As part of the emergency response to recent outbreaks of Zika virus, WHO initiated an emergency research and development (R&D) response plan addressing needs for Zika virus vector control, diagnostics, vaccines, and therapeutics, along with coordination of supportive research activities. As part of its commitment to assisting relevant R&D efforts and its role as global convener, WHO organised a meeting in Geneva on 7-9 March 2016, bringing stakeholders from relevant fields together to expedite the development of the products required for a rapid, robust response to Zika virus. This meeting was the first major international opportunity for experts in Zika virology, clinicians, product development experts, modellers, funders and others to take stock together, identify knowledge gaps, and discuss joint planning for accelerated product development and evaluation.
On the first day, the meeting received an overview of current knowledge of flaviviruses in general and Zika virus in particular, including their origins, spread, classifications and symptoms. While Zika is the current focus, increasing globalisation and more frequent contact with wild animals mean that other flaviviruses—familiar or obscure—may well emerge. The current situation regarding microcephaly and Guillain-Barré syndrome in Brazil was outlined and compared to the recent Zika outbreak in French Polynesia, where the presence of Guillain-Barré syndrome has been retrospectively evaluated as 24 per 100 000 Zika infections, which is 15-20 fold over baseline figures. A review of the major outcomes of the recent PAHO meeting on Zika was presented; a report on this meeting is imminent.
The consultation then explored the pathogenesis of microcephaly. It was stressed that microcephaly should be regarded as a medical description, and not as a disease in itself., The different aetiologies of the condition were reviewed. The potentially helpful role of modelling in the development of countermeasures was outlined, but it was emphasised that such modelling relies on data collected in the field and this data must be of high quality.
The second day looked at specific R&D product pipelines for Zika vaccines, diagnostics and vector control. The product development community has responded energetically to the need for these resources, and the pipeline is expanding rapidly. One major advance compared to the recent response to the 2014/15 Ebola epidemic seems to be the speed at which data is being shared.
Product-specific summaries
While vaccines may come too late in the short term for countries currently affected by Zika outbreaks, such development remains imperative for a potential further expansion of the outbreaks, as well as for responding to possible future infectious waves in countries affected to date. All current vaccine projects are in their early stages, but experience with other flaviviruses suggests that the end goal should be technically feasible. Efforts are, however, hampered by a lack of basic tools for Zika vaccine development, including reliable animal models, reference reagents and assays. At the meeting, a draft target product profile (TPP) was presented for an emergency use vaccine; public consultation on this draft will start soon, with the goal of a finalised TPP in May 2016. This TPP should assist in reaching consensus on regulatory requirements for evaluating prospective Zika vaccines.
Diagnostics
Diagnostics development is busy, with manufacturers proposing many potential products. The meeting established general support for development of a TPP for multiplex diagnostics able to provide differential diagnosis for, at least, dengue, Chikungunya and Zika virus infections. A draft TPP is ready and about to undergo public consultation, with a final draft due in mid April 2016. Such a product would complement Zika-specific tests. In this context, there is an urgent need for increased access to standards and reference materials and methods to facilitate product development. To help achieve this objective, benefits to encourage sample sharing should be defined and publicised. WHO encourages manufacturers to apply for Emergency Use Assessment and Listing (EUAL) of potential products, and promised to meet requests for more information on criteria used for evaluation under the EUAL.
Vector control
In the area of Zika vector control, the meeting heard strong arguments that thorough entomological investigations are imperative to fill obvious important knowledge gaps, particularly regarding the roles and behaviours of various mosquitoes in the transmission of flaviviruses in general, and Zika in particular. There is a surprising absence of evidence in the literature that implementation of classical vector control interventions have had significant impact on dengue illness, and most studies are focussed on entomological outcomes.It is imperative that investments be made in improving implementation of these interventions, notably through better community involvement, and in this regard the scientific community must be very rigorous in evaluating new and established vector control tools and methods. New tools would be discussed in depth at a WHO Advisory Committee on Vector Control emergency meeting, to be held a week after this gathering.
Therapeutics
Research into therapeutics was also presented, with emphasis on the outstanding need for more mature understanding of the stages of infection and the biology of the Zika virus, and the challenges of developing medications for use during pregnancy. There are still important potential roles for prophylaxis and therapeutics for this and other target populations; the goal must be to identify the different stages of Zika pathogenesis, enabling the identification of the window period for the various types of treatments. Known antivirals and immune-based interventions are being examined for their suitability for use as treatment, and similarities between the Zika and dengue viruses raise the possibility of repurposing existing molecules. The cellular factors in Zika infection and the interplay with the immune system could provide valuable new pathways to developing treatments; in this context there is a pressing need for relevant animal models to complement various ongoing questions and studies.
Regulation and data sharing
Regulators present at the meeting established themselves as keen to innovate, and support innovation, in response to public health emergencies and the need for accelerated vaccine development. While they would continue to take risk/benefit factors as overarching consideration, they did not wish regulation to be seen as a barrier to rapid progress. Knowledge gaps were acknowledged that must be filled in order to define products for protection against Zika, including a particular need to investigate how prior exposure to related viruses impacts immune responses to Zika vaccines. Again, the lack of animal models—and especially non-human primate models—was raised: these are needed to improve understanding of the pathogenicity of Zika and its complications, especially regarding potential reproductive toxicity of candidate vaccines. There is therefore a clear need for improved international collaboration, building on the lessons of the Ebola epidemic; major regulatory agencies, including Brazil’s ANVISA and the US FDA, have committed to expedited evaluation of Zika products, and will reach out proactively to developers to provide related advice.
The need for international reference standards for preparation was again highlighted; the UK’s National Institute for Biological Standards and Control (NIBSC) and the Paul Ehrlich Institute are working on this as part of their role as WHO Collaborating Centres. Currently, the candidate standard for the NAT Assay is the more advanced, with plans for a collaborative study to evaluate suitability to be launched as early as April 2016.
Questions around data sharing, bio-banking and other sample-sharing issues arose throughout the meeting; these were addressed on Day three, where a number of existing data-sharing platforms and initiatives—including a WHO open publication channel specific to Zika virus—were laid out and the gaps in technologies and international agreements examined. Recent developments have greatly advanced the capacity for managed data sharing, and many funders are moving towards a position of expecting rather than encouraging it; but there remains a need for a culture of informed and constructive commenting underpinned by effective tools and platforms, as well as dependable mechanisms to provide credit and recognition to those who do share data. There is a further need to compile all the new open Zika data portals/web resources to provide a single site where readers can track new Zika data as it becomes available, across different types of data.
The meeting then heard a plea for the importance of sample sharing and biobanking for priority diseases to advance disease knowledge, improve interventions and increase international capacity. Epidemic responses generate a wealth of samples that could be used to illuminate research needs, and work is underway to develop guidance on principles and considerations for material transfer agreements and Memorandums of Understandings that allow this while reflecting the needs of all stakeholders. The European Virus Archive already offers a non-profit online catalogue of quality assured resources, and has mobilised a task force to respond to the recent peak in applications for materials in response to the Zika emergency.