Development of therapeutics for treatment of Ebola virus infection

Ebola virus infection can cause Ebola virus disease (EVD). Patients usually show severe symptoms, and the fatality rate can reach up to 90%. No licensed medicine is available. In this review, development of therapeutics for treatment of Ebola virus infection and EVD will be discussed.     

Ebola in great apes – current knowledge,possibilities for vaccination,and implications for conservation and human health

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Human activities link fruit bat presence to Ebola virus disease outbreaks

1. A significant link between forest loss and fragmentation and outbreaks of Ebola virus disease (EVD) in humans has been documented. Deforestation may alter the natural circulation of viruses and change the composition, abundance, behaviour and possibly viral exposure of reservoir species. This in turn might increase contact between infected animals and humans.
2. Fruit bats of the family Pteropodidae have been suspected as reservoirs of the Ebola virus. At present, the only evidence associating fruit bats with EVD is the presence of seropositive individuals in eight species and polymerase chain reaction-positive individuals in three of these.
3. Our study investigates whether human activities can increase African fruit bat geographical ranges and whether this influence overlaps geographically with EVD outbreaks that, in turn, are favoured by deforestation.
4. We use species observation records for the 20 fruit bat species found in favourable areas for the Ebola virus to determine factors affecting the bats' range inside the predicted Ebola virus area. We do this by employing a hypothetico-deductive approach based on favourability modelling.
5. We show that the range of some fruit bat species is linked to human activities within the favourable areas for the Ebola virus. More specifically, the areas where human activities favour the presence of five fruit bat species overlap with the areas where EVD outbreaks in humans were themselves favoured by deforestation. These five species are as follows: Eidolon helvum, Epomops franqueti, Megaloglossus woermanni, Micropteropus pusillus and Rousettus aegyptiacus. Of these five, all but Megaloglossus woermanni have recorded seropositive individuals. For the remaining 15 bat species, we found no biogeographical support for the hypothesis that positive human influence on fruit bats could be associated with EVD outbreaks in deforested areas within the tropical forest biome in West and Central Africa.
6. Our work is a useful first step allowing further investigation of the networks and pathways that may lead to an EVD outbreak. The modelling framework we employ here can be used for other emerging infectious diseases.

     

Ebola Outbreak in West Africa; Is Selenium Involved?

One of the current international public health emergencies is the outbreak of Ebola virus disease (EVD), requiring extraordinary response. The current outbreak in West Africa is the most dangerous since Ebola was first discovered on 26 August 1976. Till January 6th 2015, It resulted in 13,387 laboratory confirmed human cases and 8274 deaths. Ebola virus has 5 strains, 4 are pathogenic in humans while the 5th strain Ebola reston strain is not. The current outbreak is caused by Ebola most pathogenic strain, Ebola Zaire strain whose genome differs from that of Reston Ebola virus strain, by the existence of several open reading frames containing large numbers of UGA codons. These codons act as stop codons and in addition they may encode for Selenocysteine, the 21st aminoacid, which is essential for the formation of Selenoproteins. Selenoproteins are integral to the metabolism and have been linked to the progression of certain viral diseases. In this review, we discuss the relation between Selenium and the progression of the current EVD in Africa supported by geographical distribution of Se and genetic evidence.     

Evaluating Clinical Trial Designs for Investigational Treatments of Ebola Virus Disease

BackgroundExperimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic.ConclusionsThe MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.     

Zoonotic risk factors associated with seroprevalence of Ebola virus GP antibodies in the absence of diagnosed Ebola virus disease in the Democratic Republic of Congo

BackgroundEbola virus (EBOV) is a zoonotic filovirus spread through exposure to infected bodily fluids of a human or animal. Though EBOV is capable of causing severe disease, referred to as Ebola Virus Disease (EVD), individuals who have never been diagnosed with confirmed, probable or suspected EVD can have detectable EBOV antigen-specific antibodies in their blood. This study aims to identify risk factors associated with detectable antibody levels in the absence of an EVD diagnosis.MethodologyData was collected from September 2015 to August 2017 from 1,366 consenting individuals across four study sites in the DRC (Boende, Kabondo-Dianda, Kikwit, and Yambuku). Seroreactivity was determined to EBOV GP IgG using Zaire Ebola Virus Glycoprotein (EBOV GP antigen) ELISA kits (Alpha Diagnostic International, Inc.) in Kinshasa, DRC; any result above 4.7 units/mL was considered seroreactive. Among the respondents, 113 (8.3%) were considered seroreactive. Several zoonotic exposures were associated with EBOV seroreactivity after controlling for age, sex, healthcare worker status, location, and history of contact with an EVD case, namely: ever having contact with bats, ever having contact with rodents, and ever eating non-human primate meat. Contact with monkeys or non-human primates was not associated with seroreactivity.ConclusionsThis analysis suggests that some zoonotic exposures that have been linked to EVD outbreaks can also be associated with EBOV GP seroreactivity in the absence of diagnosed EVD. Future investigations should seek to clarify the relationships between zoonotic exposures, seroreactivity, asymptomatic infection, and EVD.     

埃博拉病毒小分子抑制剂的研究进展

目前尚没有可靠的埃博拉病毒(Ebola virus,EBOV)疫苗和特异性治疗药物.2014年埃博拉病毒病在西非的爆发和肆虐警醒人类,需要加快对该病的防控研究.近几年,在EBOV小分子抑制剂的研究方面取得了较好的进展,有的已进入临床试验阶段.小分子化合物通常是针对病毒致病作用的某种机制而设计,是一个很有发展前途的研究领域.本文从抑制EBOV和其他病毒在生活周期中的穿入细胞、复制和出芽等方面综述EBOV小分子抑制剂的研究进展.     

Assessment of Environmental Contamination and Environmental Decontamination Practices within an Ebola Holding Unit,Freetown, Sierra Leone

Evidence to inform decontamination practices at Ebola holding units (EHUs) and treatment centres is lacking. We conducted an audit of decontamination procedures inside Connaught Hospital EHU in Freetown, Sierra Leone, by assessing environmental swab specimens for evidence of contamination with Ebola virus by RT-PCR. Swabs were collected following discharge of Ebola Virus Disease (EVD) patients before and after routine decontamination. Prior to decontamination, Ebola virus RNA was detected within a limited area at all bedside sites tested, but not at any sites distant to the bedside. Following decontamination, few areas contained detectable Ebola virus RNA. In areas beneath the bed there was evidence of transfer of Ebola virus material during cleaning. Retraining of cleaning staff reduced evidence of environmental contamination after decontamination. Current decontamination procedures appear to be effective in eradicating persistence of viral RNA. This study supports the use of viral swabs to assess Ebola viral contamination within the clinical setting. We recommend that regular refresher training of cleaning staff and audit of environmental contamination become standard practice at all Ebola care facilities during EVD outbreaks.     

Associations between Mental Health and Ebola-Related Health Behaviors: A Regionally Representative Cross-sectional Survey in Post-conflict Sierra Leone

BackgroundLittle attention has been paid to potential relationships between mental health, trauma, and personal exposures to Ebola virus disease (EVD) and health behaviors in post-conflict West Africa. We tested a conceptual model linking mental health and trauma to EVD risk behaviors and EVD prevention behaviors.ConclusionsIn post-conflict settings, past war trauma and mental health problems are associated with health behaviors related to combatting EVD. The associations between war trauma and both EVD risk behaviors and EVD prevention behaviors may be mediated through two key mental health variables: depression and PTSD symptoms. Considering the role of mental health in the prevention of disease transmission may help fight continuing and future Ebola outbreaks in post-conflict Sierra Leone. This sample is specific to Freetown and the Western Area and may not be representative of all of Sierra Leone. In addition, our main outcomes as well as personal EVD exposure, war exposures, and mental health predictors rely on self-report, and therefore raise the possibility of common methods bias. However, the findings of this study may be relevant for understanding dynamics related to EVD and mental health in other major capital cities in the EVD-affected countries of West Africa.     

Differences in the Comparative Stability of Ebola Virus Makona-C05 and Yambuku-Mayinga in Blood

In support of the response to the 2013–2016 Ebola virus disease (EVD) outbreak in Western Africa, we investigated the persistence of Ebola virus/H.sapiens-tc/GIN/2014/Makona-C05 (EBOV/Mak-C05) on non-porous surfaces that are representative of hospitals, airplanes, and personal protective equipment. We performed persistence studies in three clinically-relevant human fluid matrices (blood, simulated vomit, and feces), and at environments representative of in-flight airline passenger cabins, environmentally-controlled hospital rooms, and open-air Ebola treatment centers in Western Africa. We also compared the surface stability of EBOV/Mak-C05 to that of the prototype Ebola virus/H.sapiens-tc/COD/1976/Yambuku-Mayinga (EBOV/Yam-May), in a subset of these conditions. We show that on inert, non-porous surfaces, EBOV decay rates are matrix- and environment-dependent. Among the clinically-relevant matrices tested, EBOV persisted longest in dried human blood, had limited viability in dried simulated vomit, and did not persist in feces. EBOV/Mak-C05 and EBOV/Yam-May decay rates in dried matrices were not significantly different. However, during the drying process in human blood, EBOV/Yam-May showed significantly greater loss in viability than EBOV/Mak-C05 under environmental conditions relevant to the outbreak region, and to a lesser extent in conditions relevant to an environmentally-controlled hospital room. This factor may contribute to increased communicability of EBOV/Mak-C05 when surfaces contaminated with dried human blood are the vector and may partially explain the magnitude of the most recent outbreak, compared to prior outbreaks. These EBOV persistence data will improve public health efforts by informing risk assessments, structure remediation decisions, and response procedures for future EVD outbreaks.     

The development of broad-spectrum antiviral medical countermeasures to treat viral hemorrhagic fevers caused by natural or weaponized virus infections

The Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) began development of a broad-spectrum antiviral countermeasure against deliberate use of high-consequence viral hemorrhagic fevers (VHFs) in 2016. The effort featured comprehensive preclinical research, including laboratory testing and rapid advancement of lead molecules into nonhuman primate (NHP) models of Ebola virus disease (EVD). Remdesivir (GS-5734, Veklury, Gilead Sciences) was the first small molecule therapeutic to successfully emerge from this effort. Remdesivir is an inhibitor of RNA-dependent RNA polymerase, a viral enzyme that is essential for viral replication. Its robust potency and broad-spectrum antiviral activity against certain RNA viruses including Ebola virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to its clinical evaluation in randomized, controlled trials (RCTs) in human patients during the 2018 EVD outbreak in the Democratic Republic of the Congo (DRC) and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic today. Remdesivir was recently approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19 requiring hospitalization. Substantial gaps remain in improving the outcomes of acute viral infections for patients afflicted with both EVD and COVID-19, including how to increase therapeutic breadth and strategies for the prevention and treatment of severe disease. Combination therapy that joins therapeutics with complimentary mechanisms of action appear promising, both preclinically and in RCTs. Importantly, significant programmatic challenges endure pertaining to a clear drug and biological product development pathway for therapeutics targeting biodefense and emerging pathogens when human efficacy studies are not ethical or feasible. For example, remdesivir’s clinical development was facilitated by outbreaks of Ebola and SARS-CoV-2; as such, the development pathway employed for remdesivir is likely to be the exception rather than the rule.The current regulatory licensure pathway for therapeutics targeting rare, weaponizable VHF agents is likely to require use of FDA’s established Animal Rule (21 CFR 314.600–650 for drugs; 21 CFR 601.90–95 for biologics). The FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is safe and likely to produce clinical benefit in humans. In practical terms, this is anticipated to include a series of rigorous, well-documented, animal challenge studies, to include aerosol challenge, combined with human safety data. While small clinical studies against naturally occurring, high-consequence pathogens are typically performed where possible, approval for the therapeutics currently under development against biodefense pathogens will likely require the Animal Rule pathway utilizing studies in NHPs. We review the development of remdesivir as illustrative of the effort that will be needed to field future therapeutics against highly lethal, infectious agents.     

Community-Centered Responses to Ebola in Urban Liberia: The View from Below

BackgroundThe West African Ebola epidemic has demonstrated that the existing range of medical and epidemiological responses to emerging disease outbreaks is insufficient, especially in post-conflict contexts with exceedingly poor healthcare infrastructures. In this context, community-based responses have proven vital for containing Ebola virus disease (EVD) and shifting the epidemic curve. Despite a surge in interest in local innovations that effectively contained the epidemic, the mechanisms for community-based response remain unclear. This study provides baseline information on community-based epidemic control priorities and identifies innovative local strategies for containing EVD in Liberia.Conclusions/SignificanceLocal communities’ strategies and recommendations give insight into how urban Liberian communities contained the EVD outbreak while navigating the systemic failures of the initial state and international response. Communities in urban Liberia adapted to the epidemic using multiple coping strategies. In the absence of health, infrastructural and material supports, local people engaged in self-reliance in order to contain the epidemic at the micro-social level. These innovations were regarded as necessary, but as less desirable than a well-supported health-systems based response; and were seen as involving considerable individual, social, and public health costs, including heightened vulnerability to infection.     

Rapid establishment of a frontline field laboratory in response to an imported outbreak of Ebola virus disease in western Uganda,June 2019

The Democratic Republic of the Congo (DRC) declared an Ebola virus disease (EVD) outbreak in North Kivu in August 2018. By June 2019, the outbreak had spread to 26 health zones in northeastern DRC, causing >2,000 reported cases and >1,000 deaths. On June 10, 2019, three members of a Congolese family with EVD-like symptoms traveled to western Uganda’s Kasese District to seek medical care. Shortly thereafter, the Viral Hemorrhagic Fever Surveillance and Laboratory Program (VHF program) at the Uganda Virus Research Institute (UVRI) confirmed that all three patients had EVD. The Ugandan Ministry of Health declared an outbreak of EVD in Uganda’s Kasese District, notified the World Health Organization, and initiated a rapid response to contain the outbreak. As part of this response, UVRI and the United States Centers for Disease Control and Prevention, with the support of Uganda’s Public Health Emergency Operations Center, the Kasese District Health Team, the Superintendent of Bwera General Hospital, the United States Department of Defense’s Makerere University Walter Reed Project, and the United States Mission to Kampala’s Global Health Security Technical Working Group, jointly established an Ebola Field Laboratory in Kasese District at Bwera General Hospital, proximal to an Ebola Treatment Unit (ETU). The laboratory consisted of a rapid containment kit for viral inactivation of patient specimens and a GeneXpert Instrument for performing Xpert Ebola assays. Laboratory staff tested 76 specimens from alert and suspect cases of EVD; the majority were admitted to the ETU (89.3%) and reported recent travel to the DRC (58.9%). Although no EVD cases were detected by the field laboratory, it played an important role in patient management and epidemiological surveillance by providing diagnostic results in <3 hours. The integration of the field laboratory into Uganda’s National VHF Program also enabled patient specimens to be referred to Entebbe for confirmatory EBOV testing and testing for other hemorrhagic fever viruses that circulate in Uganda.     

Diagnostics in Ebola Virus Disease in Resource-Rich and Resource-Limited Settings

The Ebola virus disease (EVD) outbreak in West Africa was unprecedented in scale and location. Limited access to both diagnostic and supportive pathology assays in both resource-rich and resource-limited settings had a detrimental effect on the identification and isolation of cases as well as individual patient management. Limited access to such assays in resource-rich settings resulted in delays in differentiating EVD from other illnesses in returning travellers, in turn utilising valuable resources until a diagnosis could be made. This had a much greater impact in West Africa, where it contributed to the initial failure to contain the outbreak. This review explores diagnostic assays of use in EVD in both resource-rich and resource-limited settings, including their respective limitations, and some novel assays and approaches that may be of use in future outbreaks.     

Facility-Based Delivery during the Ebola Virus Disease Epidemic in Rural Liberia: Analysis from a Cross-Sectional,Population-Based Household Survey

BackgroundThe Ebola virus disease (EVD) epidemic has threatened access to basic health services through facility closures, resource diversion, and decreased demand due to community fear and distrust. While modeling studies have attempted to estimate the impact of these disruptions, no studies have yet utilized population-based survey data.ConclusionsWe detected a 30% decreased odds of FBD after the start of EVD in a rural Liberian county with relatively few cases. Because health facilities never closed in Rivercess County, this estimate may under-approximate the effect seen in the most heavily affected areas. These are the first population-based survey data to show collateral disruptions to facility-based delivery caused by the West African EVD epidemic, and they reinforce the need to consider the full spectrum of implications caused by public health emergencies.