Rhabdomyolysis, acute kidney injury, and mortality in Ebola virus disease: retrospective analysis of cases from Eastern Democratic Republic of the Congo, 2019.

BACKGROUND: Skeletal muscle injury in Ebola virus disease (EVD) has been reported, but its association with morbidity and mortality remains poorly defined. METHODS: Retrospective study of patients admitted to two EVD Treatment Units, over an eight-month period in 2019, during a large EVD epidemic in the Democratic Republic of the Congo. RESULTS: 333 patients (median age 30 years, 58% female) had at least one creatine kinase (CK) measurement (total 2,229 CK measurements, median 5 (IQR 1-11) per patient). 271 patients (81%) had an elevated CK (>380U/L), 202 (61%) had rhabdomyolysis (CK>1,000 IU/L), and 45 (14%) had severe rhabdomyolysis (≥5,000U/L). Among survivors, the maximum CK level was median 1,600 (IQR 550 to 3,400), peaking 3.4 days after admission (IQR 2.3 to 5.5) and decreasing thereafter. Among fatal cases, the CK rose monotonically until death, with maximum CK level of median 2,900 U/L (IQR 1,500 to 4,900). Rhabdomyolysis at admission was an independent predictor of AKI (aOR 2.2 [95%CI 1.2-3.8], p=0.0065) and mortality (aHR 1.7 [95%CI 1.03-2.9], p=0.037). CONCLUSIONS: Rhabdomyolysis is associated with AKI and mortality in EVD patients. These findings may inform clinical practice by identifying lab monitoring priorities and highlighting the importance of fluid management.

Ebola Virus Transmission Initiated by Relapse of Systemic Ebola Virus Disease.

During the 2018-2020 Ebola virus disease (EVD) outbreak in North Kivu province in the Democratic Republic of Congo, EVD was diagnosed in a patient who had received the recombinant vesicular stomatitis virus-based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) (Merck). His treatment included an Ebola virus (EBOV)-specific monoclonal antibody (mAb114), and he recovered within 14 days. However, 6 months later, he presented again with severe EVD-like illness and EBOV viremia, and he died. We initiated epidemiologic and genomic investigations that showed that the patient had had a relapse of acute EVD that led to a transmission chain resulting in 91 cases across six health zones over 4 months. (Funded by the Bill and Melinda Gates Foundation and others.).

A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.

BACKGROUND: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. RESULTS: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. CONCLUSIONS: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

A platform trial design for preventive vaccines against Marburg virus and other emerging infectious disease threats.

BACKGROUND: The threat of a possible Marburg virus disease outbreak in Central and Western Africa is growing. While no Marburg virus vaccines are currently available for use, several candidates are in the pipeline. Building on knowledge and experiences in the designs of vaccine efficacy trials against other pathogens, including SARS-CoV-2, we develop designs of randomized Phase 3 vaccine efficacy trials for Marburg virus vaccines. METHODS: A core protocol approach will be used, allowing multiple vaccine candidates to be tested against controls. The primary objective of the trial will be to evaluate the effect of each vaccine on the rate of virologically confirmed Marburg virus disease, although Marburg infection assessed via seroconversion could be the primary objective in some cases. The overall trial design will be a mixture of individually and cluster-randomized designs, with individual randomization done whenever possible. Clusters will consist of either contacts and contacts of contacts of index cases, that is, ring vaccination, or other transmission units. RESULTS: The primary efficacy endpoint will be analysed as a time-to-event outcome. A vaccine will be considered successful if its estimated efficacy is greater than 50% and has sufficient precision to rule out that true efficacy is less than 30%. This will require approximately 150 total endpoints, that is, cases of confirmed Marburg virus disease, per vaccine/comparator combination. Interim analyses will be conducted after 50 and after 100 events. Statistical analysis of the trial will be blended across the different types of designs. Under the assumption of a 6-month attack rate of 1% of the participants in the placebo arm for both the individually and cluster-randomized populations, the most likely sample size is about 20,000 participants per arm. CONCLUSION: This event-driven design takes into the account the potentially sporadic spread of Marburg virus. The proposed trial design may be applicable for other pathogens against which effective vaccines are not yet available.

Serologic Evidence of Ebolavirus Infection in a Population With No History of Outbreaks in the Democratic Republic of the Congo.

Background: Previous studies suggest that cases of Ebola virus disease (EVD) may go unreported because they are asymptomatic or unrecognized, but evidence is limited by study designs and sample size. Methods: A large population-based survey was conducted (n = 3415) to assess animal exposures and behaviors associated with Ebolavirus antibody prevalence in rural Kasai Oriental province of the Democratic Republic of Congo (DRC). Fourteen villages were randomly selected and all healthy individuals ≥1 year of age were eligible. Results: Overall, 11% of subjects tested positive for Zaire Ebolavirus (EBOV) immunoglobulin G antibodies. Odds of seropositivity were higher for study participants older than 15 years of age and for males. Those residing in Kole (closer to the outbreak site) tested positive at a rate 1.6× higher than Lomela, with seropositivity peaking at a site located between Kole and Lomela. Multivariate analyses of behaviors and animal exposures showed that visits to the forest or hunting and exposure to rodents or duikers predicted a higher likelihood of EBOV seropositivity. Conclusions: These results provide serologic evidence of Ebolavirus exposure in a population residing in non-EBOV outbreak locations in the DRC and define statistically significant activities and animal exposures that associate with EBOV seropositivity.

High prevalence of IgG antibodies to Ebola virus in the Efé pygmy population in the Watsa region, Democratic Republic of the Congo.

BACKGROUND: Factors related to the natural transmission of Ebola virus (EBOV) to humans are still not well defined. Results of previous sero-prevalence studies suggest that circulation of EBOV in human population is common in sub-Saharan Africa. The Efé pygmies living in Democratic Republic of the Congo are known to be exposed to potential risk factors of EBOV infection such as bush meat hunting, entry into caves, and contact with bats. We studied the pygmy population of Watsa region to determine seroprevalence to EBOV infection and possible risks factors. METHOD: Volunteer participants (N = 300) aged 10 years or above were interviewed about behavior that may constitute risk factors for transmission of EBOV, including exposures to rats, bats, monkeys and entry into caves. Samples of venous blood were collected and tested for IgG antibody against EBOV by enzyme-linked immunosorbent assay (ELISA). The χ2-test and Fisher's exact test were used for the comparison of proportions and the Student's t-test to compare means. The association between age group and anti-EBOV IgG prevalence was analysed by a nonparametric test for trend. RESULTS: The prevalence of anti-EBOV IgG was 18.7 % overall and increased significantly with age (p = 0.023). No association was observed with exposure to risk factors (contacts with rats, bats, monkeys, or entry into caves). CONCLUSIONS: The seroprevalence of IgG antibody to EBOV in pygmies in Watsa region is among the highest ever reported, but it remains unclear which exposures might lead to this high infection rate calling for further ecological and behavioural studies.

Safety and immunogenicity of DNA vaccines encoding Ebolavirus and Marburgvirus wild-type glycoproteins in a phase I clinical trial.

BACKGROUND: Ebolavirus and Marburgvirus cause severe hemorrhagic fever with high mortality and are potential bioterrorism agents. There are no available vaccines or therapeutic agents. Previous clinical trials evaluated transmembrane-deleted and point-mutation Ebolavirus glycoproteins (GPs) in candidate vaccines. Constructs evaluated in this trial encode wild-type (WT) GP from Ebolavirus Zaire and Sudan species and the Marburgvirus Angola strain expressed in a DNA vaccine. METHODS: The VRC 206 study evaluated the safety and immunogenicity of these DNA vaccines (4 mg administered intramuscularly by Biojector) at weeks 0, 4, and 8, with a homologous boost at or after week 32. Safety evaluations included solicited reactogenicity and coagulation parameters. Primary immune assessment was done by means of GP-specific enzyme-linked immunosorbent assay. RESULTS: The vaccines were well tolerated, with no serious adverse events; 80% of subjects had positive enzyme-linked immunosorbent assay results (≥30) at week 12. The fourth DNA vaccination boosted the immune responses. CONCLUSIONS: The investigational Ebolavirus and Marburgvirus WT GP DNA vaccines were safe, well tolerated, and immunogenic in this phase I study. These results will further inform filovirus vaccine research toward a goal of inducing protective immunity by using WT GP antigens in candidate vaccine regimens. CLINICAL TRIALS REGISTRATION: NCT00605514.

Exploring host-virus interaction to improve immunotherapy against Ebola virus.

Recent immunological advances have led to the development of FDA-approved immunotherapies against Ebola virus (EBOV). However, patients with high viral loads have not seen as large a benefit as mild cases. Here we discuss areas of investigation that may lead to adjunctive immune therapy for patients with severe EBOV disease.

The prophylactic and therapeutic efficacy of the broadly active antiviral ribonucleoside N4-Hydroxycytidine (EIDD-1931) in a mouse model of lethal Ebola virus infection.

The unprecedented magnitude of the 2013-2016 Ebola virus (EBOV) epidemic in West Africa resulted in over 11 000 deaths and spurred an international public health emergency. A second outbreak in 2018-2020 in DRC resulted in an additional >3400 cases and nearly 2300 deaths (WHO, 2020). These large outbreaks across geographically diverse regions highlight the need for the development of effective oral therapeutic agents that can be easily distributed for self-administration to populations with active disease or at risk of infection. Herein, we report the in vivo efficacy of N4-hydroxycytidine (EIDD-1931), a broadly active ribonucleoside analog and the active metabolite of the prodrug EIDD-2801 (molnupiravir), in murine models of lethal EBOV infection. Twice daily oral dosing with EIDD-1931 at 200 mg/kg for 7 days, initiated either with a prophylactic dose 2 h before infection, or as therapeutic treatment starting 6 h post-infection, resulted in 92-100% survival of mice challenged with lethal doses of EBOV, reduced clinical signs of Ebola virus disease (EVD), reduced serum virus titers, and facilitated weight loss recovery. These results support further investigation of molnupiravir as a potential therapeutic or prophylactic treatment for EVD.

The Human Mpox Global Outbreak: Available Control Tools and the Opportunity to Break a Cycle of Neglect in Endemic Countries.

The 2022 global outbreak of human Mpox (formerly monkeypox) virus (MPXV) infection outside of the usual endemic zones in Africa challenged our understanding of the virus's natural history, transmission dynamics, and risk factors. This outbreak has highlighted the need for diagnostics, vaccines, therapeutics, and implementation research, all of which require more substantial investments in equitable collaborative partnerships. Global multidisciplinary networks need to tackle MPXV and other neglected emerging and reemerging zoonotic pathogens to address them locally and prevent or quickly control their worldwide spread. Political endorsement from individual countries and financial commitments to maintain control efforts will be essential for long-term sustainability.

Cost-effectiveness of incorporating Ebola prediction score tools and rapid diagnostic tests into a screening algorithm: A decision analytic model.

BACKGROUND: No distinctive clinical signs of Ebola virus disease (EVD) have prompted the development of rapid screening tools or called for a new approach to screening suspected Ebola cases. New screening approaches require evidence of clinical benefit and economic efficiency. As of now, no evidence or defined algorithm exists. OBJECTIVE: To evaluate, from a healthcare perspective, the efficiency of incorporating Ebola prediction scores and rapid diagnostic tests into the EVD screening algorithm during an outbreak. METHODS: We collected data on rapid diagnostic tests (RDTs) and prediction scores' accuracy measurements, e.g., sensitivity and specificity, and the cost of case management and RDT screening in EVD suspect cases. The overall cost of healthcare services (PPE, procedure time, and standard-of-care (SOC) costs) per suspected patient and diagnostic confirmation of EVD were calculated. We also collected the EVD prevalence among suspects from the literature. We created an analytical decision model to assess the efficiency of eight screening strategies: 1) Screening suspect cases with the WHO case definition for Ebola suspects, 2) Screening suspect cases with the ECPS at -3 points of cut-off, 3) Screening suspect cases with the ECPS as a joint test, 4) Screening suspect cases with the ECPS as a conditional test, 5) Screening suspect cases with the WHO case definition, then QuickNavi™-Ebola RDT, 6) Screening suspect cases with the ECPS at -3 points of cut-off and QuickNavi™-Ebola RDT, 7) Screening suspect cases with the ECPS as a conditional test and QuickNavi™-Ebola RDT, and 8) Screening suspect cases with the ECPS as a joint test and QuickNavi™-Ebola RDT. We performed a cost-effectiveness analysis to identify an algorithm that minimizes the cost per patient correctly classified. We performed a one-way and probabilistic sensitivity analysis to test the robustness of our findings. RESULTS: Our analysis found dual ECPS as a conditional test with the QuickNavi™-Ebola RDT algorithm to be the most cost-effective screening algorithm for EVD, with an effectiveness of 0.86. The cost-effectiveness ratio was 106.7 USD per patient correctly classified. The following algorithms, the ECPS as a conditional test with an effectiveness of 0.80 and an efficiency of 111.5 USD per patient correctly classified and the ECPS as a joint test with the QuickNavi™-Ebola RDT algorithm with an effectiveness of 0.81 and a cost-effectiveness ratio of 131.5 USD per patient correctly classified. These findings were sensitive to variations in the prevalence of EVD in suspected population and the sensitivity of the QuickNavi™-Ebola RDT. CONCLUSIONS: Findings from this study showed that prediction scores and RDT could improve Ebola screening. The use of the ECPS as a conditional test algorithm and the dual ECPS as a conditional test and then the QuickNavi™-Ebola RDT algorithm are the best screening choices because they are more efficient and lower the number of confirmation tests and overall care costs during an EBOV epidemic.

Recombinant adenovirus serotype 26 (Ad26) and Ad35 vaccine vectors bypass immunity to Ad5 and protect nonhuman primates against ebolavirus challenge.

The use of adenoviruses (Ad) as vaccine vectors against a variety of pathogens has demonstrated their capacity to elicit strong antibody and cell-mediated immune responses. Adenovirus serotype C vectors, such as Ad serotype 5 (Ad5), expressing Ebolavirus (EBOV) glycoprotein (GP), protect completely after a single inoculation at a dose of 10(10) viral particles. However, the clinical application of a vaccine based on Ad5 vectors may be hampered, since impairment of Ad5 vaccine efficacy has been demonstrated for humans and nonhuman primates with high levels of preexisting immunity to the vector. Ad26 and Ad35 segregate genetically from Ad5 and exhibit lower seroprevalence in humans, making them attractive vaccine vector alternatives. In the series of studies presented, we show that Ad26 and Ad35 vectors generate robust antigen-specific cell-mediated and humoral immune responses against EBOV GP and that Ad5 immune status does not affect the generation of GP-specific immune responses by these vaccines. We demonstrate partial protection against EBOV by a single-shot Ad26 vaccine and complete protection when this vaccine is boosted by Ad35 1 month later. Increases in efficacy are paralleled by substantial increases in T- and B-cell responses to EBOV GP. These results suggest that Ad26 and Ad35 vectors warrant further development as candidate vaccines for EBOV.

Demonstration of cross-protective vaccine immunity against an emerging pathogenic Ebolavirus Species.

A major challenge in developing vaccines for emerging pathogens is their continued evolution and ability to escape human immunity. Therefore, an important goal of vaccine research is to advance vaccine candidates with sufficient breadth to respond to new outbreaks of previously undetected viruses. Ebolavirus (EBOV) vaccines have demonstrated protection against EBOV infection in nonhuman primates (NHP) and show promise in human clinical trials but immune protection occurs only with vaccines whose antigens are matched to the infectious challenge species. A 2007 hemorrhagic fever outbreak in Uganda demonstrated the existence of a new EBOV species, Bundibugyo (BEBOV), that differed from viruses covered by current vaccine candidates by up to 43% in genome sequence. To address the question of whether cross-protective immunity can be generated against this novel species, cynomolgus macaques were immunized with DNA/rAd5 vaccines expressing ZEBOV and SEBOV glycoprotein (GP) prior to lethal challenge with BEBOV. Vaccinated subjects developed robust, antigen-specific humoral and cellular immune responses against the GP from ZEBOV as well as cellular immunity against BEBOV GP, and immunized macaques were uniformly protected against lethal challenge with BEBOV. This report provides the first demonstration of vaccine-induced protective immunity against challenge with a heterologous EBOV species, and shows that Ebola vaccines capable of eliciting potent cellular immunity may provide the best strategy for eliciting cross-protection against newly emerging heterologous EBOV species.

Development of Ebola virus disease prediction scores: Screening tools for Ebola suspects at the triage-point during an outbreak.

BACKGROUND: The control of Ebola virus disease (EVD) outbreaks relies on rapid diagnosis and prompt action, a daunting task in limited-resource contexts. This study develops prediction scores that can help healthcare workers improve their decision-making at the triage-point of EVD suspect-cases during EVD outbreaks. METHODS: We computed accuracy measurements of EVD predictors to assess their diagnosing ability compared with the reference standard GeneXpert® results, during the eastern DRC EVD outbreak. We developed predictive scores using the Spiegelhalter-Knill-Jones approach and constructed a clinical prediction score (CPS) and an extended clinical prediction score (ECPS). We plotted the receiver operating characteristic curves (ROCs), estimated the area under the ROC (AUROC) to assess the performance of scores, and computed net benefits (NB) to assess the clinical utility (decision-making ability) of the scores at a given cut-off. We performed decision curve analysis (DCA) to compare, at a range of threshold probabilities, prediction scores' decision-making ability and to quantify the number of unnecessary isolation. RESULTS: The analysis was done on data from 10432 subjects, including 651 EVD cases. The EVD prevalence was 6.2% in the whole dataset, 14.8% in the subgroup of suspects who fitted the WHO Ebola case definition, and 3.2% for the set of suspects who did not fit this case definition. The WHO clinical definition yielded 61.6% sensitivity and 76.4% specificity. Fatigue, difficulty in swallowing, red eyes, gingival bleeding, hematemesis, confusion, hemoptysis, and a history of contact with an EVD case were predictors of EVD. The AUROC for ECPS was 0.88 (95%CI: 0.86-0.89), significantly greater than this for CPS, 0.71 (95%CI: 0.69-0.73) (p < 0.0001). At -1 point of score, the CPS yielded a sensitivity of 85.4% and specificity of 42.3%, and the ECPS yielded sensitivity of 78.8% and specificity of 81.4%. The diagnostic performance of the scores varied in the three disease contexts (the whole, fitting or not fitting the WHO case definition data sets). At 10% of threshold probability, e.g. in disease-adverse context, ECPS gave an NB of 0.033 and a net reduction of unnecessary isolation of 67.1%. Using ECPS as a joint approach to isolate EVD suspects reduces the number of unnecessary isolations by 65.7%. CONCLUSION: The scores developed in our study showed a good performance as EVD case predictors since their use improved the net benefit, i.e., their clinical utility. These rapid and low-cost tools can help in decision-making to isolate EVD-suspicious cases at the triage point during an outbreak. However, these tools still require external validation and cost-effectiveness evaluation before being used on a large scale.

Development of the PREDS score to predict in-hospital mortality of patients with Ebola virus disease under advanced supportive care: Results from the EVISTA cohort in the Democratic Republic of the Congo.

Background: As mortality remains high for patients with Ebola virus disease (EVD) despite new treatment options, the ability to level up the provided supportive care and to predict the risk of death is of major importance. This analysis of the EVISTA cohort aims to describe advanced supportive care provided to EVD patients in the Democratic Republic of the Congo (DRC) and to develop a simple risk score for predicting in-hospital death, called PREDS. Methods: In this prospective cohort (NCT04815175), patients were recruited during the 10th EVD outbreak in the DRC across three Ebola Treatment Centers (ETCs). Demographic, clinical, biological, virological and treatment data were collected. We evaluated factors known to affect the risk of in-hospital death and applied univariate and multivariate Cox proportional-hazards analyses to derive the risk score in a training dataset. We validated the score in an internal-validation dataset, applying C-statistics as a measure of discrimination. Findings: Between August 1st 2018 and December 31th 2019, 711 patients were enrolled in the study. Regarding supportive care, patients received vasopressive drug (n = 111), blood transfusion (n = 101), oxygen therapy (n = 250) and cardio-pulmonary ultrasound (n = 15). Overall, 323 (45%) patients died before day 28. Six independent prognostic factors were identified (ALT, creatinine, modified NEWS2 score, viral load, age and symptom duration). The final score range from 0 to 13 points, with a good concordance (C = 86.24%) and calibration with the Hosmer-Lemeshow test (p = 0.12). Interpretation: The implementation of advanced supportive care is possible for EVD patients in emergency settings. PREDS is a simple, accurate tool that could help in orienting early advanced care for at-risk patients after external validation. Funding: This study was funded by ALIMA.

Virus kinetics and biochemical derangements among children with Ebolavirus disease.

Background: A paucity of data is available on virologic and biochemical characteristics of paediatric Ebolavirus disease (EVD), compared to adults. Methods: We conducted a retrospective chart review of children (<16 years old) and a comparator group of young adults (16-44 years) from two treatment centres during the 2018-2020 EVD epidemic in Eastern Democratic Republic of the Congo. Statistical methods included chi-squared and Fisher's exact tests (dichotomous and categorical variables), Mann-Whitney U-test (continuous variables), multivariable linear regression (for determinants of admission viral load), linear mixed-effects models (for analysis of longitudinal viral load), and Cox proportional hazard models (to examine risk factors for mortality). Findings: We included 73 children and 234 adults admitted from April to October 2019. Paediatric patients commonly had electrolytes imbalances: hypokalaemia in 26/73 (36%), hyperkalaemia in 38/73 (52%), and hyponatraemia in 54/73 (74%). Hypoglycaemia occurred in 20/73 (27%), acute kidney injury in 43/73 (59%), and rhabdomyolysis in 35/73 (48%). Biochemical abnormalities were detected in a similar proportion of children and adults. The viral load (VL, log10 copies/mL) at admission (7.2 versus 6.5, p=0.0001), the peak viral load (7.5 versus 6.7, p=<0.0001), and the time for viraemia clearance (16 days versus 12 days, p=<0.0001) were significantly different in children. The duration of hospital stay was prolonged in children (20 versus 16 days, p=<0.0001). Risk factors for mortality in children were: VL >7.6 log10copies/mL, alanine transaminase >525 U/L, C-reactive protein >100 mg/L, blood urea nitrogen >7.5 mmol/L, rhabdomyolysis, and.acute kidney injury. Interpretation: Paediatric EVD patients, like adults, experience multiorgan dysfunction with life-threatening electrolyte imbalances, hypoglycaemia, kidney injury, liver injury, and rhabdomyolysis. Paediatric patients have significantly higher VLs throughout the course of EVD than adults. Funding: This study was not funded.

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.