Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial

BackgroundTKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated.ConclusionsAdministration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls.

Trial registration

Pan African Clinical Trials Registry PACTR201501000997429     

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.     

Transforming Clinical Data into Actionable Prognosis Models: Machine-Learning Framework and Field-Deployable App to Predict Outcome of Ebola Patients

BackgroundAssessment of the response to the 2014–15 Ebola outbreak indicates the need for innovations in data collection, sharing, and use to improve case detection and treatment. Here we introduce a Machine Learning pipeline for Ebola Virus Disease (EVD) prognosis prediction, which packages the best models into a mobile app to be available in clinical care settings. The pipeline was trained on a public EVD clinical dataset, from 106 patients in Sierra Leone.Conclusions/SignificanceThis method demonstrates how to address small sample sizes and missing data, while creating predictive models that can be readily deployed to assist treatment in future outbreaks of EVD and other infectious diseases. By generating an ensemble of predictors instead of relying on a single model, we are able to handle situations where patient data is partially available. The prognosis app can be updated as new data become available, and we made all the computational protocols fully documented and open-sourced to encourage timely data sharing, independent validation, and development of better prediction models in outbreak response.     

Novel Ordered Stepped-Wedge Cluster Trial Designs for Detecting Ebola Vaccine Efficacy Using a Spatially Structured Mathematical Model

BackgroundDuring the 2014 Ebola virus disease (EVD) outbreak, policy-makers were confronted with difficult decisions on how best to test the efficacy of EVD vaccines. On one hand, many were reluctant to withhold a vaccine that might prevent a fatal disease from study participants randomized to a control arm. On the other, regulatory bodies called for rigorous placebo-controlled trials to permit direct measurement of vaccine efficacy prior to approval of the products. A stepped-wedge cluster study (SWCT) was proposed as an alternative to a more traditional randomized controlled vaccine trial to address these concerns. Here, we propose novel “ordered stepped-wedge cluster trial” (OSWCT) designs to further mitigate tradeoffs between ethical concerns, logistics, and statistical rigor.Conclusions/SignificanceOrdering clusters in a step-wedge trial based on the cluster’s underlying risk of infection as predicted by a spatial model can increase the statistical power of a SWCT. In the event of another hemorrhagic fever outbreak, implementation of our proposed OSWCT designs could improve statistical power when a step-wedge study is desirable based on either ethical concerns or logistical constraints.     

Qualitative evidence syntheses of attitudes and preferences to inform guidelines on infant feeding in the context of Ebola Virus Disease (EVD) transmission risk

BackgroundBreast-feeding holds considerable potential to reduce infant mortality. Feeding choices, already complex, take on additional complexity against a backdrop of the risk of transmissible Ebola Virus. This review describes the factors that influence infant feeding and attitudes of pregnant women, mothers, family members and health practitioners, policy makers and providers (midwives) concerning infant feeding when there is a risk of Mother-to-Child (MTC) transmission of Ebola Virus Disease (EVD).MethodologyA systematic review of qualitative studies identified through rigorous searches of thirteen online databases and additional citation searches of included studies was undertaken. Search terms included breast-feeding, breast-feeding, infant feeding; Ebola; and qualitative, interview(s) and findings. Independent extraction of data by two reviewers using predefined extraction forms. Studies were assessed using the CASP Qualitative checklist.Principal findings5219 references were screened. 38 references related specifically to Ebola, and five papers met the inclusion criteria with data gathered from two settings: Guinea and Sierra Leone. The EVD outbreak had a significant impact on beliefs, attitudes, and resources to support infant feeding practices negatively affecting the nutritional status of children. The evidence from these studies highlight the need for guidance and appropriate psychosocial support need to be available to mothers who display symptoms and become infected and to front-line staff who are giving advice. Communities need to be engaged because stigma and fear may hinder uptake of appropriate interventions. The EVD outbreak caused multi-level system disruption akin to that seen following a natural disaster, meaning that logistics and coordination are critical and need adequate resourcing. Food production and distribution, and malnutrition screening are also disrupted and thereby compounding compromised nutritional status. The limited number of relevant studies highlights the need for further primary research, particularly in translation of messages to local settings.ConclusionsAn EVD outbreak causes multi-level disruption that negatively impacts infant feeding and child care practices. Negative impacts have multiple causes and successful planning for Ebola outbreaks requires that nutrition of infants and young children is a priority. Lessons from the Ebola pandemic have wider applicability to other pandemic contexts including Covid-19.     

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.     

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.     

The Impact of the West Africa Ebola Outbreak on Obstetric Health Care in Sierra Leone

Background

As Sierra Leone celebrates the end of the Ebola Virus Disease (EVD) outbreak, we can begin to fully grasp its impact on already weak health systems. The EVD outbreak in West Africa forced many hospitals to close down or reduce their activity, either to prevent nosocomial transmission or because of staff shortages. The aim of this study is to assess the potential impact of EVD on nationwide access to obstetric care in Sierra Leone.

Methods and Findings

Community health officers collected weekly data between January 2014—May 2015 on in-hospital deliveries and caesarean sections (C-sections) from all open facilities (public, private for-profit and private non-profit sectors) offering emergency obstetrics in Sierra Leone. This was compared to official data of EVD cases per district. Logistic and Poisson regression analyses were used to compute risk and rate estimates. Nationwide, the number of in-hospital deliveries and C-sections decreased by over 20% during the EVD outbreak. The decline occurred early on in the EVD outbreak and was mainly attributable to the closing of private not-for-profit hospitals rather than government facilities. Due to difficulties in collecting data in the midst of an epidemic, limitations of this study include some missing data points.

Conclusions

Both the number of in-hospital deliveries and C-sections substantially declined shortly after the onset of the EVD outbreak. Since access to emergency obstetric care, like C-sections, is associated with decreased maternal mortality, many women are likely to have died due to the reduced access to appropriate care during childbirth. Future research on indirect health effects of health system breakdown should ideally be nationwide and continue also into the recovery phase. It is also important to understand the mechanisms behind the deterioration so that important health services can be reestablished.     

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.     

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.     

Lassa viral dynamics in non-human primates treated with favipiravir or ribavirin

Lassa fever is an haemorrhagic fever caused by Lassa virus (LASV). There is no vaccine approved against LASV and the only recommended antiviral treatment relies on ribavirin, despite limited evidence of efficacy. Recently, the nucleotide analogue favipiravir showed a high antiviral efficacy, with 100% survival obtained in an otherwise fully lethal non-human primate (NHP) model of Lassa fever. However the mechanism of action of the drug is not known and the absence of pharmacokinetic data limits the translation of these results to the human setting. Here we aimed to better understand the antiviral effect of favipiravir by developping the first mathematical model recapitulating Lassa viral dynamics and treatment. We analyzed the viral dynamics in 24 NHPs left untreated or treated with ribavirin or favipiravir, and we put the results in perspective with those obtained with the same drugs in the context of Ebola infection. Our model estimates favipiravir EC₅₀ in vivo to 2.89 μg.mL^-1, which is much lower than what was found against Ebola virus. The main mechanism of action of favipiravir was to decrease virus infectivity, with an efficacy of 91% at the highest dose. Based on our knowledge acquired on the drug pharmacokinetics in humans, our model predicts that favipiravir doses larger than 1200 mg twice a day should have the capability to strongly reduce the production infectious virus and provide a milestone towards a future use in humans.     

Successful Control of Ebola Virus Disease: Analysis of Service Based Data from Rural Sierra Leone

IntroductionThe scale and geographical distribution of the current outbreak in West Africa raised doubts as to the effectiveness of established methods of control. Ebola Virus Disease (EVD) was first detected in Sierra Leone in May 2014 in Kailahun district. Despite high case numbers elsewhere in the country, transmission was eliminated in the district by December 2014. We describe interventions underpinning successful EVD control in Kailahun and implications for EVD control in other areas.MethodsInternal service data and published reports from response agencies were analysed to describe the structure and type of response activities, EVD case numbers and epidemic characteristics. This included daily national situation reports and District-level data and reports of the Sierra Leone Ministry of Health and Sanitation, and Médecins Sans Frontières (MSF) patient data and internal epidemiological reports. We used EVD case definitions provided by the World Health Organisation over the course of the outbreak. Characteristics assessed included level of response activities and epidemiological features such as reported exposure (funeral-related or not), time interval between onset of illness and admission to the EVD Management Centre (EMC), work-related exposures (health worker or not) and mortality. We compared these characteristics between two time periods—June to July (the early period of response), and August to December (when coverage and quality of response had improved). A stochastic model was used to predict case numbers per generation with different numbers of beds and a varying percentage of community cases detected.ResultsThere were 652 probable/confirmed EVD cases from June-December 2014 in Kailahun. An EMC providing patient care opened in June. By August 2014 an integrated detection, treatment, and prevention strategy was in place across the district catchment zone. From June-July to August-December 2014 surveillance and contact tracing staff increased from 1.0 to 8.8 per confirmed EVD case, EMC capacity increased from 32 to 100 beds, the number of burial teams doubled, and health promotion activities increased in coverage. These improvements in response were associated with the following changes between the same periods: the proportion of confirmed/probable cases admitted to the EMC increased from 35% to 83% (χ² p-value<0·001), the proportion of confirmed patients admitted to the EMC <3 days of symptom onset increased from 19% to 37% (χ² p-value <0·001), and reported funeral contact in those admitted decreased from 33% to 16% (χ² p-value <0·001). Mathematical modelling confirmed the importance of both patient management capacity and surveillance and contact tracing for EVD control.DiscussionOur findings demonstrate that control of EVD can be achieved using established interventions based on identification and appropriate management of those who are at risk of and develop EVD, including in the context of ongoing transmission in surrounding regions. Key attributes in achieving control were sufficient patient care capacity (including admission to specialist facilities of suspect and probable cases for assessment), integrated with adequate staffing and resourcing of community-based case detection and prevention activities. The response structure and coverage targets we present are of value in informing effective control in current and future EVD outbreaks.     

Immunogenicity and safety of primary fractional-dose yellow fever vaccine in autoimmune rheumatic diseases

BackgroundBrazil faced a yellow fever(YF) outbreak in 2016–2018 and vaccination was considered for autoimmune rheumatic disease patients(ARD) with low immunosuppression due to YF high mortality.ObjectiveThis study aimed to evaluate, prospectively for the first time, the short-term immunogenicity of the fractional YF vaccine(YFV) immunization in ARD patients with low immunossupression.Methods and ResultsA total of 318 participants(159 ARD and 159 age- and sex-matched healthy controls) were vaccinated with the fractional-dose(one fifth) of 17DD-YFV. All subjects were evaluated at entry(D0), D5, D10, and D30 post-vaccination for clinical/laboratory and disease activity parameters for ARD patients. Post-vaccination seroconversion rate(83.7%vs.96.6%, p = 0.0006) and geometric mean titers(GMT) of neutralizing antibodies[1143.7 (95%CI 1012.3–1292.2) vs.731 (95%CI 593.6–900.2), p<0.001] were significantly lower in ARD compared to controls. A lower positivity rate of viremia was also identified for ARD patients compared to controls at D5 (53%vs.70%, p = 0.005) and the levels persisted in D10 for patients and reduced for controls(51%vs.19%, p = 0.0001). The viremia was the only variable associated with seroconvertion. No serious adverse events were reported. ARD disease activity parameters remained stable at D30(p>0.05).ConclusionFractional-dose 17DD-YF vaccine in ARD patients resulted in a high rate of seroconversion rate(>80%) but lower than controls, with a longer but less intense viremia. This vaccine was immunogenic, safe and did not induce flares in ARD under low immunosuppression and may be indicated in YF outbreak situations and for patients who live or travel to endemic areas.Trial registrationThis clinical trial was registered with Clinicaltrials.gov (#{"type":"clinical-trial","attrs":{"text":"NCT03430388","term_id":"NCT03430388"}}NCT03430388).     

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.     

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.     

Ebola Outbreak Response; Experience and Development of Screening Tools for Viral Haemorrhagic Fever (VHF) in a HIV Center of Excellence Near to VHF Epicentres

Introduction

There have been 3 outbreaks of viral hemorrhagic fever (VHF) in Uganda in the last 2 years. VHF often starts with non-specific symptoms prior to the onset of haemorrhagic signs. HIV clinics in VHF outbreak countries such as Uganda see large numbers of patients with HIV 1/2 infection presenting with non-specific symptoms every day. Whilst there are good screening tools for general health care facilities expecting VHF suspects, we were unable to find tools for use in HIV or other non-acute clinics.

Methods

We designed tools to help with communication to staff, infection control and screening of HIV patients with non-specific symptoms in a large HIV clinic during the outbreaks in Uganda. We describe our experiences in using these tools in 2 Ebola Virus Disease outbreaks in Uganda.

Results

During the Ebola Virus Disease (EVD) outbreaks, enhanced infection control and communication procedures were implemented within 24 hours of the WHO/Ministry of Health announcement of the outbreaks. During course of these outbreaks the clinic saw 12,544 patients with HIV 1/2 infection, of whom 3,713 attended without an appointment, suggesting new symptoms. Of these 4 were considered at risk of EVD and seen with full infection procedures; 3 were sent home after further investigation. One patient was referred to the National Referral Hospital VHF unit, but discharged on the same day. One additional VHF suspect was identified outside of a VHF outbreak; he was transferred to the National Referral Hospital and placed in isolation within 2 hours of arriving at the HIV clinic.

Discussion

Use of simple screening tools can be helpful in managing large numbers of symptomatic patients attending for routine and non-routine medical care (including HIV care) within a country experiencing a VHF outbreak, and can raise medical staff awareness of VHF outside of the epidemics.     

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.