Research in the time of Zika (and other diseases)

Professor Trudie Lang is Professor of Global Health Research at the Nuffield Department of Medicine, and the head of the Global Health Network. She is also part of the ISARIC network, an international consortium aiming to enable research during disease outbreaks.

She has helped lead research in extraordinary conditions, such as the 2015 Ebola outbreak in West Africa. Currently she is involved with the recent Zika virus outbreak: In Brazil, infection with this virus seems to be behind an increase in the number of babies born with small brains, and some survivors suffer from post-viral Guillain-Barré syndrome, associated with temporary paralysis.

With Zika infection rates now seeming to be on the increase, the Oxford Science Blog talked to Professor Lang about why it is so important to develop capacity for doing research in places where research doesn't normally happen, and what ISARIC and the Global Health Network are doing to help make sure that such research happens.

OxSciBlog: What sort of places have you carried out research in?

Local research organisations really need to have the research response embedded in the immediate flurry of activity that first happens when an outbreak is recognized. So we are working through ISARIC and the Global Health Network to support local researchers in Brazil and South America.

Professor Trudie Lang, Centre for Tropical Medicine and Global Health

Trudie Lang: The most recent example is West Africa, during the Ebola outbreak: as the 2015 outbreak picked up pace, my colleague Professor Peter Horby, a virologist, came in from the office next door, and said, ‘You can run clinical trials, can’t you?’ The outbreak was officially announced in August 2014, and by September, we had won funding to put together a trial for candidate Ebola treatments. Our trial then started in the beginning of January 2015 – it normally takes about 18 months to set up a clinical trial, but we did it in a matter of weeks. We thrashed out the science of how to do a trial in the middle of an Ebola outbreak in about a day, writing out our thoughts on the back of a poster - which is now framed for posterity!

Most of us had never worked with Ebola before, but the important thing to remember is that process of setting up a trial is broadly the same, regardless of the disease. More important than the disease is the ability to take a scientific question, turn it into a clinical protocol, and deliver it safely and ethically within that clinical setting. That is the real challenge.

OSB: How does the Global Health Network help to meet this challenge?

TL: The big problem during the Ebola epidemics was that the research capacity in Liberia, Sierra Leone and Guinea was very low. So we needed to take in external research teams to support and work with local healthcare workers. Now that the Ebola research has finished, it is very important that the experience is not lost, and that the local research teams we worked with continue to develop their research capacity. They can then plan, led and deliver research themselves to tackle current and future local health issues.

This is what we’re trying to do with the Global Health Network: we teach people (especially frontline health workers such as doctors, nurses, midwives and other field workers) how to think about research. We train health workers in research methods, so that they can measure the outcomes of their efforts, and so improve local practice and health outcomes.

OSB: What sort of research do you hope that this training will result in?

TL: Clinical trials are not just about testing a new drug or vaccine: this research training will enable people to assess quite simple interventions, such as evaluating new ways of managing hygiene in a maternity setting. Gaining evidence on how to make practical and accessible changes can make quite big differences to public health.

OSB: What are some of the lessons from the Ebola clinical trials?

TL: With Ebola, the medical and humanitarian response kicked in March 2014, and the World Health Organization officially announced it as a medical emergency in in August that year. The response from the research community and relief organizations was amazing, but the research response lagged behind the medical humanitarian relief. The challenge we had with Ebola is the same as what we have for future outbreaks: we don’t have a treatment or vaccine, we don’t know how to manage the disease, and we don’t fully understand how the virus works. So when a disease outbreak begins, there is a small window of time when you have the chance to answer all of these questions and to test the potential treatments.

For Ebola, this window was already closing by the time trials started. The amount of work done during this short window was phenomenal: there has never been a clinical trial during an active disease outbreak before, and researchers from Oxford managed to run not one by multiple trials testing candidate Ebola treatments and vaccines.

But we were too late in many ways: the outbreak was already burning itself out, which meant that often there weren’t enough patients left to provide definitive answers to some of the research questions that need to be answered.

This jump from normal clinical practice to research is quite a big leap – that’s why it usually takes about 18 months, because it is very cumbersome and bureaucratic process!

Professor Trudie Lang

OSB: How is the response to the potential Zika virus outbreak different?

TL: Local research organisations really need to have the research response embedded in the immediate flurry of activity that first happens when an outbreak is recognized. So we are working through ISARIC and the Global Health Network to support local researchers in Brazil and South America who are leading the effort to gather data and evidence to understand this virus, learn how to diagnosis infection and ultimately, to test any potential treatments.

This seems to be working, and we hope that research can begin at a much earlier stage: we are only just realizing that there is a potential outbreak of Zika, but the steps needed before research can begin are already well underway.

To move into research is a major under taking. If taking and storing samples and clinical data is done with an aim of sharing with others researchers and publishing then it becomes research and not standard clinical care. So before this can happen a study protocol and ethics approval need to be in place, and then the patients need to be informed and asked for consent to be part of the research.

This jump from normal clinical practice to research is quite a big leap – that’s why it usually takes about 18 months, because it is very cumbersome and bureaucratic process!

OSB: How can you facilitate this big leap while clinicians are busy dealing with an outbreak?

TL: The ISARIC network is facilitating discussions between local researchers and other experienced scientists from around the world, so that they can work together to develop study protocols, research forms and processes. This helps the local teams get the studies set up as quickly as possible. To allow others to do the same, we are also making all the research tools and resources available for sharing and use by any researchers who would like to get involved. Developing the research protocols and forms in this way ensures that the research is high quality and also that everyone collects standardised data.

This is really important because it means that data can be shared and combined later, meaning that even more can be learnt.

As part of this effort we have just launched the research portal www.zikainfection.org on the Global Health Network. We will be putting all the shared research documents here, and discuss with colleagues about the gaps in research: what needs testing, what the knowns and unknowns are, and what the current clinical data looks like. We’re doing this in the hope that local research teams can move really quickly to record data and samples correctly.

OSB: Why is it important to record this information correctly?

TL: Without research protocols, you learn nothing about a disease. This is the reason that we learnt very little from the early months of the 2014-2015 Ebola outbreak: it took so long to get research underway. The current model of medical intervention first, research later has to change: research has to be part of the process from the beginning.

To do this, we need to collaborate with the organizations that respond to a disease outbreak, and make sure that they understand why research is needed. We need to explain how research requirements, whilst differing from delivery of care, do not need to be a distraction. We also need to have people ready to mobilize on the ground. In Brazil, at least this part of the process is easier than in West Africa, since there is stronger local research capacity. However, local research effort  can still be strengthened and sped up by an international combined effort. ISARIC has therefore been bringing together all of these groups, to figure out how research can be embedded in the immediate response to an outbreak.

OSB: Could carrying out research in this early phase potentially slow down immediate relief during an outbreak?

TL: It shouldn’t, and in fact, carrying out research should help raise standards for clinical treatment – a good research protocol helps standardize clinical practice, and recording what you’re doing helps maintain standards too. It should never slow anything down, and the research comparisons we make are with existing treatments. So treatment is never withheld from any patient. A good research protocol also needs to be pragmatic, working within the existing clinical setting, rather than attempting to change practice.

I actually think it is unethical not to do research in these settings, because it means that you learn nothing about treating the disease. For example, while health workers with Ebola returning to the UK were quite rightly given a number of experimental Ebola treatments, this wasn’t within a research protocol. We therefore didn’t learn anything that would be useful for other Ebola patients: in these 'compassionate use' situations: we don’t know if any of the treatments given actually worked, and if so which ones, or whether the symptoms simply improved on their own.

Unless low and middle-income countries become the generators rather than consumers of health data, there are unlikely to be large changes in public health outcomes in these regions.

Professor Trudie Lang

OSB: What reactions do you get from local populations as you work with them to increase their research capacity?

TL: Health workers in low income regions do initially think that research is not something for them, and that it is expensive and difficult to do.  It can be sometimes be hard to explain what research is: for example, when we were working in East Africa, we found that there is no word in Swahili (the local language) for 'experiment'. The nearest world meant ‘to try’, as in trying on a pair of shoes. So the idea of a comparative experiment was quite a difficult concept to get across!  But we did manage it, and the response was incredible. We find the people we work with, whether midwives or field workers, are really very keen to do better for the people that they treat.

Once we can get them over the hurdle of thinking that research is just Westerners coming in and doing something like a vaccine trial, and explain that something as simple as testing the effects of a different handwashing regime counts as an experiment, people really get it. The skillset needed for a million-dollar vaccine trial or evaluating how to train nurses in a new way to improve outcomes in paediatric wards is really the same – and that’s what we teach, not only to the people carrying out the research, but also to local ethics boards and scientific review committees.

OSB: Why is it important to develop this local research capacity?

TL: A recent WHO report clearly states that that unless low and middle-income countries become the generators rather than consumers of health data, there are unlikely to be large changes in public health outcomes in these regions. Currently less that 10% of all health research spending is spent on 90% of the burden of diseases globally, i.e. the diseases of poverty that affect the poorest places in the world. Furthermore, every time an outbreak happens, it will be us in the West, telling local people what needs to be done. Instead, the leadership needs to come locally.