Ebola disease outbreak caused by the Sudan virus in Uganda, 2022: a descriptive epidemiological study.

BACKGROUND: Uganda has had seven Ebola disease outbreaks, between 2000 and 2022. On Sept 20, 2022, the Ministry of Health declared a Sudan virus disease outbreak in Mubende District, Central Uganda. We describe the epidemiological characteristics and transmission dynamics. METHODS: For this descriptive study, cases were classified as suspected, probable, or confirmed using Ministry of Health case definitions. We investigated all reported cases to obtain data on case-patient demographics, exposures, and signs and symptoms, and identified transmission chains. We conducted a descriptive epidemiological study and also calculated basic reproduction number (Ro) estimates. FINDINGS: Between Aug 8 and Nov 27, 2022, 164 cases (142 confirmed, 22 probable) were identified from nine (6%) of 146 districts. The median age was 29 years (IQR 20-38), 95 (58%) of 164 patients were male, and 77 (47%) patients died. Symptom onsets ranged from Aug 8 to Nov 27, 2022. The case fatality rate was highest in children younger than 10 years (17 [74%] of 23 patients). Fever (135 [84%] of 160 patients), vomiting (93 [58%] patients), weakness (89 [56%] patients), and diarrhoea (81 [51%] patients) were the most common symptoms; bleeding was uncommon (21 [13%] patients). Before outbreak identification, most case-patients (26 [60%] of 43 patients) sought care at private health facilities. The median incubation was 6 days (IQR 5-8), and median time from onset to death was 10 days (7-23). Most early cases represented health-care-associated transmission (43 [26%] of 164 patients); most later cases represented household transmission (109 [66%]). Overall Ro was 1·25. INTERPRETATION: Despite delayed detection, the 2022 Sudan virus disease outbreak was rapidly controlled, possibly thanks to a low Ro. Children (aged <10 years) were at the highest risk of death, highlighting the need for targeted interventions to improve their outcomes during Ebola disease outbreaks. Initial care-seeking occurred at facilities outside the government system, showing a need to ensure that private and public facilities receive training to identify possible Ebola disease cases during an outbreak. Health-care-associated transmission in private health facilities drove the early outbreak, suggesting gaps in infection prevention and control. FUNDING: None.

Discovery of Thiophene Derivatives as Potent, Orally Bioavailable, and Blood-Brain Barrier-Permeable Ebola Virus Entry Inhibitors.

The endemic nature of the Ebola virus disease in Africa underscores the need for prophylactic and therapeutic drugs that are affordable and easy to administer. Through a phenotypic screening employing viral pseudotypes and our in-house chemical library, we identified a promising hit featuring a thiophene scaffold, exhibiting antiviral activity in the micromolar range. Following up on this thiophene hit, a new series of compounds that retain the five-membered heterocyclic scaffold while modifying several substituents was synthesized. Initial screening using a pseudotype viral system and validation assays employing authentic Ebola virus demonstrated the potential of this new chemical class as viral entry inhibitors. Subsequent investigations elucidated the mechanism of action through site-directed mutagenesis. Furthermore, we conducted studies to assess the pharmacokinetic profile of selected compounds to confirm its pharmacological and therapeutic potential.

Improving Ebola virus disease outbreak control through targeted post-exposure prophylaxis.

Ebola virus disease kills more than half of people infected. Since the disease is transmitted via close human contact, identifying individuals at the highest risk of developing the disease is possible on the basis of the type of contact (correlated with viral exposure). Different candidates for post-exposure prophylaxis (PEP; ie, vaccines, antivirals, and monoclonal antibodies) each have their specific benefits and limitations, which we discuss in this Viewpoint. Approved monoclonal antibodies have been found to reduce mortality in people with Ebola virus disease. As monoclonal antibodies act swiftly by directly targeting the virus, they are promising candidates for targeted PEP in contacts at high risk of developing disease. This intervention could save lives, halt viral transmission, and, ultimately, help curtail outbreak propagation. We explore how a strategic integration of monoclonal antibodies and vaccines as PEP could provide both immediate and long-term protection against Ebola virus disease, highlighting ongoing clinical research that aims to refine this approach, and discuss the transformative potential of a successful PEP strategy to help control viral haemorrhagic fever outbreaks.

Evaluation of centralised and decentralised models of care during the 2020 Ebola Virus Disease outbreak in Equateur Province, Democratic Republic of the Congo: A brief report.

Background: Traditionally in the Democratic Republic of the Congo (DRC), centralised Ebola treatment centres (ETCs) have been set exclusively for Ebola virus disease (EVD) case management during outbreaks. During the 2020 EVD outbreak in DRC's Equateur Province, existing health centres were equipped as decentralised treatment centres (DTC) to improve access for patients with suspected EVD. Between ETCs and DTCs, we compared the time from symptom onset to admission and diagnosis among patients with suspected EVD. Methods: This was a cohort study based on analysis of a line-list containing demographic and clinical information of patients with suspected EVD admitted to any EVD health facility during the outbreak. Results: Of 2359 patients with suspected EVD, 363 (15%) were first admitted to a DTC. Of 1996 EVD-suspected patients initially admitted to an ETC, 72 (4%) were confirmed as EVD-positive. Of 363 EVD-suspected patients initially admitted to a DTC, 6 (2%) were confirmed and managed as EVD-positive in the DTC. Among all EVD-suspected patients, the median (interquartile range) duration between symptom onset and admission was 2 (1-4) days in a DTC compared to 4 (2-7) days in an ETC (p<0.001). Similarly, time from symptom onset to admission was significantly shorter among EVD-suspected patients ultimately diagnosed as EVD-negative. Conclusions: Since <5% of the EVD-suspected patients admitted were eventually diagnosed with EVD, there is a need for better screening to optimise resource utilization and outbreak control. Only one in seven EVD-suspected patients were admitted to a DTC first, as the DTCs were piloted in a limited and phased manner. However, there is a case to be made for considering decentralized care especially in remote and hard-to-reach areas in places like the DRC to facilitate early access to care, contain viral shedding by patients with EVD and ensure no disrupted provision of non-EVD services.

Long-term cellular immunity of vaccines for Zaire Ebola Virus Diseases.

Recent Ebola outbreaks underscore the importance of continuous prevention and disease control efforts. Authorized vaccines include Merck's Ervebo (rVSV-ZEBOV) and Johnson & Johnson's two-dose combination (Ad26.ZEBOV/MVA-BN-Filo). Here, in a five-year follow-up of the PREVAC randomized trial (NCT02876328), we report the results of the immunology ancillary study of the trial. The primary endpoint is to evaluate long-term memory T-cell responses induced by three vaccine regimens: Ad26-MVA, rVSV, and rVSV-booster. Polyfunctional EBOV-specific CD4+ T-cell responses increase after Ad26 priming and are further boosted by MVA, whereas minimal responses are observed in the rVSV groups, declining after one year. In-vitro expansion for eight days show sustained EBOV-specific T-cell responses for up to 60 months post-prime vaccination with both Ad26-MVA and rVSV, with no decline. Cytokine production analysis identify shared biomarkers between the Ad26-MVA and rVSV groups. In secondary endpoint, we observed an elevation of pro-inflammatory cytokines at Day 7 in the rVSV group. Finally, we establish a correlation between EBOV-specific T-cell responses and anti-EBOV IgG responses. Our findings can guide booster vaccination recommendations and help identify populations likely to benefit from revaccination.

Using mHealth Technologies for Case Finding in Tuberculosis and Other Infectious Diseases in Africa: Systematic Review.

BACKGROUND: Mobile health (mHealth) technologies are increasingly used in contact tracing and case finding, enhancing and replacing traditional methods for managing infectious diseases such as Ebola, tuberculosis, COVID-19, and HIV. However, the variations in their development approaches, implementation scopes, and effectiveness introduce uncertainty regarding their potential to improve public health outcomes. OBJECTIVE: We conducted this systematic review to explore how mHealth technologies are developed, implemented, and evaluated. We aimed to deepen our understanding of mHealth's role in contact tracing, enhancing both the implementation and overall health outcomes. METHODS: We searched and reviewed studies conducted in Africa focusing on tuberculosis, Ebola, HIV, and COVID-19 and published between 1990 and 2023 using the PubMed, Scopus, Web of Science, and Google Scholar databases. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to review, synthesize, and report the findings from articles that met our criteria. RESULTS: We identified 11,943 articles, but only 19 (0.16%) met our criteria, revealing a large gap in technologies specifically aimed at case finding and contact tracing of infectious diseases. These technologies addressed a broad spectrum of diseases, with a predominant focus on Ebola and tuberculosis. The type of technologies used ranged from mobile data collection platforms and smartphone apps to advanced geographic information systems (GISs) and bidirectional communication systems. Technologies deployed in programmatic settings, often developed using design thinking frameworks, were backed by significant funding and often deployed at a large scale but frequently lacked rigorous evaluations. In contrast, technologies used in research settings, although providing more detailed evaluation of both technical performance and health outcomes, were constrained by scale and insufficient funding. These challenges not only prevented these technologies from being tested on a wider scale but also hindered their ability to provide actionable and generalizable insights that could inform public health policies effectively. CONCLUSIONS: Overall, this review underscored a need for organized development approaches and comprehensive evaluations. A significant gap exists between the expansive deployment of mHealth technologies in programmatic settings, which are typically well funded and rigorously developed, and the more robust evaluations necessary to ascertain their effectiveness. Future research should consider integrating the robust evaluations often found in research settings with the scale and developmental rigor of programmatic implementations. By embedding advanced research methodologies within programmatic frameworks at the design thinking stage, mHealth technologies can potentially become technically viable and effectively meet specific contact tracing health outcomes to inform policy effectively.

Replication, safety and immunogenicity of the vectored Ebola vaccine rVSV-ΔG-ZEBOV-GP in a sub-Saharan African paediatric population: A randomised controlled, open-label trial in children aged 1-12 years living in Lambaréné, Gabon.

BACKGROUND: Unlike adults, children experienced stronger and longer vector replication in plasma and shedding in saliva following rVSVΔG-ZEBOV-GP vaccination. The resulting risks of immunosuppression or immune hyperactivation leading to increased Adverse Events (AEs) and altered antibody responses are concerns that have been addressed in the present manuscript. METHODS: Children aged 1-12 years living in Gabon received either rVSVΔG-ZEBOV-GP (ERVEBO®) vaccine or the varicella-zoster virus (VZV) vaccine (VZV). The concentration of rVSVΔG vector in blood and saliva, the occurrence of AEs up to day 28; the anti-rVSVΔG-ZEBOV-GP and anti-VZV IgG antibody titres, neutralising and avidity functions of anti-rVSVΔG-ZEBOV-GP by day 365; were assessed in serum. (PACTR202005733552021) FINDINGS: In the rVSVΔG-ZEBOV-GP group, 70% and 7% of children had >0 copies/ml of rVSVΔG respectively in plasma by day 3 and in saliva by day 14 after vaccination, with no detection on day 28. Significantly higher but transient AEs occurred in the rVSVΔG-ZEBOV-GP group. Both vaccines induced seroconversion on day 28 and sustainable IgG antibody titres by day 365. Avidity and neutralisation functions of the anti-rVSVΔG-ZEBOV-GP antibodies peaked at day 28 and were maintained by day 365. INTERPRETATION: The replication and shedding do not affect the favourable risk-benefit balance of the rVSVΔG-ZEBOV-GP in children.

Afucosylated anti-EBOV antibody MIL77-3 engages sGP to elicit NK cytotoxicity.

MIL77-3 is one component of antibody cocktail that is produced in our lab and represents an effective regimen for animals suffering from Zaire Ebolavirus (EBOV) infection. MIL77-3 is engineered to increase its affinity for the FcγRIIIa (CD16a) by deleting the fucose in the framework region. The potential effects of this modification on host immune responses, however, remain largely unknown. Herein, we demonstrated that MIL77-3 recognized secreted glycoproptein (sGP), produced by EBOV, and formed the immunocomplex to potently augment antibody-dependent cytotoxicity of human peripheral blood-derived natural killer cells (pNKs), including CD56dim and CD56bright subpopulations, in contrast to the counterparts (Mab114, rEBOV548, fucosylated MIL77-3). Intriguingly, this effect was not observed when NK92-CD16a cell line was utilized and restored by the addition of beads-coupled or membrane-anchored sGP in combination with MIL77-3. Furthermore, sGP bound to unrecognized receptors on T cells contaminated in pNKs rather than NK92-CD16a cells. Administration of beads-coupled sGP/MIL77-3 complex in mice elicited NK activation. Overall, this work reveals an immune-stimulating function of sGP/MIL77-3 complex by triggering cytotoxic activity of NK cells, highlighting the necessity to evaluate the potential impact of MIL77-3 on host immune reaction in clinical trials. IMPORTANCE: Zaire Ebolavirus (EBOV) is highly lethal and causes sporadic outbreaks. The passive administration of monoclonal antibodies (mAbs) represents a promising treatment regimen against EBOV. Mounting evidence has shown that the efficacy of a subset of therapeutic mAbs in vivo is intimately associated with its capacity to trigger NK activity, supporting glycomodification of Fc region of anti-EBOV mAbs as a putative strategy to enhance Fc-mediated immune effector function as well as protection in vivo. Our work here uncovers the potential harmful influence of this modification on host immune responses, especially for mAbs with cross-reactivity to secreted glycoproptein (sGP) (e.g., MIL77-3), and highlights it is necessary to evaluate the NK-stimulating activity of a fucosylated mAb engaged with sGP when a new candidate is developed.

Assessment of prevalence and determinants of anxiety and psychological distress symptoms in Ebola child and adolescent survivors and orphans in Eastern Democratic Republic of the Congo during the COVID-19 pandemic.

BACKGROUND: To date, only three studies investigated the mental health of youth affected by Ebola virus disease (EVD). None explored anxiety and psychological distress symptoms in survivors or orphans. This study aimed to investigate the prevalence and determinants of anxiety and psychological distress symptoms among survivors and orphans of the 2018-2020 Ebola epidemic in Eastern Democratic Republic of the Congo (DRC) during the COVID-19 pandemic. METHODS: A representative sample of 416 participants (mean age = 13.37, SD = 2.79, 51.20 % girls, 146 survivors, 233 orphans, and 34 orphan-survivor participants) completed measures evaluating anxiety, psychological distress, exposure, resilience, stigmatization related to Ebola and COVID-19. RESULTS: 55.88 % and 55.96 % of survivors and orphans experienced severe symptoms of anxiety and psychological distress. Participants who were both survivors and orphans presented higher prevalence of anxiety and psychological distress (94.12 % and 100 %) compared to survivors (74.03 % and 81.82 %) or orphans (37.99 % and 33.33 %), χ2 = 70.63, p < .001; χ2 = 113.50, p < .001. Ebola and COVID-19 related stigmatization were the most important determinants of anxiety (B = 0.40, p < .001; B = 0.37, p < .001) and psychological distress (B = 0.48, p < .001; B = 0.44, p < .001). Resilience was negatively associated with both anxiety and psychological distress. The final regression models explained 49 % and 85 % of the variance of anxiety and psychological distress. LIMITATIONS: The cross-sectional design used prevents to establish causal link. CONCLUSIONS: Ebola children and adolescents' survivors and orphans are at major risk of experiencing anxiety and psychological distress in Eastern RDC affected by years of armed conflict. Massive resources are needed to develop and implement programs to reduce stigma and support mental health.

Fully human monoclonal antibodies against Ebola virus possess complete protection in a hamster model.

Ebola disease is a lethal viral hemorrhagic fever caused by ebolaviruses within the Filoviridae family with mortality rates of up to 90%. Monoclonal antibody (mAb) based therapies have shown great potential for the treatment of EVD. However, the potential emerging ebolavirus isolates and the negative effect of decoy protein on the therapeutic efficacy of antibodies highlight the necessity of developing novel antibodies to counter the threat of Ebola. Here, 11 fully human mAbs were isolated from transgenic mice immunized with GP protein and recombinant vesicular stomatitis virus-bearing GP (rVSV-EBOV GP). These mAbs were divided into five groups according to their germline genes and exhibited differential binding activities and neutralization capabilities. In particular, mAbs 8G6, 2A4, and 5H4 were cross-reactive and bound at least three ebolavirus glycoproteins. mAb 4C1 not only exhibited neutralizing activity but no cross-reaction with sGP. mAb 7D8 exhibited the strongest neutralizing capacity. Further analysis on the critical residues for the bindings of 4C1 and 8G6 to GPs was conducted using antibodies complementarity-determining regions (CDRs) alanine scanning. It has been shown that light chain CDR3 played a crucial role in binding and neutralization and that any mutation in CDRs could not improve the binding of 4C1 to sGP. Importantly, mAbs 7D8, 8G6, and 4C1 provided complete protections against EBOV infection in a hamster lethal challenge model when administered 12 h post-infection. These results support mAbs 7D8, 8G6, and 4C1 as potent antibody candidates for further investigations and pave the way for further developments of therapies and vaccines.

Hippo signaling pathway regulates Ebola virus transcription and egress.

Filovirus-host interactions play important roles in all stages of the virus lifecycle. Here, we identify LATS1/2 kinases and YAP, key components of the Hippo pathway, as critical regulators of EBOV transcription and egress. Specifically, we find that when YAP is phosphorylated by LATS1/2, it localizes to the cytoplasm (Hippo "ON") where it sequesters VP40 to prevent egress. In contrast, when the Hippo pathway is "OFF", unphosphorylated YAP translocates to the nucleus where it transcriptionally activates host genes and promotes viral egress. Our data reveal that LATS2 indirectly modulates filoviral VP40-mediated egress through phosphorylation of AMOTp130, a positive regulator of viral egress, but more surprisingly that LATS1/2 kinases directly modulate EBOV transcription by phosphorylating VP30, an essential regulator of viral transcription. In sum, our findings highlight the potential to exploit the Hippo pathway/filovirus axis for the development of host-oriented countermeasures targeting EBOV and related filoviruses.

Genome-wide CRISPR/Cas9 screen identifies SLC39A9 and PIK3C3 as crucial entry factors for Ebola virus infection.

The Ebola virus (EBOV) has emerged as a significant global health concern, notably during the 2013-2016 outbreak in West Africa. Despite the clinical approval of two EBOV antibody drugs, there is an urgent need for more diverse and effective antiviral drugs, along with comprehensive understanding of viral-host interactions. In this study, we harnessed a biologically contained EBOVΔVP30-EGFP cell culture model which could recapitulate the entire viral life cycle, to conduct a genome-wide CRISPR/Cas9 screen. Through this, we identified PIK3C3 (phosphatidylinositide 3-kinase) and SLC39A9 (zinc transporter) as crucial host factors for EBOV infection. Genetic depletion of SLC39A9 and PIK3C3 lead to reduction of EBOV entry, but not impact viral genome replication, suggesting that SLC39A9 and PIK3C3 act as entry factors, facilitating viral entry into host cells. Moreover, PIK3C3 kinase activity is indispensable for the internalization of EBOV virions, presumably through the regulation of endocytic and autophagic membrane traffic, which has been previously recognized as essential for EBOV internalization. Notably, our study demonstrated that PIK3C3 kinase inhibitor could effectively block EBOV infection, underscoring PIK3C3 as a promising drug target. Furthermore, biochemical analysis showed that recombinant SLC39A9 protein could directly bind viral GP protein, which further promotes the interaction of viral GP protein with cellular receptor NPC1. These findings suggests that SLC39A9 plays dual roles in EBOV entry. Initially, it serves as an attachment factor during the early entry phase by engaging with the viral GP protein. Subsequently, SLC39A9 functions an adaptor protein, facilitating the interaction between virions and the NPC1 receptor during the late entry phase, prior to cathepsin cleavage on the viral GP. In summary, this study offers novel insights into virus-host interactions, contributing valuable information for the development of new therapies against EBOV infection.

Prevalence of human filovirus infections in sub-Saharan Africa: A systematic review and meta-analysis protocol.

BACKGROUND: Recent outbreaks of Ebola virus disease (EVD) and Marburg virus disease (MVD) in sub-Saharan Africa illustrate the need to better understand animal reservoirs, burden of disease, and human transmission of filoviruses. This protocol outlines a systematic literature review to assess the prevalence of filoviruses that infect humans in sub-Saharan Africa. A secondary aim is to qualitatively describe and evaluate the assays used to assess prevalence. METHODS: The data sources for this systematic review include PubMed, Embase, and Web of Science. Titles, abstracts, and full texts will be reviewed for inclusion by a primary reviewer and then by a team of secondary reviewers, and data will be extracted using a pre-specified and piloted data extraction form. The review will include human cross-sectional studies, cohort studies, and randomized controlled trials conducted in sub-Saharan Africa up until March 13, 2024 that have been published in peer-reviewed scientific journals, with no language restrictions. Prevalence will be stratified by pathogen, population, assay, and sampling methodology and presented in forest plots with estimated prevalence and 95% confidence intervals. If there are enough studies within a stratum, I2 statistics will be calculated (using R statistical software), and data will be pooled if heterogeneity is low. In addition, assays used to detect infection will be evaluated. All studies included in the review will be assessed for quality and risk of bias using the JBI Prevalence Critical Appraisal Tool and for certainty using the GRADE certainty ratings. DISCUSSION: Accurately measuring the rate of exposure to filoviruses infecting humans in sub-Saharan Africa using prevalence provides an essential understanding of natural history, transmission, and the role of subclinical infection. This systematic review will identify research gaps and provide directions for future research seeking to improve our understanding of filovirus infections. Understanding the natural history, transmission, and the role of subclinical infection is critical for predicting the impact of an intervention on disease burden. SYSTEMATIC REVIEW REGISTRATION: In accordance with the guidelines outlined in the PRISMA-P methodology, this protocol was registered with PROSPERO on April 7, 2023 (ID: CRD42023415358).

Can global health security frameworks measure One Health implementation in West Africa?A mixed-methods study.

BACKGROUND: The 2014 outbreak of the Ebola virus disease highlighted the importance of overhauling and transforming healthcare systems in West Africa to improve the ability of individual countries to deal with infectious diseases. As part of this effort, in November 2016 the West African Health Organization (WAHO) began the process of institutionalizing the One Health (OH) approach to health security across the Economic Community of West African States (ECOWAS). The lack of clear metrics and evaluation frameworks to measure the progress of OH implementation in West Africa has been reported as a challenge. Therefore, this study sought to assess and explore whether the existing metrics of global health security frameworks can measure the successful implementation of OH activities, evaluate the progress made since 2016, and identify key areas for improvement in the region. METHOD: The study employed predetermined keywords to select indicators from the International Health Regulations (IHR) Monitoring Frameworks, specifically the State Party Self-Assessment Annual Report (SPAR) and Joint External Evaluation (JEE), deemed relevant to the OH approach. In addition, the COVID-19 performance index scores (severity and recovery) for June 2022 were extracted from the Global COVID-19 Index (GCI). The GCI Recovery Index evaluated the major recovery parameters reported daily to indicate how a country performed on the path to recovery from the COVID-19 pandemic compared to other countries. National documents were also analyzed using categorical variables to assess the performance status of OH platforms across implementing countries. A quantitative analysis of these indicators was conducted and supplemented with qualitative data gathered through interviews with key stakeholders. Between March and April 2022, we conducted 18 key informant interviews with purposively selected representatives from regional governmental agencies and international multilateral agencies, including ECOWAS member states. Interviews were conducted online, transcribed, and analysed following the tenets of thematic analysis. RESULTS: Our quantitative analysis revealed no significant association between the implementation status of OH activities and any of the selected indicators from SPAR and JEE. The descriptive analysis of the JEE scores at the country level revealed that countries with existing OH platforms scored relatively higher on the selected JEE indicators than other countries in the pre-implementation stage. OH implementation status did not significantly affect COVID-19 recovery and severity indices. The qualitative findings with relevant stakeholders revealed noteworthy challenges related to insufficient human capacity, inadequate coordination, and a lack of government funding for the sustainability of OH initiatives. Nonetheless, countries in the ECOWAS region are making progress toward the integration of OH into their health security systems. CONCLUSION: Standardized metrics were used to assess the implementation and efficacy of OH systems in the ECOWAS region. Current indicators for monitoring global health security frameworks lack specificity and fail to comprehensively capture essential OH components, particularly at the sub-national level. To ensure consistency and effectiveness across countries, OH implementation metrics that align with global frameworks such as IHR should be developed.

Beyond SIRD models: a novel dynamic model for epidemics, relating infected with entries to health care units and application for identification and restraining policy.

Epidemic models of susceptibles, exposed, infected, recovered and deceased (SΕIRD) presume homogeneity, constant rates and fixed, bilinear structure. They produce short-range, single-peak responses, hardly attained under restrictive measures. Tuned via uncertain I,R,D data, they cannot faithfully represent long-range evolution. A robust epidemic model is presented that relates infected with the entry rate to health care units (HCUs) via population averages. Model uncertainty is circumvented by not presuming any specific model structure, or constant rates. The model is tuned via data of low uncertainty, by direct monitoring: (a) of entries to HCUs (accurately known, in contrast to delayed and non-reliable I,R,D data) and (b) of scaled model parameters, representing population averages. The model encompasses random propagation of infections, delayed, randomly distributed entries to HCUs and varying exodus of non-hospitalized, as disease severity subdues. It closely follows multi-pattern growth of epidemics with possible recurrency, viral strains and mutations, varying environmental conditions, immunity levels, control measures and efficacy thereof, including vaccination. The results enable real-time identification of infected and infection rate. They allow design of resilient, cost-effective policy in real time, targeting directly the key variable to be controlled (entries to HCUs) below current HCU capacity. As demonstrated in ex post case studies, the policy can lead to lower overall cost of epidemics, by balancing the trade-off between the social cost of infected and the economic contraction associated with social distancing and mobility restriction measures.

Transport of Patients With High-Consequence Infectious Diseases: Development of European Capacity in Norway.

Infection of Western aid workers with Ebola virus disease during the 2014-2016 West African outbreak demonstrated the need for medical evacuation to high-level isolation units in Europe and the United States. In Norway, an ad hoc preparedness team was established for aeromedical evacuation in case of need. In October 2014, this team transported an infected aid worker from the military section of Oslo Airport to Oslo University Hospital. To maintain and strengthen the capacity for domestic ambulance transport on the ground and in the air, the Norwegian Medical Emergency Response Team for High Consequence Infectious Diseases (in Norway known as "Nasjonalt medisinsk utrykningsteam for høyrisikosmitte"), or NORTH, was established as a permanent service in 2017. Recognizing the expertise of this domestic team, Norway was subsequently entrusted with the task of enhancing the European aeromedical transport capacity for high-consequence infectious diseases and establishing the Norwegian rescEU Jet Air Ambulance for Transport of Highly Infectious Patients, or NOJAHIP, in 2022. In this case study, we present experiences and lessons learned from these 2 services and discuss how they can be further developed.

Feasibility Assessment of a Novel Isolation Care Tent in Uganda During the 2022 Sudan ebolavirus Outbreak.

This case study describes a feasibility assessment of a novel isolation care tent used in health facilities in Uganda during the 2022 Sudan ebolavirus outbreak. The Isolation System for Treatment and Agile Response to High-Risk Infections Model 1B (ISTARI 1B) is a single-occupancy, portable, negative-pressure isolation tent designed for the safe delivery of standard care to patients with a communicable disease, including Ebola disease (Sudan). At the request of the Uganda Ministry of Health, the Makerere University Infectious Diseases Institute and University of Nebraska Medical Center partnered to evaluate 7 health facilities across 4 districts in Uganda for infrastructure, case management, and infection prevention and control (IPC) capacity relevant to isolation care and ISTARI 1B use. A 3-day workshop was held with IPC leaders to provide familiarization and hands-on experience with the ISTARI 1B, delineate appropriate use scenarios in Ugandan healthcare settings, contextualize ISTARI 1B use in case management and IPC workflows, develop a framework for site assessment and implementation readiness, and consider ongoing monitoring, assessment, and intervention tools. Workshop participants performed a comprehensive site assessment and mock deployment of the ISTARI 1B. In this case study, we describe lessons learned from health facility assessments and workshop outcomes and offer recommendations to support successful ISTARI 1B implementation. Use scenarios and implementation strategies were identified across facility levels, including tools for site assessment, training, risk communication, and ongoing quality and safety monitoring.

Non-Ebola Filoviruses: Potential Threats to Global Health Security.

Filoviruses are negative-sense single-stranded RNA viruses often associated with severe and highly lethal hemorrhagic fever in humans and nonhuman primates, with case fatality rates as high as 90%. Of the known filoviruses, Ebola virus (EBOV), the prototype of the genus Orthoebolavirus, has been a major public health concern as it frequently causes outbreaks and was associated with an unprecedented outbreak in several Western African countries in 2013-2016, affecting 28,610 people, 11,308 of whom died. Thereafter, filovirus research mostly focused on EBOV, paying less attention to other equally deadly orthoebolaviruses (Sudan, Bundibugyo, and Taï Forest viruses) and orthomarburgviruses (Marburg and Ravn viruses). Some of these filoviruses have emerged in nonendemic areas, as exemplified by four Marburg disease outbreaks recorded in Guinea, Ghana, Tanzania, and Equatorial Guinea between 2021 and 2023. Similarly, the Sudan virus has reemerged in Uganda 10 years after the last recorded outbreak. Moreover, several novel bat-derived filoviruses have been discovered in the last 15 years (Lloviu virus, Bombali virus, Menglà virus, and Dehong virus), most of which are poorly characterized but may display a wide host range. These novel viruses have the potential to cause outbreaks in humans. Several gaps are yet to be addressed regarding known and emerging filoviruses. These gaps include the virus ecology and pathogenicity, mechanisms of zoonotic transmission, host range and susceptibility, and the development of specific medical countermeasures. In this review, we summarize the current knowledge on non-Ebola filoviruses (Bombali virus, Bundibugyo virus, Reston virus, Sudan virus, Tai Forest virus, Marburg virus, Ravn virus, Lloviu virus, Menglà virus, and Dehong virus) and suggest some strategies to accelerate specific countermeasure development.

Healthcare Providers' and Frontline Workers' Experiences of an Ebola Vaccine Trial in the Boende Health District of the Democratic Republic of the Congo.

This study explored the experiences of healthcare providers (HCPs) and frontline workers who were involved in an Ebola vaccine trial in the Democratic Republic of the Congo. The researchers interviewed a total of 99 participants (HCPs and frontline workers) living and working in the Boende health district during the period of the study, from February to March 2022. These individuals included a mix of trial participants and non-trial participants (staff of the trial, local health authorities, and head nurses of health centers). In-depth individual interviews, as well as focus group discussions (FGDs), were used to understand interviewees' experiences and perceptions. The data were analyzed to identify the main themes. The findings unveiled a multitude of positive experiences among interviewees/FGD participants. The commitment of the trial investigators to improve the study site and to equip the volunteers with necessary skills and knowledge greatly contributed to a positive trial experience. However, some interviewees felt that the reimbursement for time and travel expenses during their trial visits was insufficient in comparison with their expectations. Additionally, there were expressions of worry about the frequency of blood draws during scheduled trial visits. Our findings emphasize the critical importance of addressing and continuously considering the perspectives and concerns of trial participants before designing and implementing vaccine trials. By actively incorporating their inputs, researchers can mitigate concerns and tailor communication strategies, potentially enhancing the overall success and impact of the vaccine trial.

Comparison of Routes of Administration, Frequency, and Duration of Favipiravir Treatment in Mouse and Guinea Pig Models of Ebola Virus Disease.

Favipiravir is a ribonucleoside analogue that has been explored as a therapeutic for the treatment of Ebola Virus Disease (EVD). Promising data from rodent models has informed nonhuman primate trials, as well as evaluation in patients during the 2013-2016 West African EVD outbreak of favipiravir treatment. However, mixed results from these studies hindered regulatory approval of favipiravir for the indication of EVD. This study examined the influence of route of administration, duration of treatment, and treatment schedule of favipiravir in immune competent mouse and guinea pig models using rodent-adapted Zaire ebolavirus (EBOV). A dose of 300 mg/kg/day of favipiravir with an 8-day treatment was found to be fully effective at preventing lethal EVD-like disease in BALB/c mice regardless of route of administration (oral, intraperitoneal, or subcutaneous) or whether it was provided as a once-daily dose or a twice-daily split dose. Preclinical data generated in guinea pigs demonstrates that an 8-day treatment of 300 mg/kg/day of favipiravir reduces mortality following EBOV challenge regardless of route of treatment or duration of treatments for 8, 11, or 15 days. This work supports the future translational development of favipiravir as an EVD therapeutic.