A community-based contact isolation strategy to reduce the spread of Ebola virus disease: an analysis of the 2018-2020 outbreak in the Democratic Republic of the Congo.

INTRODUCTION: Despite tremendous progress in the development of diagnostics, vaccines and therapeutics for Ebola virus disease (EVD), challenges remain in the implementation of holistic strategies to rapidly curtail outbreaks. We investigated the effectiveness of a community-based contact isolation strategy to limit the spread of the disease in the Democratic Republic of Congo (DRC). METHODS: We did a quasi-experimental comparison study. Eligible participants were EVD contacts registered from 12 June 2019 to 18 May 2020 in Beni and Mabalako Health Zones. Intervention group participants were isolated to specific community sites for the duration of their follow-up. Comparison group participants underwent contact tracing without isolation. The primary outcome was measured as the reproduction number (R) in the two groups. Secondary outcomes were the delay from symptom onset to isolation and case management, case fatality rate (CFR) and vaccination uptake. RESULTS: 27 324 EVD contacts were included in the study; 585 in the intervention group and 26 739 in the comparison group. The intervention group generated 32 confirmed cases (5.5%) in the first generation, while the comparison group generated 87 (0.3%). However, the 32 confirmed cases arising from the intervention contacts did not generate any additional transmission (R=0.00), whereas the 87 confirmed cases arising from the comparison group generated 99 secondary cases (R=1.14). The average delay between symptom onset and case isolation was shorter (1.3 vs 4.8 days; p<0.0001), CFR lower (12.5% vs 48.4%; p=0.0001) and postexposure vaccination uptake higher (86.0% vs 56.8%; p<0.0001) in the intervention group compared with the comparison group. A significant difference was also found between intervention and comparison groups in survival rate at the discharge of hospitalised confirmed patients (87.9% vs 47.7%, respectively; p=0.0004). CONCLUSION: The community-based contact isolation strategy used in DRC shows promise as a potentially effective approach for the rapid cessation of EVD transmission, highlighting the importance of rapidly implemented, community-oriented and trust-building control strategies.

Hidden Tales of Ebola: Airing the Forgotten Voices of Ugandan "Ebola Nurses".

INTRODUCTION: According to the Centers for Disease Control and Prevention, Ebola has affected the lives of thousands, including health care workers. With few studies describing the experience of nurses who survived Ebola, the study aimed to describe Ugandan nurses' experiences. METHOD: Using a phenomenological design, in-depth interviews were conducted among five Ugandan nurses who contracted Ebola and survived. RESULT: Thematic analysis revealed themes of expectations of dying, hopelessness, loneliness, and betrayal by family, community, and the health system. DISCUSSION: Results support the need for policies targeting holistic practice protocols to protect all health care professionals during future outbreaks. Last, nursing survivors should have access to government-guaranteed support programs, including free health care and financial stipends. These results and recommendations transcend to the current reality of living with COVID-19 (coronavirus disease 2019). Efficient practice protocols could protect all rights and privileges and contribute to access to treatment and stigma removal.

Review: Insights on Current FDA-Approved Monoclonal Antibodies Against Ebola Virus Infection.

The unprecedented 2013-2016 West Africa Ebola outbreak accelerated several medical countermeasures (MCMs) against Ebola virus disease (EVD). Several investigational products (IPs) were used throughout the outbreak but were not conclusive for efficacy results. Only the Randomized Controlled Trial (RCT) on ZMapp was promising but inconclusive. More recently, during the second-largest Ebola outbreak in North Kivu and Ituri provinces, Democratic Republic of the Congo (DRC), four IPs, including one small molecule (Remdesivir), two monoclonal antibody (mAb) cocktails (ZMapp and REGN-EB3) and a single mAb (mAb114), were evaluated in an RCT, the Pamoja Tulinde Maisha (PALM) study. Two products (REGN-EB3 and mAb114) demonstrated efficacy as compared to the control arm, ZMapp. There were remarkably few side effects recorded in the trial. The FDA approved both medications in this scientifically sound study, marking a watershed moment in the field of EVD therapy. These products can be produced relatively inexpensively and can be stockpiled. The administration of mAbs in EVD patients appears to be safe and effective, while several critical knowledge gaps remain; the impact of early administration of Ebola-specific mAbs on developing a robust immune response for future Ebola virus exposure is unknown. The viral mutation escape, leading to resistance, presents a potential limitation for single mAb therapy; further improvements need to be explored. Understanding the contribution of Fc-mediated antibody functions such as antibody-dependent cellular cytotoxicity (ADCC) of those approved mAbs is still critical. The potential merit of combination therapy and post-exposure prophylaxis (PEP) need to be demonstrated. Furthermore, the PALM trial has accounted for 30% of mortality despite the administration of specific treatments. The putative role of EBOV soluble Glycoprotein (sGP) as a decoy to the immune system, the virus persistence, and relapses might be investigated for treatment failure. The development of pan-filovirus or pan-species mAbs remains essential for protection. The interaction between FDA-approved mAbs and vaccines remains unclear and needs to be investigated. In this review, we summarize the efficacy and safety results of the PALM study and review current research questions for the further development of mAbs in pre-exposure or emergency post-exposure use.

Why is repositioning public health innovation towards a social paradigm necessary? A reflection on the field of public health through the examples of Ebola and Covid-19.

Health innovations are generally oriented on a techno-economic vision. In this perspective, technologies are seen as an end in themselves, and there is no arrangement between the technical and the social values of innovation. This vision prevails in sanitary crises, in which management is carried out based on the search for punctual, reactive, and technical solutions to remedy a specific problem without a systemic/holistic, sustainable, or proactive approach. This paper attempts to contribute to the literature on the epistemological orientation of innovations in the field of public health. Taking the Covid-19 and Ebola crises as examples, the primary objective is to show how innovation in health is oriented towards a techno-economic paradigm. Second, we propose a repositioning of public health innovation towards a social paradigm that will put more emphasis on the interaction between social and health dimensions in the perspective of social change. We will conclude by highlighting the roles that public health could play in allowing innovations to have more social value, especially during sanitary crises.

The Impact of Water Sanitation and Hygiene (WASH) Improvements on Hand Hygiene at Two Liberian Hospitals during the Recovery Phase of an Ebola Epidemic.

Fourteen years of civil war left Liberia with crumbling infrastructure and one of the weakest health systems in the world. The 2014-2015 Ebola virus disease (EVD) outbreak exposed the vulnerabilities of the Liberian health system. Findings from the EVD outbreak highlighted the lack of infection prevention and control (IPC) practices, exacerbated by a lack of essential services such as water, sanitation, and hygiene (WASH) in healthcare facilities. The objective of this intervention was to improve IPC practice through comprehensive WASH renovations conducted at two hospitals in Liberia, prioritized by the Ministry of Health (MOH). The completion of renovations was tracked along with the impact of improvements on hand hygiene (HH) practice audits of healthcare workers pre- and post-intervention. An occurrence of overall HH practice was defined as the healthcare worker practicing compliant HH before and after the care for a single patient encounter. Liberia Government Hospital Bomi (LGH Bomi) and St. Timothy Government Hospital (St. Timothy) achieved World Health Organization (WHO) minimum global standards for environmental health in healthcare facilities as well as Liberian national standards. Healthcare worker (HCW) overall hand hygiene compliance improved from 36% (2016) to 89% (2018) at LGH Bomi hospital and from 86% (2016) to 88% (2018) at St. Timothy hospital. Improved WASH services and IPC practices in resource-limited healthcare settings are possible if significant holistic WASH infrastructure investments are made in these settings.

Preparing Frontline Hospitals for Dangerous Special Pathogens Beyond Ebola.

Frontline hospitals are at the forefront of all travel-related, emerging and reemerging infectious diseases and special pathogens. Yet, the readiness of frontline hospitals and their ability to identify, isolate, and inform on Ebola and other special pathogens is uncertain. This article addresses the resources necessary to support screening for Ebola and other special pathogens and presents the decision-making algorithm for the transport of patients with high-consequence infectious diseases within the New York City Health + Hospitals integrated healthcare delivery network, which includes 10 frontline hospitals and the Region 2 Ebola and Other Special Pathogen Treatment Center.

'The cat that kills people:' community beliefs about Ebola origins and implications for disease control in Eastern Democratic Republic of the Congo.

The current Ebola epidemic in Eastern Democratic Republic of Congo (DRC) has surpassed 1 700 deaths. Social resistance, a major barrier to control efforts, invites exploration of community beliefs around Ebola and its origins. We conducted a mixed-methods study, using four focus group discussions (FGDs) involving 20 participants, and a 19-item survey questionnaire, administered to a nonprobability sample of 286 community members throughout the outbreak zone. FGDs and surveys were conducted between 4 and 17 August 2018. FGDs revealed a widespread rumor early in the epidemic of two twins bewitched by their aunt after eating her cat, who developed bleeding symptoms and triggered the epidemic. However, this myth appeared to dissipate as the epidemic progressed and biomedical transmission became generally accepted. In our survey, 6% of respondents endorsed supernatural origins of Ebola. These respondents were more likely to believe that traditional medicine practitioners can cure Ebola. Wild animals were recognized as sources of Ebola by 53% and FGD participants commented that 'Ebola leaves the forest and hides in the hospital,' recognizing that zoonotic origins gave way to nosocomial transmission as the epidemic progressed. Taken together, our findings suggest that a dynamic syncretism of mythical and biomedical understanding of Ebola may have shaped transmission patterns. Mythical conceptions and fear of contagion may have fueled the 'underground' transmission of Ebola, as patients sought care from traditional healers, who are ill-equipped to deal with a highly contagious biohazard. A deeper understanding of beliefs around Ebola origins may illuminate strategies to engage communities in control efforts.

Can Ebola Virus Vaccines Have Universal Immune Correlates of protection?

Testing vaccine efficacy against the highly lethal Ebola virus (EBOV) in humans is almost impossible due to obvious ethical reasons and the sporadic nature of outbreaks. For such situations, the 'animal rule' was established, requiring the product be tested in animal models, expected to predict the response observed in humans. For vaccines, this testing aims to identify immune correlates of protection, such as antibody or cell-mediated responses. In the wake of the 2013-2016 EBOV epidemic, and despite advancement of promising candidates into clinical trials, protective correlates remain ambiguous. In the hope of identifying a reliable correlate by comparing preclinical and clinical trial data on immune responses to vaccination, we conclude that correlates are not universal for all EBOV vaccines.

Ebola: Lessons on Vaccine Development.

The West African Ebola virus (EBOV) epidemic has fast-tracked countermeasures for this rare, emerging zoonotic pathogen. Until 2013-2014, most EBOV vaccine candidates were stalled between the preclinical and clinical milestones on the path to licensure, because of funding problems, lack of interest from pharmaceutical companies, and competing priorities in public health. The unprecedented and devastating epidemic propelled vaccine candidates toward clinical trials that were initiated near the end of the active response to the outbreak. Those trials did not have a major impact on the epidemic but provided invaluable data on vaccine safety, immunogenicity, and, to a limited degree, even efficacy in humans. There are plenty of lessons to learn from these trials, some of which are addressed in this review. Better preparation is essential to executing an effective response to EBOV in the future; yet, the first indications of waning interest are already noticeable.

Intranasal vaccination with ebola virus GP amino acids 258-601 protects mice against lethal challenge.

Ebola virus (EBOV) disease (EVD) leads to lethal hemorrhagic fever with a case fatality rate as high as 90%, thus posing a serious global public health concern. However, while several vaccines based on the EBOV glycoprotein have been confirmed to be effective in animal experiments, no licensed vaccines or effective treatments have been approved since the first outbreak was reported in 1976. In this study, we prepared the extracellular domain of the EBOV GP protein (designated as N20) by prokaryotic expression and purification via chromatography. Using CTA1-DD (designated as H45) as a mucosal adjuvant, we evaluated the immunogenicity of N20 by intranasal administration and the associated protective efficacy against mouse-adapted EBOV challenge in mice. We found that intranasal vaccination with H45-adjuvanted N20 could stimulate humoral immunity, as supported by GP-specific IgG titers; Th1 cellular immunity, based on IgG subclasses and IFN-γ/IL-4 secreting cells; and mucosal immunity, based on the presence of anti-EBOV IgA in vaginal lavages. We also confirmed that the vaccine could completely protect mice against a lethal mouse-adapted EBOV (MA-EBOV) challenge with few side effects (based on weight loss). In comparison, mice that received N20 or H45 alone succumbed to lethal MA-EBOV challenge. Therefore, mucosal vaccination with H45-adjuvanted N20 represents a potential vaccine candidate for the prevention of EBOV in an effective, safe, and convenient manner.

Community health workers during the Ebola outbreak in Guinea, Liberia, and Sierra Leone.

BACKGROUND: The role of community health workers (CHWs) in the West Africa Ebola outbreak has been highlighted to advocate for increasing numbers of CHWs globally to build resilience, strengthen health systems, and provide emergency response capacity. However, the roles CHWs played, the challenges they faced, and their effectiveness during the outbreak are not well documented. This study assessed the impact of Ebola on community-based maternal, newborn, and child health (MNCH) services, documented the contribution of CHWs and other community-based actors to the Ebola response, and identified lessons learned to strengthen resilience in future emergencies. METHODS: This mixed methods study was conducted in Guinea, Liberia, and Sierra Leone, with data collected in four Ebola-affected districts of each country. Qualitative data were collected through in-depth interviews and focus group discussions with stakeholders at national, district, and community levels. Quantitative program data were used to assess trends in delivery of community-based MNCH services. RESULTS: There was a sharp decline in MNCH service provision due to weak service delivery, confusion over policy, and the overwhelming nature of the outbreak. However, many CHWs remained active in their communities and were willing to continue providing services. When CHWs received clear directives and were supported, service provision rebounded. Although CHWs faced mistrust and hostility from community members because of their linkages to health facilities, the relationship between CHWs and communities proved resilient over time, and CHWs were more effectively able to carry out Ebola-related activities than outsiders. Traditional birth attendants, community health committees, community leaders, and traditional healers also played important roles, despite a lack of formal engagement or support. Service delivery weaknesses, especially related to supply chain and supervision, limited the effectiveness of community health services before, during, and after the outbreak. CONCLUSIONS: CHWs and other community-level actors played important roles during the Ebola outbreak. However, maintenance of primary care services and the Ebola response were hampered because community actors were engaged late in the response and did not receive sufficient support. In the future, communities should be placed at the forefront of emergency preparedness and response plans and they must be adequately supported to strengthen service delivery.

The vesicular stomatitis virus-based Ebola virus vaccine: From concept to clinical trials.

The devastating Ebola virus (EBOV) epidemic in West Africa in 2013-2016 accelerated the progress of several vaccines and antivirals through clinical trials, including the replication-competent vesicular stomatitis virus-based vaccine expressing the EBOV glycoprotein (VSV-EBOV). Extensive preclinical testing in animal models demonstrated the prophylactic and post-exposure efficacy of this vaccine, identified the mechanism of protection, and suggested it was safe for human use. Based on these data, VSV-EBOV was extensively tested in phase 1-3 clinical trials in North America, Europe and Africa. Although some side effects of vaccination were observed, these clinical trials showed that the VSV-EBOV was safe and immunogenic in humans. Moreover, the data supported the use of VSV-EBOV as an emergency vaccine in individuals at risk for Ebola virus disease. In this review, we summarize the results of the extensive preclinical and clinical testing of the VSV-EBOV vaccine.

Lessons learned from Ebola Vaccine R&D during a public health emergency.

In spite of a complete lack of Research and Development (R&D) preparedness, the 2013-2016 West-Africa Ebola experience demonstrated that it is possible to compress R&D timelines to less than a single year, from a more usual decade or longer. This is mostly to be credited to an unprecedented collaborative effort building on the availability of a small number of candidate diagnostic tests, drugs and vaccines that could be moved rapidly into the clinical phase evaluation. The World Health Organization (WHO) led international consultations and activities - including the organization of a successful Ebola vaccine efficacy trial in Guinea - as a contribution to the unprecedented global efforts to control the Ebola epidemic. Since 2015, WHO expert teams and partners are implementing a novel R&D model for emerging infectious pathogens which are the most likely to cause severe outbreaks in the future, and for which no or only few medical countermeasures are available: the WHO R&D Blueprint. The objective for the Blueprint is the fostering of a R&D environment which is prepared for quickly and effectively responding to outbreaks due to emerging infectious disease.

From bench to almost bedside: the long road to a licensed Ebola virus vaccine.

INTRODUCTION: The Ebola virus (EBOV) disease epidemic during 2014-16 in West Africa has accelerated the clinical development of several vaccine candidates that have demonstrated efficacy in the gold standard nonhuman primate (NHP) model, namely cynomolgus macaques. AREAS COVERED: This review discusses the pre-clinical research and if available, clinical evaluation of the currently available EBOV vaccine candidates, while emphasizing the translatability of pre-clinical data generated in the NHP model to clinical data in humans. EXPERT OPINION: Despite the existence of many successful EBOV vaccine candidates in the pre-clinical stages, only two platforms became the focus of Phase 2/3 efficacy trials in Liberia, Sierra Leone, and Guinea near the peak of the epidemic: the Vesicular stomatitis virus (VSV)-vectored vaccine and the chimpanzee adenovirus type 3 (ChAd3)-vectored vaccine. The results of three distinct clinical trials involving these candidates may soon pave the way for a licensed, safe and efficacious EBOV vaccine to help combat future epidemics.

Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects.

Global health is threatened by emerging viral infections, which largely lack effective vaccines or therapies. Targeting host pathways that are exploited by multiple viruses could offer broad-spectrum solutions. We previously reported that AAK1 and GAK, kinase regulators of the host adaptor proteins AP1 and AP2, are essential for hepatitis C virus (HCV) infection, but the underlying mechanism and relevance to other viruses or in vivo infections remained unknown. Here, we have discovered that AP1 and AP2 cotraffic with HCV particles in live cells. Moreover, we found that multiple viruses, including dengue and Ebola, exploit AAK1 and GAK during entry and infectious virus production. In cultured cells, treatment with sunitinib and erlotinib, approved anticancer drugs that inhibit AAK1 or GAK activity, or with more selective compounds inhibited intracellular trafficking of HCV and multiple unrelated RNA viruses with a high barrier to resistance. In murine models of dengue and Ebola infection, sunitinib/erlotinib combination protected against morbidity and mortality. We validated sunitinib- and erlotinib-mediated inhibition of AAK1 and GAK activity as an important mechanism of antiviral action. Additionally, we revealed potential roles for additional kinase targets. These findings advance our understanding of virus-host interactions and establish a proof of principle for a repurposed, host-targeted approach to combat emerging viruses.

Ethnomedical and ethnobotanical investigations on the response capacities of Guinean traditional health practioners in the management of outbreaks of infectious diseases: The case of the Ebola virus epidemic.

ETHNOPHARMACOLOGICAL RELEVANCE: The recent outbreak of Ebola virus infections has mostly remained confined to the West African countries Guinea-Conakry, Sierra-Leone and Liberia. Due to intense national and international mobilizations, a significant reduction in Ebola virus transmission has been recorded. While international efforts focus on new vaccines, medicines and diagnostics, no coherent national or international approach exists to integrate the potential of the traditional health practitioners (THPs) in the management of infectious diseases epidemics. Nevertheless, the first contact of most of the Ebola infected patients is with the THPs since the symptoms are similar to those of common traditionally treated diseases or symptoms such as malaria, hemorrhagic syndrome, typhoid or other gastrointestinal diseases, fever and vomiting. MATERIALS AND METHODS: In an ethnomedical survey conducted in the 4 main Guinean regions contacts were established with a total of 113 THPs. The socio-demographic characteristics, the professional status and the traditional perception of Ebola Virus Disease (EVD) were recorded. RESULTS: The traditional treatment of the main symptoms was based on 47 vegetal recipes which were focused on the treatment of diarrhea (22 recipes), fever (22 recipes), vomiting (2 recipes), external antiseptic (2 recipes), hemorrhagic syndrome (2 recipes), convulsion and dysentery (one recipe each). An ethnobotanical survey led to the collection of 54 plant species from which 44 identified belonging to 26 families. The most represented families were Euphorbiaceae, Caesalpiniaceae and Rubiaceae. Literature data on the twelve most cited plant species tends to corroborate their traditional use and to highlight their pharmacological potential. CONCLUSIONS: It is worth to document all available knowledge on the traditional management of EVD-like symptoms in order to evaluate systematically the anti-Ebola potential of Guinean plant species.

Characterization of the inhibitory effect of an extract of Prunella vulgaris on Ebola virus glycoprotein (GP)-mediated virus entry and infection.

Currently, no approved antiviral therapeutic is available for treatment or prevention of Ebola virus (EBOV) infection. In this study, we characterized an EBOV-glycoprotein (GP) pseudotyped HIV-1-based vector system in different cell cultures, including human umbilical vein endothelial cells (HUVECs) and human macrophages, for the screening of anti-EBOV-GP agent(s). Based on this system, we demonstrated that an aqueous extract (CHPV) from the Chinese herb Prunella vulgaris displayed a potent inhibitory effect on EBOV-GP pseudotyped virus (EBOV-GP-V)-mediated infection in various cell lines, including HUVEC and macrophage. In addition, our results indicated that CHPV was able to block an eGFP-expressing Zaire ebola virus (eGFP-ZEBOV) infection in VeroE6 cells. The anti-EBOV activity of CHPV was exhibited in a dose-dependent manner. At a 12.5 µg/ml concentration, the CHPV showed a greater than 80% inhibition of EBOV-GP-V and eGFP-EBOV infections. Likewise, our studies suggested that the inhibitory effect of CHPV occurred by binding directly to EBOV-GP-Vs and blocking the early viral events. Interestingly, our results have shown that CHPV was able to enhance the anti-EBOV activity of the monoclonal antibody MAb 2G4 against EBOV-GP. Overall, this study provides evidence that CHPV has anti-EBOV activity and may be developed as a novel antiviral approach against EBOV infection.

Recurrence and reinfection--a new paradigm for the management of Ebola virus disease.

Ebola virus disease (EVD) is an understudied infection and many aspects of viral transmission and clinical course remain unclear. With over 17000 EVD survivors in West Africa, the World Health Organization has focused its strategy on managing survivors and the risk of re-emergence of outbreaks posed by persistence of the virus during convalescence. Sexual transmission from survivors has also been documented following the 2014 epidemic and there are documented cases of survivors readmitted to hospital with 'recurrence' of EVD symptoms. In addition to persistence of virus in survivors, there is also some evidence for 'reinfection' with Ebola virus. In this paper, the evidence for recurrence and reinfection of EVD and implications for epidemic control are reviewed.

Teicoplanin inhibits Ebola pseudovirus infection in cell culture.

There is currently no approved antiviral therapy for treatment of Ebola virus disease. To discover readily available approved drugs that can be rapidly repurposed for treatment of Ebola virus infections, we screened 1280 FDA-approved drugs and identified glycopeptide antibiotic teicoplanin inhibiting Ebola pseudovirus infection by blocking virus entry in the low micromolar range. Teicoplanin could be evaluated further and incorporated into ongoing clinical studies.