11. Therapeutic interventions

Till date, there is no precise treatment for Ebola virus disease which constitutes one of the major draw backs in its management. Treatments available for Ebola virus infection are basically supportive and symptomatic remedies for dehydration, maintenance of oxygen saturation and blood pressure, replenishment of nutrients, antivirals as well as antibiotics for concomitant infections [65]. Administration of sufficient fluids by oral or intravenous route serve to maintain circulatory stability and replenish electrolytes and fluids lost during the infection. A broad-spectrum of antibiotics are used to manage potential concomitant bacterial infections; antimalarials are used for the treatment of malaria while antiretrovirals are used to inhibit viral replication. Antipyretics and analgesics are frequently used for the control of fever or body temperature and pain respectively. Also, specific drugs could be administered for the control of organ failure.

visibly detected following immune complex between viral proteins and gold-labelled antibodies bound along the test line in less than 30 minutes. Validation of the test performance of the OraQuick RDT based on a retrospective study in Sierra Leone as reported by WHO showed the OraQuick RDT with a 84% sensitivity and 98% specificity compared to clinical

SD Q Line Ebola Zaire Ag test by SD Biosensor, Inc. is the third and most recent RDT kit to be approved by WHO on EUA status [62]. Unlike ReEBOV and OraQuick RDTs which detects only VP40 in EBOV, SUDV, and BDBV species, SD Q Line Ebola Zaire Ag test is a chromatographic deep stick test that simultaneously detects GP, NP, and VP40 antigens of EBOV in whole blood, serum or plasma. In this test, the presence of the three antigens in the sample forms complex with their specific gold-labelled mouse monoclonal antibodies at three different test boundaries at which visible lines are seen. Thus, three drops of sample are added to a sample port on the assay device and visualized at 20–30 min. The presence of at least any of the three test lines is interpreted as positive result. A WHO validation study in Sierra Leone using a total of 446 specimens including 100 fresh venous whole blood and 346 frozen plasma showed SD Q Line Ebola Zaire Ag test with 84.9% sensitivity and 99.7% specificity when

In a nutshell, these RDT kits are very effective in diagnosis Ebola virus and useful for field settings especially during outbreaks as results can be obtained within a very short time without the use of any electronic equipment and does not require refrigeration for storage. The approval of these RDTs is of major importance for public health management of the disease as prompt diagnosis especially in the field following Ebola outbreaks is key to effective treatment. Recently, a new immunochromatographic strip and a smartphone reader based on Sudan virus (SUDV) glycoprotein monoplex which detects and semiquantifies Ebola-specific IgG antibodies in human survivors has been developed [63, 64]. When the point-of-care test was tested in freshly collected patient samples including 90 SUDV survivors and 31 non-infected controls in Uganda, it showed a sensitivity of 100% and a specificity of 98% compared to standard enzyme-linked immunosorbent assay (ELISA) of whole Ebola antigen [64]. More so, a multiplex test which simultaneous detects antibodies against three recombinant SUDV proteins has also been developed. A pilot study involving 15 survivors and 5 non-infected controls showed sensitivity and specificity of 100% compared to standard ELISA [64]. Also, another multiplex subtype assay for the identification of three Ebola species: BDBV, SUDV, and EBOV based on recombinant viral glycoproteins has been developed [64]. The advantage of this multiplex viral species test is that it could differentiate the host's immunity to

compared to the RealStar Filovirus Screen RT-PCR kit 1.0 as gold standard [62].

specific viral species and also identify cross-reactive immunity in infected patients.

Till date, there is no precise treatment for Ebola virus disease which constitutes one of the major draw backs in its management. Treatments available for Ebola virus infection are basically supportive and symptomatic remedies for dehydration, maintenance of oxygen

real-time RT-PCR testing [60].

138 Current Topics in Tropical Emerging Diseases and Travel Medicine

11. Therapeutic interventions

With no specific treatment against the disease, considerable efforts in research have been ongoing for the identification of possible drug candidates for therapeutic interventions. One of such clinical investigation was conducted in 1995 during the Ebola epidemic in Kikwit where blood of improving patients was transfused to eight Ebola patients as a means of passive immunization. Among the eight patients, seven of them successfully survived the infection while only one patient died [66]. However, subsequent in vitro assays showed antibodies not to have neutralizing action against Ebola virus. As such, clinical investigation based on passive immunization has not been conducted in subsequent outbreaks. Furthermore, in vitro assays showed monoclonal antibodies against the GP of Ebola virus to exhibit defensive and healing properties in mice but were unable to protect non- human primates [67, 68]. Also, immunoglobulins which were raised in goat and had undergone pre-clinical test on laboratory animals were administered to infected scientists with Ebola haemorrhagic fever during an outbreak showed some degree of protection against the disease. Thus, these immunoglobulins were suggested to be beneficial as an emergency cure for individuals inadvertently infected with Ebola virus [69]. More so, a series of nucleoside analogue inhibitors for carbocyclic 3 deazaadenosine and S-adenosylhomocysteine hydrolase were shown to avert death in infected mice by inhibiting Ebola virus replication [70].

With such preliminary studies showing immunoglobulins to have protective effects against the infection, several researches have dueled on this aspect as well as other targets and several clinical trials have been ongoing to assess some potential drug candidates. The main classes of drugs which are being evaluated for potential therapeutic effect against Ebola virus infection include monoclonal antibodies such as ZMapp, nucleoside analogues, RNA inhibitor based (TKM-Ebola) agents, positively charged phosphorodiamidate morpholino oligomers as well as antisense-based (AVI-7537) drugs [71]. Among these drug candidates, ZMapp is one of the most promising therapeutic interventions against Ebola virus disease that affects viral replication inhibiting its expression.

ZMapp is an experimental drug by Mapp Biopharmaceutical, Inc., which comprises of a combination of 3 monoclonal humanized murine antibodies produced in mice infected with Ebola virus and subsequently generated in tobacco plants [71, 72]. In vivo pre-clinical animal study showed 43% of infected mice treated with Zmapp to survived infection [73]. Though pre-clinical studies had exhibited therapeutic effect of Zmapp against Ebola virus, the experimental drug came into the lamplight when two US citizens who were health workers in Liberia during the 2014 West-Africa outbreak became infected and were successfully treated with ZMapp in Atlanta USA. Following this success, the drug was then used as an experimental treatment in the 2014 West-Africa Ebola outbreak and several patients survived and recovered from the infection [74]. Though this experimental drug was helpful during the outbreak, its therapeutic efficacy remained inconclusive since no randomized controlled clinical trial had been conducted as of 2014 [74, 75].

chimpanzee Adenovirus serotypes; Ad3, Ad7 and Ad62 [82]. Recombinant Adenovirus 5 (rAd5) was the first recombinant Ebola vaccine to show protection to Non-human primates against the EBOV virus but required a period of over 6 months to attain complete immunization [83]. A double-blinded, placebo-controlled phase I clinical trial in 2010 showed rAd5 vaccine encoding the envelope GP from EBOV and SEBOV 1976 strain to be safe and immunogenic [84]. Following the 2014 West Africa outbreak, another phase 1 clinical trial was conducted with another rAd5 vaccine which encoded the envelope GP of EBOV 2014 strain. The findings showed that the vaccine was immunogenic and safe at high dose of immunization [85]. Studies with other recombinant adenovirus vaccines such as rAd26 and rAd35 have them to be immunogenic by stimulating T-cell responses of CD4+ and CD8+ as well as increase cytokine (TNF/IFN-γ) secretion. Recently, rAd26 vaccine expressing the full-length GP of

Ebola Virus Disease: Progress So Far in the Management of the Disease

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ChAd3-EBOV defined as chimpanzee adenovirus serotype 3 encoding the monovalent Zaire strain of Ebola virus glycoprotein is a genetically modified non-replicative vaccine candidate produced by GlaxoSmithKline in collaboration with the National Institutes of Health, USA. In 2014, five phase 1 trials of ChAd3 conducted in Europe, North America, and Africa confirmed the vaccine to be immunogenic and safe [87]. As a result, Phase II and III trials were initiated in

A recombinant Vesicular Stomatitis Virus (rVSV) was the first replicating Ebola virus vaccine developed in 2005. This vaccine was shown to provide 100% protection in non-human primates eliciting both humoral and cellular immune responses against lethal EBOV challenged animals [90]. Since then, eight human phase I trials of rVSV-EBOV vaccine has been conducted across Europe, North America and Africa. A phase III trial involving 7651 individuals to evaluate the efficacy of rVSV-ZEBOV showed a 100% vaccine efficacy after 6 days of vaccination [91]. These findings have shown that rVSV confers protection against Ebola between 6 and

Other potential vaccine candidates [35] which have initiated phase I clinical trials in 2015 include; EBOV GP Vaccine which is a recombinant nanoparticle vaccine using adjuvant Matrix-M. It is the first Ebola vaccine candidate based on the 2014 Guinea Ebola strain genetic sequence. DNA-EBOV is a multiagent filovirus DNA vaccine delivered into the body through intramuscular electroporation. Recombinant rabies EBOV is a chemically killed inactivated

Other forms of vaccine candidates include virus-like particle vaccines (VLPs). VLPs are produced by expressing certain viral proteins that mimics the conformation of natural Ebola virus in cells without any viral genetic material. EBOV VLPs have been produced by simultaneously expressing NP, GP, and VP40 proteins of EBOV in 293T cells. These particles when administered three times to NHPs in combination with Ribi adjuvant protected against EBOV [93, 94]. Following the recent Ebola outbreak in DRC, an experimental Ebola vaccine (rVSV-ZEBOV) developed by Merck, a German pharmaceutical company which is not yet licensed but was

EBOV is currently undergoing phase III trials [86].

Sierra Leone, Liberia, and Guinea in 2015 [88, 89].

rabies virus virions containing EBOV glycoprotein.

12.2. Recombinant Vesicular Stomatitis Virus

21 days after vaccination [92].

Another hopeful candidate drug that act by preventing viral replication is favipiravir (T-705), a pyrazinecarboxamide derivative which has shown to be effective against EBOV in in vitro and in vivo studies [76]. Also, a promising experimental drug for Ebola virus infection is BCX4430. This drug possesses antiviral activity for marburg, yellow and Ebola fever and it is also being tested for its ability to inhibit target enzymes in Ebola virus. BCX4430 has been shown to be effective in infected animals if the treatment was administered within 48 h after the infection [77]. Other therapeutic candidate drugs include RNA polymerase inhibitors as well as small interfering RNA nano particles that act as protein synthesis inhibitors. Studies in Ebola infected guinea pigs and non-human primate models showed small interfering RNAs agents and gene-silencing drugs to protect against Ebola infections [78].

One of the major challenges for the availability of treatment against Ebola virus disease is the inconsistency and sporadic nature of the virus which has limited clinical trials in humans. In as much as several drug candidates have emerged and have been effective in pre-clinical studies, without clinical trials in humans, there is no guarantee that these experimental drugs can effectively treat infected patients. It is relevant for such trials to be conducted even though it remains difficult as the disease usually emerges periodically as outbreaks. Even though these challenges are limiting, efforts in identifying other potential drugs targets should be encouraged with emphasis on the key viral surface proteins as well as nucleoproteins involved in viral replication and pathogenesis.
