Ebola virus disease: An update on current prevention and management strategies
Introduction
Zaire ebolavirus (EBOV), Sudan ebolavirus (SUDV), Bundibugyo ebolavirus (BDBV), Taï Forest ebolavirus (TAFV), and the only Asian species Reston ebolavirus (RESTV) [1]. The first three of these have previously caused large outbreaks in the Democratic Republic of Congo, Sudan, Gabon, Republic of Congo, and Uganda [2]. The most recent and largest outbreak involving over 28,000 cases in West Africa was caused by a variant strain of EBOV with an estimated overall case fatality rate of around 40% [3].
EVD is primarily a diarrheal illness that requires copious amounts of fluid and electrolyte replacement [4]. Failure to address such requirements contributes to mortality and thus an intensive level of support is required to optimize outcomes. This is challenging in resource limited settings.
There were no approved therapeutics to treat Ebola virus disease (EVD) during the 2014–15 outbreak, that devastated three West African countries [5]. A small number of cases were treated with putative therapeutics in the U.S and Europe before formalised clinical trials were established late in the outbreak [6]. Potentially, an effective therapeutic available in large quantities could not only treat individual cases but halt outbreaks.
Although a number of experimental vaccines and antivirals against Ebola virus had been developed prior to the large EVD outbreak in West Africa in 2014-15, phase II/III field studies did not get underway until late in the epidemic [6]. Consequently, some studies will now have insufficient recruitment to establish efficacy [40]. This highlights the unique difficulties encountered in conducting clinical trials in the midst of a health emergency, particularly in resource poor settings. Nevertheless, for a disease such as EVD, which has such a high mortality and no proven directed therapy, it is imperative that an integral part of the international response be to facilitate clinical trials of therapeutic agents.
International agencies setting up treatment centres must be willing to recruit patients into clinical trials, and have structures in place to manage the ethical and medico-legal requirements to facilitate their conduct [6]. Ethical considerations around the design of clinical trials in such settings can be complex, and it has been argued that randomized, placebo controlled designs are not ideal as they may lead to withholding of potentially beneficial treatment (albeit experimental) from those with a condition that otherwise has a very poor outcome [6]. Using historical controls can circumvent this issue, but calls into question the robustness of the study outcomes. Adaptive trial designs where ongoing planned interim monitoring of the outcome data can be used to alter the trial design after commencement to maximize the potential benefit to study participants while maintaining statistical reliability, have also been advocated for such studies [55]. Other challenges to conducting clinical trials in such settings are the need for study personnel to enter the “red zone” of Ebola treatment centres (ETCs) to consent patients, thereby risking exposure to Ebola themselves, obtaining consent from very unwell patients for complex studies when next of kin are unable to be present at the bedside, and co-ordinating and expediting the ethical review process between multiple governmental and non-governmental healthcare organisations and research institutions. [55] Consent procedures can be further complicated by the cultural and linguistic barriers.
This paper will review proposed therapeutics (including vaccines, antibody based therapies, and small molecules) – many of which have only been tested in vivo on rodents or non-human primates (NHPs) [2].
Section snippets
Vaccines against Ebola virus disease
Vaccines are a potential cornerstone for limiting or fully preventing an EVD outbreak. There are numerous vaccine trials including two leading candidates in phase 3 trials (Table 1) rVSV-EBOV vaccines (recombinant vesicular stomatitis virus vector) and ChAd3-ZEBOV (adenovirus vector) [7], [8]. Other potential candidates have been described elsewhere [9].
Antibody based therapies
Human survivors of EBOV tend to mount early, vigorous, and long standing neutralizing antibodies (NAbs) that can bind to EBOV structural envelop glycoprotein (GP) [52]. Identification of such NAbs and their mechanism of activity has been essential in the development of immunotherapies and vaccines against EBOV. The breadth of protection of such NAbs is variable and still undergoing study [53].
Favipiravir
The pyrazinecarboxamide derivative T-705 (favipiravir) is licensed in Japan for the treatment of influenza not responding to conventional therapies [34]. It has antiviral activity against other negative stranded RNA viruses, and has been used in the European centres that treated EVD in the last outbreak (Table 1). It induced rapid Ebola viral clearance in a rodent model when administered as late as day 6 following inoculation with Ebola virus, in addition to a 100% survival rate compared to
Supportive care
In the absence of any available directed therapy, the mainstay of management in EVD has been supportive care. This includes rehydration, electrolyte replacement, supplemental oxygen, treatment of concomitant infections, blood products, antipyretics, anti-emetics and anti-diarrhoeal agents, nutritional support and psychologic care. The level of sophistication of these interventions varies from basic oral rehydration therapy without laboratory investigations in the most resource poor settings,
Follow-up
With around 10,000 survivors of this disease now across West Africa, there is an increasing demand for the medical management of complications related to EVD in this survivor cohort. Most notably ocular complications, chronic pain – especially arthralgias, cognitive, post traumatic stress syndrome and hearing deficits [64]. The emerging knowledge regarding immune privileged sites (e.g, eye, semen, cerebrospinal fluid) where the virus can remain sequestered, highlights the importance of ongoing
Discussion
There is evidence that current vaccines might have the potential to halt an outbreak, if a ring vaccination strategy is followed [10]. Both candidate vaccines seem to be well tolerated, however, we still do not have data on the duration of their protection or safety in subjects with underlying disease or medical conditions. There are also no data regarding their safety in paediatric or pregnant populations.
Supportive strategies and blood products have been commonly used, and there is
Conclusion
Clinics to follow-up on the survivors to establish the natural history of EVD and its long term sequelae is an apparently straight forward opportunity for us to learn.
It is to the credit of WHO to establish a research and development blueprint for action to prevent epidemics by accelerating availability of vaccines, effective tests, and medicines at a large scale [66]. Indeed, there is a pipeline of interesting molecules that potentially could target EBOV [69]. We hope this will be a
Conflict of interest statement
The authors declare no conflicts of interests
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