted over 56,000 cases with the response. I have a statistic here. In response to the October and November appeal for NHS volunteers, over 1,000 people came forward. We should recognise that bravery, because many people put their lives at risk. I know that each and every witness here today played their part. I would like to put on record the gratitude of all members of the Committee to you for the work you have done, and the work that I know you will keep doing, in trying to avert similar crises in future. I hope that some of the recommendations we make in our report will contribute a little as well. Thank you very much. That brings this session to an end. Oral evidence: Science in emergencies: UK lessons from Ebola, HC 469 2 [1] The witness later clarified that this sentence should say, “It was much more long term and in-depth, with many scientists who did not work on SAGE itself.” [2] The witness later clarified that this sentence should say, “We did not need to wait for a drug company to produce them. They were licensed.”