What is the role of research in outbreak preparedness and response?

SPEAKER: This slide explains why. This is a typical epi curve showing cases occurring over time during an outbreak. In the past, the public health and preclinical responses, such as basic science and even animal studies, have been faster than the clinical research response. I witnessed exactly that in 2009-2010. What a number of initiatives are trying to do is bring that clinical research response in faster so that it can provide results to inform the response, policy, and patient care sooner. By the end of the 2009-10 flu pandemic, I was frustrated at not being able to give evidence-based advice to the clinicians who were looking after hospitalised cases of H1N1.

I was having to extrapolate from small case numbers of other flu virus subtypes that had caused severe disease, quoting data that was not from high-quality studies. When you are a clinician with a very ill person in front of you, the last thing you need is a procrastinating public health outbreak response advisor. You want hard, confident facts to inform your decision. You want to base decisions on robust evidence. One example where research during an outbreak has made an impact is the study of the ring vaccination trial of an rVSV-vectored vaccine for Ebola virus disease. This was done in Guinea, carried out by national researchers, WHO, the London School and other partners.

This study was revolutionary on a number of fronts– the first Ebola vaccine to be studied, confronting the ethical challenges through the design of the study to ensure that those eligible all received the vaccine. Some were in the delayed group to allow for comparison. The researchers used cluster randomisation and opened up eligibility to children as soon as preliminary safety data was available. This proved to be successful in helping to contain the outbreak and has shown high efficacy. The Guineans, who were trained at the time, have since responded twice to an outbreak in the Democratic Republic of Congo, ruling out a similar study in response– great example of South-to-South collaboration and capacity building.

To launch a rapid research response, we have to prepare in advance. It sounds simple, but actually there is a lot to consider to build a research response infrastructure, response of the researchers, the regulators, industry, public health, laboratories, et cetera. One approach which has proved successful is for funders to create this with researchers, regional networks such as PREPARE, ZIKAlliance, ZIKAPlan, ZIKAction, REDe, ISARIC, APPRISE, PANDORA-ID, and ALERRT. These are networks with either global or regional reach who run studies or help set up studies in the inter-epidemic period to bolster preparedness. As a result, this speeds up the research response during an epidemic. Such platforms should be able to successfully pivot to that required for an outbreak focus.

This preparedness step, in itself, takes practise and planning. This regional approach facilitates a regional response to research questions that are relevant to that region.

These networks mainly have their own research agenda. However, in conjunction with the WHO and affected countries, can be agile to respond to disease threats, perhaps with studies which were not in the initial portfolio– for example, ALERRT in a Lassa fever clinical trial using ribavirin in Nigeria. Regional or global networks information can be found on the GloPID-R funders website. The role of networks in outbreak preparedness and response will be explored in more depth later in this course. To help facilitate our rapid research response, WHO has developed a framework called the R&D Blueprint, which is a small team in Geneva working with partners to better facilitate a rapid research response focused on therapeutics, vaccines, and diagnostics for a list of priority diseases.

They do this by convening and developing road maps for - for example, Lassa fever - writing target product profiles to guide companies as they design diagnostics, working on research study design in advance of an outbreak. Additionally, the Blueprint team work with regulators in advance of outbreaks and publish an ethical guidance and good participatory practice, all of which can be found in the references. And please see, also, the sections at the end of this step. This has proved a successful template to coordinate, align development of vaccines, therapeutics, and diagnostics to the agreed upon priority diseases, including Disease X. The priority diseases are reviewed each year and are listed on the slide.

Disease X means a novel disease which poses an epidemic or pandemic threat. There are political, ethical, administrative, regulatory, logistical or legal, and societal barriers to carrying out timely clinical research during an outbreak, otherwise known as the PEARLES. Many of these need to be considered and addressed in advance of an outbreak. Recently, PREPARE and the funders consortium GloPID-R held a meeting to discuss these barriers and any solutions found.

Some of these solutions are listed here: the pre-positioning of protocols; an enabling regulatory and socio-political environment; partnerships and collaborations; and data sharing processes in place. In my experience, people tend to expect ethical approval to be the main delay in research being launched. But we have found that it is the contracts, the agreement of contracts between new partners who find themselves needing to work together for the research response.

In addition to the diagnostic therapeutics and vaccine research previously mentioned, the non-product related research is also necessary– for example, understanding how Lassa fever is transmitted from rodents to humans. GOARN has formed a research arm. The aim is to facilitate the members’ support of the countries on key research areas involving non-product related research, including how to actually improve the response on social science research. A number of GOARN members are supporting the Nigerian Centre for Disease Control and researching the topic of community transmission of Lassa. Once the evidence is available, it will inform the public health interventions. Another example would be social science research to support Ebola where it is clear that an engaged community is essential to response.

A cross-cutting component to the research preparedness and response is common data variables. A component which has been discussed a lot over the years is a need for a minimal data set, a set of core variables to be collected to help standardise the data collection and facilitate the data analysis across studies at a later date. This has been worked on by a number of consortia– for example, ISARIC’s Clinical Characterisation Protocols. For example, this pre-approved protocol was able to recruit patients with MERS and Monkey pox within 24 hours of diagnosis. Ideally, the coordinated variables could be modularised to allow for flexibility for the researcher to choose which are relevant to them under a tiered approach relevant to resource settings.

In their article about plague in Madagascar, Bond et al see an opportunity for Madagascar to strengthen their health care system, and demonstrate in the diagram how data collection and analysis can cross cut all levels of health care. I would go further and say that research can do the same. Strengthened health systems are grounded in three components.

One, horizontal readiness includes: supply chain management; adequate and well-trained staff; medicines and infrastructure that must be available at all levels of care; primary care through basic health centres and community health programmes; secondary hospital care; and tertiary care in national referral and university hospitals.

Two, vertically-integrated programmes include: routine clinical programmes such as maternal-child health and infectious disease management; prevention activities such as vaccine campaigns; and emergency response to plague and other outbreaks. Three, integrated data from health management information systems and epidemiological surveillance– research could be central to all that too. The good news is that GOARN and WHO are integrating research into response to outbreaks more and more.

“Response is not complete without research–” a quote from Dr. Yoti at a meeting. Preparedness is key to an early research response. Working in a collaborative manner is necessary. Identify cross-cutting areas and prepare, such as common data variables and how data will be shared in a timely fashion. Together, we can.