Ebola virus disease (EVD) is a life-threatening disease caused by Ebola virus (EBOV; Zaire ebolavirus).
Viruses of the genus Ebolavirus (of the family Filoviridae) can cause life-threatening disease. To date, six filoviruses have been discovered in humans, four in the genus Ebolavirus (Bundibugyo virus, EBOV, Sudan virus and Tai Forest virus) (1). The remaining two human filoviruses belong to the genus Marburgvirus (Marburg virus and Ravn virus). EBOV causes outbreaks of EVD, historically the most severe and most frequent (2). This guidance, due to the evidence available, is directed only to the treatment of EVD, the disease caused by EBOV (Zaire ebolavirus).
During early EVD, patients present with a non-specific febrile illness, followed by gastrointestinal signs and symptoms that frequently lead to hypovolaemia, metabolic acidosis, hypoglycaemia and multi-organ failure (2). EVD (6,7). This guideline aims to summarize high-quality evidence for EVD therapeutics and make recommendations for their use.

# Methods: how this guideline was created
This WHO guideline was developed according to standards and methods for trustworthy guidelines, aligned with the WHO Handbook for guideline development, 2nd edition (8), and according to a pre-approved protocol by the Guideline Review Committee (GRC). The guideline development process utilized the GRADE methodology (9).
Step 1: Convening the Therapeutics for Ebola virus disease Guideline Development Group
WHO selected GDG members to ensure global geographical representation, gender balance, appropriate technical and clinical expertise, and patient representation. The technical unit collected and managed DOIs. In addition to the distribution of a DOI form, during the meeting, the WHO Secretariat described the DOI process and provided an opportunity for GDG members to declare any interests not provided in written form. Web searches did not identify any additional interests that could be perceived to affect an individual's objectivity and independence during the development of the recommendations. No GDG member was judged to have a significant conflict of interest.
Biographies of GDG members were posted on 10 November 2021 and can be found online 3.
The pre-selected expert GDG convened on two occasions: the first meeting, held on 17 November 2021, introduced the members of the GDG to the WHO guideline development process and explained GRADE methodology. The GDG was tasked to review and finalize the research question (population, intervention, comparator, outcomes; decide on which possible population subgroup hypotheses to explore; select therapeutic interventions of interest; consider variation in the standard of care comparator; and prioritize patient important outcomes. The GDG agreed to only consider RCT-level evidence in the evidence synthesis. A full report of the first GDG meeting can be found online (10).
Step 2: Finalizing the research question (population, intervention, comparator, and outcomes)
The GDG agreed that the overarching population would be all patients with RT-PCR confirmed EVD.
The GDG specified population subgroups of interest (see Table 1). The number of subgroups was limited to a maximum of five to avoid undermining the credibility of any apparent subgroup effect detected. Analyses addressed only subgroups with a clear pre-specified direction of effect. The table shows the pre-specified risk of mortality and the postulated direction of the effect.

# Risk of mortality by category Postulated direction of effect

# Table 1. Population subgroups and pre-specified direction of effect
The GDG suggested the following therapeutics to be included in the research question: antiviral agents, neutralizing monoclonal antibodies, convalescent plasma, anti-inflammatories, corticosteroids, anti-tumor necrosis factor (anti-TNF), interleukin-6 (IL-6) receptor blockers, blood products, endothelial stabilization agents (Fx06), interferon, antimalarials and antifibrinolytics.
The GDG acknowledged large heterogeneity in the standard of care and CFR for EVD by location, between outbreaks, and over time. This limitation was noted and is discussed in the limitations section (Section 5). Acknowledging the heterogeneity in available standard of care and in the related CFR of EVD outbreaks, the Steering Committee included two baseline risk estimates for mortality in the network meta-analysis (NMA). The group utilized the lowest and highest CFRs in outbreaks with no fewer than 100 diagnosed cases since 2013 reported by WHO (11). The lowest baseline risk estimate of 39.5% CFR was derived from the 2013-2016, West African EVD outbreak and the highest baseline risk estimate of 66% CFR was derived from the 2018-2020 Democratic Republic of the Congo and Uganda outbreak.
The GDG developed a list of 13 outcomes of interest to patients, families and health care providers. Outcomes were then prioritized through an online survey. The online survey was sent to 38 participants of the WHO Steering Committee and GDG members. The survey was also sent to five recovered EVD patients in Sierra Leone and five recovered EVD patients in the Democratic Republic of the Congo. Participants rated each outcome from 1 to 9: 7 to 9 as critically important, 4 to 6 as important, and 1 to 3 as of limited importance. The survey was provided in both French and English.

# Outcome prioritization results
A total of 25/38 (66%) GDG and WHO Steering Committee members completed the survey, and 10/10 (100%) of EVD patients completed the survey. There were no partial or incomplete responses, and no apparent evidence of scale inversion. Survey results were compiled centrally, the results are displayed as mean (standard deviation) in Table 2.
Four outcomes were ranked in the top five by both the GDG and WHO Steering Committee and EVD patients: mortality, adverse maternal outcomes, duration of admission and risk of onward transmission. The GDG included serious adverse effects in their top five, whilst EVD patients included functional status post-EVD. EVD patients reported higher overall mean prioritization scores than GDG members. All outcomes with a score  6.5 as ranked by all participants were included in the systematic review search strategy.
These steps led to the generation of a final PICO, displayed in Table 3. Step 3: Evidence synthesis and GRADE
Based on the final PICO in Table 3, the systematic review team, as requested by the GDG, performed an independent systematic review. The systematic review team included systematic review experts, clinical experts, clinical epidemiologists and biostatisticians. Team members had expertise in GRADE methodology and rating certainty of evidence specifically in NMAs. The systematic review team considered deliberations from the initial GDG meeting, specifically focusing on the outcomes and subgroups prioritized by the GDG. The methods team rated credibility of subgroups using the ICEMAN tool (12). The systematic review methods and results are published in Lancet Microbe DOI: . org/10.1016/S2666-5247(22)00123-9 (13). From the meta-analysis results summary of the evidence was GRADED with the WHO core EVD Steering Committee, clinical co-chairs and GDG methodologist.
The following criteria were used to standardize the GRADE process: Certainty of the evidence was rated according to an effect greater or less than the minimally important difference. These were determined as: -Mortality: 10 per 1000 -Serious adverse events: 20 per 1000 -Time to viral clearance: 1 day -Duration of admission: 1 day. Certainty of the evidence was rated down 1 level for imprecision if the 95% CI lower limit or higher limit crossed the threshold. Certainty of the evidence was rated down 2 levels for imprecision if the 95% CI lower limit and higher limit both crossed the threshold of both important harm and important benefit. Certainty of the evidence was rated down 3 levels for imprecision if 95% CI included both large benefit and large harm.
The 95% CIs were described as wide when they span a clearly important effect and an effect that is substantially less or not important. The 95% CIs were described as very wide when they include a large effect and minimal or no effect, or when they include important benefit and important harm. The 95% CIs were described as extremely wide when they include large benefit and moderate or large harm, or large harm and moderate or large benefit.
Step 4: Final recommendations
The second expert GDG meeting was held on 23 February 2022 and focused on reviewing the evidence and deciding on recommendations. The GRADE approach provided the framework for establishing evidence certainty and generating both the direction and strength of recommendations (9,14). If the GDG members had disagreed regarding the evidence assessment or strength of recommendations, the panel chairs would have applied established WHO voting rules (14,15). This proved unnecessary;
there was no voting and all decisions were made by consensus.
The following key factors informed transparent and trustworthy recommendations: absolute benefits and harms for all patient-important outcomes through structured evidence summaries (e.g. GRADE summary of findings tables) (16); quality/certainty of the evidence (9,17); values and preferences of patients (15); resources and other considerations (including considerations of feasibility, applicability and equity) (15); effect estimates and confidence intervals for each outcome, with an associated rating of certainty in the evidence, as presented in summary of findings tables. If such data are not available, the GDG reviews narrative summaries (16);
recommendations are rated as either conditional or strong, as defined by GRADE.
Results of the systematic review

# Recommendation for mAb114 and REGN-EB3
We recommend treatment with either mAb114 or REGN-EB3 for patients with RT-PCR confirmed EVD and for neonates of unconfirmed EVD status, 7 days or younger, born to mothers with confirmed EVD (strong recommendation for.
- mAb114 and REGN-EB3 should not be given together, and should be viewed as alternatives. The choice of whether to use mAb114 and REGN-EB3 depends on availability. - This recommendation only applies to EVD caused by Ebola virus (EBOV; Zaire ebolavirus).

# Strong recommendation for

# Evidence to decision
Benefits and harms mAb114 and REGN-EB3 probably reduce mortality compared with standard of care when using the lowest and the highest baseline risk estimates. Whether mAb114 and REGN-EB3 increase serious adverse events compared with standard of care is very uncertain. mAb114 and REGN-EB3 may have little or no effect on time to viral clearance.

# Subgroup effects
No subgroup effects were found for mortality for mAb114 or REGN-EB3 vs standard of care by age group or CT value. Neither were subgroup effects found for mortality for mAb114 vs REGN-EB3 in a head-to-head comparison, by age group, CT value, self-reported prior EVD vaccination, or duration of symptoms at admission.

# Certainty of the evidence
For the key outcome of mortality, the panel rated the evidence as moderate certainty. Due to the lack of a standard care arm in the PALM study, indirect comparisons for mAb114 and REGN-EB3 via the PREVAIL II study informed the estimate. The PREVAIL II study included only 71 participants, resulting in very wide CIs; this was the rationale for rating down certainty from high to moderate.
The high certainty evidence of the superiority of mAb114 and REGN-EB3 versus ZMapp and remdesivir and the low likelihood that both ZMapp and remdesivir increase mortality in EVD patients further support the inference of the beneficial effect of mAb114 and REGN-EB3.
Whether mAb114 and REGN-EB3 increase serious adverse events is very uncertain due to very serious imprecision with extremely wide CIs, and due to risk of bias generated by the unblinded design of the PALM RCT.
Due to very serious imprecision with wide CIs that include both benefit and harm, there is low certainty of evidence for any effect of mAb114 and REGN-EB3 on time to viral clearance.

# Values and preferences
The panel inferred that all patients would place a very high value on the mortality reduction conferred by mAb114 and REGN-EB3.

# Resources and other considerations
Access to these therapeutics is challenging (pricing and future supply remain unknown) in many parts of the world and, without concerted effort, is likely to remain so, especially in resource-poor areas. It is therefore possible that this strong recommendation could exacerbate health inequity. Therefore, given the demonstrated benefits for patients, it should also provide a stimulus to engage all possible mechanisms to improve global access to these treatments.
On 5 October 2021 the WHO Prequalification Unit published the 1st Invitation to Manufacturers of therapeutics against Ebola Virus Disease to submit an Expression of Interest (EOI) for Product Evaluation 4.

# Acceptability and feasibility
Compared with remdesivir and ZMapp, mAb114 and REGN-EB3 are simpler to administer as a single dose via intravenous infusion, which is likely both acceptable to the patient and feasible to administer. In comparison with remdesivir, mAb114 and REGN-EB3 are easier to monitor, and do not require ongoing viral load monitoring.
Ensuring availability for mAb114 and REGN-EB3 should not be at the expense of providing optimized supportive care. In the PALM RCT recruitment only began once every study site could deliver the standard optimized supportive care to all participants. Therefore the therapeutics build upon the platform of optimized supportive care and are not a replacement or alternative to it.
Due to very similar evidence profiles of mAb114 and REGN-EB3 versus standard of care, and low certainty evidence suggesting little or no difference between the two agents in mortality and serious side-effects in the head-to-head comparison, the GDG decided on a strong recommendation for both drugs without any expression of preference for one or the other.
Both mAb114 and REGN-EB3 likely have important reductions in mortality, the most important outcome for patients, relative to standard of care:
The absolute benefit of mAb114 for mortality of between 229 and 383 fewer deaths per 1000 patients is an important reduction in mortality.
The absolute benefit of REGN-EB3 for mortality of between 237 and 396 fewer deaths per 1000 patients is an important reduction in mortality.
The GDG decided to include neonates less than 7 days old, of unconfirmed EVD status, born to mothers with EVD in this recommendation. The GDG decided to maintain the eligibility criteria that were used in the PALM RCT with the underlying rationale that mother and neonate are a connected pair, that transmission to neonate is extremely likely, mortality in this group very high, and delaying treatment would be prejudicial to the neonate's health.
The dearth of evidence establishing any increase in serious adverse effects further supports the recommendation.

# Practical information
To maximize likelihood of therapeutic effect, mAb114 or REGN-EB3 should be administered as soon as possible after diagnosis.
Both mAb114 and REGN-EB3 are given as a single dose by intravenous infusion. See Annexes 1 and 2.

# mAb114 prescribing information

# Available formulation of mAb114
A vial contains: 400 mg off-white to white lyophilized powder. Upon reconstitution, one vial contains 8 mL of solution, containing 50 mg/mL of mAb114.

# Dosage and route of mAb114
The recommended dose of mAb114 for adult and paediatric patients is 50 mg/kg (or 1 mL/kg) reconstituted with Sterile Water for Injection, further diluted and administered as a single intravenous infusion over 60 minutes.
For detailed information on dosing, see Annex 1.

# REGN-EB3 prescribing information

# Available formulation of REGN-EB3
A vial of REGN-EB3 (14.5 mL) contains: 241.7 mg (16.67 mg per mL) of atoltivimab; 241.7 mg (16.67 mg per mL) of maftivimab; and 241.7 mg (16.67 mg per mL) of odesivimab.

# Dosage and route of REGN-EB3
The recommended dosage of REGN-EB3 is 150 mg/kg (equivalent to 3 mL/kg): 50 mg of atoltivimab; 50 mg of maftivimab; and 50 mg of odesivimab.
per kg diluted and administered as a single intravenous infusion over 2 to 4 hours depending on body weight.
For detailed information on dosing, see Annex 2.

# PICO Population: Patients with Ebola virus disease Intervention: mAb114
Comparator: Standard care

# Evidence summary
The evidence for mAb114 compared with standard care was informed by the PALM and PREVAIL II studies.
For patients with confirmed EVD, the GRADE summary of findings table (see Fig. 1) shows the relative and absolute effects of mAb114 compared with standard care for the outcomes of interest, with certainty ratings, informed by the systematic review. The network plot of the indirect comparison between mAb114 and standard care is shown below.

# Evidence summary
The evidence for REGN-EB3 compared with mAb114 is informed by the PALM study. The direct comparison of REGN-EB3 with mAb114 is shown below. For patients with confirmed EVD, the GRADE summary of findings table (see Fig. 3) shows the relative and absolute effects of REGN-EB3 compared with mAb114 for the outcomes of interest, with certainty ratings, informed by the systematic review. The network plot of the direct comparison between REGN-EB3 and mAb114 is shown below.

# Fig. 3 Network plot of direct comparison of REGN-EB3 to mAb114

# Mechanism of action for mAb114 and REGN-EB3
mAb114 mAb114 is a single monoclonal neutralizing antibody which binds to a conserved epitope within the glycoprotein subunit 1 (GP1) within the receptor binding domain (RBD) (19). It was derived from memory B cells from a recovered EVD patient from the 1995 EVD outbreak in Kikwit, Democratic Republic of the Congo, approximately 11 years after infection. mAb114 exerts antiviral effects by binding and neutralizing virus particles present in circulation, thus inhibiting cell entry (20).
REGN-EB3 is a cocktail of three antibodies: atoltivimab, odesivimab and maftivimab, selected from a pool of antibodies generated in genetically engineered mice exposed to EBOV. The three antibodies bind to non-overlapping epitopes on the Ebola glycoprotein; atoltivimab binds the GP1 head, odesivimab targets the outer glycan cap, and maftivimab targets the conserved GP2 fusion loop (10,20). REGN-EB3 exerts antiviral effects by binding and neutralizing virus particles present in circulation, thus inhibiting cell entry. Activation of effector functions through antibodydependent cellular cytotoxicity, antibody-dependent cellular phagocytosis and antibody-dependent complement deposition are also implicated in activity of REGN-EB3.

# Recommendation for remdesivir
We suggest against treatment with remdesivir for patients with RT-PCR confirmed EVD (conditional recommendation against.
This recommendation only applies to EVD caused by Ebola virus (EBOV; Zaire ebolavirus).

# Conditional recommendation against

# Evidence to decision

# Benefits and harms
In patients with EVD, the effects of remdesivir on mortality and serious adverse events remain very uncertain.
Low certainty evidence indicates that remdesivir may have little or no effect on time to viral clearance.
No subgroup effects were found for age group or CT value for remdesivir vs standard of care.

# Certainty of the evidence
Due to the lack of a standard care arm in the PALM study, indirect comparisons via the PREVAIL II study informed the estimates of remdesivir versus standard care. Whether remdesivir reduces mortality compared with standard care for patients with EVD is very uncertain, due to extremely serious imprecision, with the possibility of both large benefit and large harm, for both the lowest and highest baseline risk estimates.
Whether remdesivir increases serious adverse events is very uncertain due to very serious imprecision with wide CIs that include substantial benefit and large harm, and due to risk of bias as a result of the unblinded design of the PALM RCT.
Remdesivir may have, in relation to standard care, little or no effect on time to viral clearance.
No subgroup effects were found for age group or CT value for remdesivir versus standard of care.

# Values and preferences
The GDG inferred that most patients would be reluctant to use a medication for which the evidence left high uncertainty regarding effects on mortality and other outcomes important to patients. This is particularly so when the evidence includes a possibility of important harm, such as an increase in mortality.

# Resources and other considerations
Remdesivir is a broad-spectrum antiviral, whereas the other three therapeutics included in this guideline are neutralizing monoclonal antibodies. Due to remdesivir's different mechanism of action, there may be a rationale to include this therapeutic in future trials of combination therapy, especially for patients at higher risk of mortality.
Given the recommendation against the use of remdesivir, efforts to ensure access to drugs should focus on those that are currently recommended.

# Acceptability and feasibility
Remdesivir was administered intravenously as a loading dose on day 1 (200 mg in adults, and adjusted for body weight in paediatric patients), followed by a daily maintenance dose (100 mg in adults) starting on day 2 and continuing for 9 to 13 days dependent on viral load. Relative to the single dose regimens of mAb114 and REGN-EB3, remdesivir is a complex therapeutic to administer, involving infusions on multiple days and regular monitoring of viral load.
For mortality, the most important outcome for patients, absolute benefits of remdesivir versus standard care ranged from 280 fewer to 154 more deaths per 1000 patients using the lowest baseline risk estimate, and 469 fewer to 257 more deaths per 1000 patients using the highest baseline risk estimate. Given the wide CIs include both important benefit and important harm, the panel decided on a conditional recommendation against the use of remdesivir.
It remains very uncertain whether remdesivir has any important benefits relative to standard care, or whether it causes important adverse effects. Under these circumstances, the panel inferred that most fully informed patients would decline the use of remdesivir, especially if the recommended therapeutics mAb114 or REGN-EB3 are available.
In a situation where neither mAb114 or REGN-EB3 are available, some patients may accept the higher level of risk of remdesivir in terms of direct harm (due to wide CIs and uncertainty) and serious adverse events, and opt for treatment with remdesivir.
Given that the mechanism of action of remdesivir is different to the recommended neutralizing monoclonal antibodies mAb114 and REGN-EB3 there may be a rationale in including remdesivir, or alternative therapeutics with intracellular mechanism of action, in future combination therapy trials.

# Practical information
In the PALM study, remdesivir was administered intravenously as a loading dose on day 1 (200 mg in adults, and adjusted for body weight in paediatric patients), followed by a daily maintenance dose (100 mg in adults) starting on day 2 and continuing for 9 to 13 days dependent on viral load.

# Evidence summary
The evidence for remdesivir compared with standard care was informed by the PALM and PREVAIL II studies. For patients with confirmed EVD, the GRADE summary of findings table (see Fig. 4) shows the relative and absolute effects of remdesivir compared with standard care for the outcomes of interest, with certainty ratings, informed by the systematic review. The network plot of the indirect comparison between remdesivir and standard care is shown below.
The indirect comparison of remdesivir with standard care via ZMapp is shown below.

# Mechanism of action for remdesivir
Remdesivir is an RNA-directed RNA polymerase-inhibiting nucleoside. It exhibits broad-spectrum antiviral activity. Intracellularly, remdesivir acts as an analogue of adenosine triphosphate and directly competes with it for incorporation into nascent viral RNA, inhibiting viral replication via RNA chain termination (21).

# Recommendation for ZMapp
We suggest against treatment with ZMapp for patients with RT-PCR confirmed EVD (conditional recommendation against.

# This recommendation only applies to EVD caused by Ebola virus (EBOV; Zaire ebolavirus).

# Conditional recommendation against

# Evidence to decision

# Benefits and harms
Although point estimates raise the possibility of an important mortality benefit and a small but potentially important increase in serious adverse events, with only 36 patients in the ZMapp and standard care groups, the evidence leaves us very uncertain regarding any true benefits or harms of ZMapp.

# Certainty of the evidence
Whether ZMapp reduces mortality compared with standard care for patients with EVD is very uncertain, due to extremely serious imprecision, with the possibility of both large benefit and large harm, for both the lowest and highest baseline risk estimates.
Whether ZMapp increases serious adverse events is very uncertain due to very serious imprecision with wide CIs, and due to risk of bias generated by the unblinded design of the PALM RCT. ZMapp may have little or no effect on time to viral clearance compared with standard care, the low certainty evidence due to very serious imprecision, with wide CIs consistent with both important increases and important decreases in time to viral clearance. ZMapp may reduce the duration of admission compared with standard care; the low certainty evidence is due to serious risk of bias and serious imprecision.
No subgroup effects were found for mortality for ZMapp vs standard care by age group or CT value.

# Values and preferences
The GDG inferred that most patients would be reluctant to use a medication for which the evidence left high uncertainty regarding effects on the outcomes important to patients. This is particularly so when the possibility of important harm remains.

# Resources and other considerations
The GDG noted that, given the recommendation against use of ZMapp, efforts to ensure access to drugs should focus on those that are currently recommended.

# Acceptability and feasibility
Patients in the ZMapp group received an intravenous infusion of 50 mg per kg of body weight every third day beginning on day 1 (for a total of three doses). Whilst this regimen is likely to be acceptable and feasible to patients, it is more complex to administer than the single dose infusions of mAb114 and REGN-EB3.
For mortality, the most important outcome for patients, absolute benefits of ZMapp vs standard care ranged from 284 fewer to 103 more deaths per 1000 patients using the lowest baseline risk estimate, and 475 fewer to 172 more deaths per 1000 patients using the highest baseline risk estimate. Given that the wide CIs include both important benefit and important harm, the panel decided on a conditional recommendation against the use of ZMapp.
It remains very uncertain whether ZMapp has any important benefits relative to standard care, or whether it causes important adverse effects. Under these circumstances, the panel inferred that most fully informed patients would decline the use of ZMapp, especially if the recommended therapeutics mAb114 or REGN-EB3 are available.
In a situation where neither mAb114 or REGN-EB3 are available, some patients may accept the higher level of risk of ZMapp in terms of direct harm and serious adverse events, and opt for treatment with ZMapp.
Given that the mechanism of action of ZMapp is similar to the recommended neutralizing monoclonal antibodies mAb114 and REGN-EB3, there appears to be little benefit in including ZMapp in future combination therapy trials for EVD.

# Practical information
ZMapp in the PREVAIL II RCT and PALM RCT was prescribed and administered as three intravenous infusions of 50 mg per kg of body weight, administered every third day.

# Evidence summary
The evidence for ZMapp vs standard care was informed by the PREVAIL II study. PREVAIL II was an RCT of ZMapp vs standard of care. Patients were stratified according to baseline PCR CT value for the virus ( 22 vs > 22) and country of enrolment. Patients of any age were enrolled. No pregnant women were recruited in this trial. The primary endpoint was 28-day mortality. A total of 72 patients 36 per group were enrolled at two sites in Liberia, seven sites in Sierra Leone, one site in Guinea, and one site in the United States of America, from March to November 2015. Of the 71 patients who could be evaluated, 21 died, representing an overall CFR of 30%.
For patients with confirmed EVD, the GRADE summary of findings table (see Fig. 5) shows the relative and absolute effects of ZMapp compared with standard care for the outcomes of interest, with certainty ratings, informed by the systematic review. The network plot of the direct comparison between ZMapp and standard care is shown below.

# Fig. 5 Network plot of direct comparison between ZMapp and standard care

# Mechanism of action for ZMapp
ZMapp is a cocktail of three monoclonal antibodies: 2G4, 4G7 and 13C6. 13C6 is a non-neutralizing humanized mouse antibody that binds to GP1 and can activate effector functions through antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis and antibodydependent complement deposition. 2G4 is a neutralizing humanized mouse antibody that binds at the GP1-GP2 interface, preventing insertion of the fusion loop into the endosome membrane. 4G7 is a neutralizing human mouse antibody that binds to the GP1-GP2 interface to prevent insertion of the fusion loop into the membrane (19).

# How to access and use this guideline
How to access the guideline

# How to navigate this guideline
The guideline is written, disseminated and updated in MAGICapp, with a format and structure that ensures user-friendliness and ease of navigation. It accommodates dynamic updating of evidence and recommendations that can focus on what is new while keeping existing recommendations, as appropriate, within the guideline.
The purpose of the online formats and additional tools, such as the infographics, is to make it easier to navigate and make use of the guideline in busy clinical practice (22). The online multilayered formats are designed to allow end-users to find recommendations first and then drill down to find supporting evidence and other information pertinent to applying the recommendations in practice, including tools for shared decision-making (clinical encounter decision aids (23)).
End-users will also need to understand what is meant by strong and weak/conditional recommendations (displayed immediately below) and certainty of evidence (the extent to which the estimates of effect from research represent true effects from treatment).
For each recommendation additional information is available through the following tabs: Research evidence: Readers can find details about the research evidence underpinning the recommendations as GRADE summary of findings tables and narrative evidence summaries.

# Evidence to decision:
The absolute benefits and harms are summarized, along with other factors such as the values and preferences of patients, practical issues around delivering the treatment as well as considerations concerning resources, applicability, feasibility, equity and human rights. These latter factors are particularly important for those adapting the guidelines for national or local contexts. Justification: Explanation of how the GDG considered and integrated evidence to decision factors when creating the recommendations, focusing on controversial and challenging issues is provided under this heading.
Practical information: This section provides dosing, duration and administration of drugs, or how to apply tests to identify patients in practice.

# Decision aids:
Here tools for shared decision-making in clinical encounters (21) are included.
This guideline will be disseminated via the WHO website and additional access options as detailed above. In addition a multinational EVD case management training course is planned to take place in 2022, organized by the WHO African Region, with 22 nation states invited to participate. The curriculum includes two modules on therapeutics for EVD; an efficient mechanism to disseminate this guideline.

# Additional EVD guidance and implementation tools for health workers
Optimized supportive care for Ebola virus disease manual (6).
Guidelines for the management of pregnant and breastfeeding women in the context of Ebola virus disease (24).
Facility estimator for EVD (25). This tool provides an estimation of the essential items needed to open and/or manage a treatment centre according to inputs provided by users such number of beds, average length of hospitalization and period considered.

# Uncertainties and future research
Whilst the GDG were able to make strong recommendations for the use of two therapeutics, there are many remaining uncertainties. A non-exhaustive list of future research questions are listed below.
There is a need for further research into EVD therapeutics, aspects of EVD supportive care, and to improve understanding and characterization of EVD as an acute and longer term disease. The GDG noted that even with the recommended therapeutics, the EVD CFR remains unacceptably high, especially for patients who present later in the disease course. The GDG noted that no data are available for several outcomes prioritized by patients and the GDG, including functional status post EVD and risk of onward transmission.

# Areas of future research
Cross-cutting research needs are to develop core outcome sets for EVD trials, increase use of standardized case report forms, and ensure continued inclusion of vulnerable populations (pregnant women, neonates, children and older people).

# Disease characterization
There is a need to develop our understanding of the natural history of the disease, including both acute EVD and EVD sequelae. What is the pathogenesis of end organ failure in EVD (e.g. mechanism of acute kidney injury)? What is the incidence and symptomology of EVD sequelae? What are the mechanisms underlying EVD sequelae? How can EVD sequelae be prevented and/or managed? What is the prevalence of viral persistence in recovered EVD patients at different timepoints after recovery? What is the incidence/frequency of relapse? What is the potential for onward transmission of EVD from a recovered patient to another person?
The GDG noted that the available RCTs concerned only EVD caused by EBOV (Zaire ebolavirus) and encouraged research and development for other ebolaviruses and marburgviruses.

# Annex 1
Neutralizing monoclonal antibody mAb114 for Ebola virus disease (EVD): guidance for health care workers

# CLINICAL INDICATIONS
- All patients with RT-PCR con rmed EVD caused by Zaire ebolavirus, including children, pregnant women, breastfeeding women and older people.
- Neonates < 7 days, without EVD RT-PCR con rmation, born to mothers with RT-PCR con rmed EVD.
Patients should receive mAb114 as soon as possible after con rmation of RT-PCR diagnosis of EVD.
Both mAb114 and REGN-EB3 are recommended for use in EVD. The two drugs should not be given together.
The choice of which monoclonal antibody to use depends on availability, including emerging information about effectiveness.

# AVAILABLE FORMULATION
A vial contains: 400 mg off-white to white lyophilized powder. Upon reconstitution, one vial contains 8 mL of solution, containing 50 mg/mL of mAb114.
Note: Each vial is used for only one patient, it must not be used for multiple patients.

# DOSAGE AND ROUTE
The dose of mAb114 for adult and paediatric patients is 50 mg/kg (or 1 mL/kg) reconstituted with sterile water for injection, further diluted and administered as a single intravenous (IV) infusion over 60 minutes.
The expiration date for the product is available via a productspeci c website which is frequently updated. Access the website using the QR code provided on the product.

# Prior to reconstitution
Store refrigerated at 2 C to 8 C (36 F to 46 F) in the original carton to protect from light. Do not freeze. Do not shake.

# After reconstitution
The maximum storage time for reconstituted solution in the vial and the diluted solution in the IV bag is 4 hours.
- If the infusion is stopped for any reason, it can be restarted on the same patient as long as the time from dilution to restarting and completing the infusion remains within 4 hours.
- If the timeframe has been exceeded the remaining dosage required for the patient should be calculated, new vials prepared, diluted then administered and the excess diluted drug should be safely disposed. Drugs should not be moved from high-risk to low-risk zones for temporary storage.
Neutralizing monoclonal antibody mAb114 for Ebola virus disease (EVD)
mAb114 is also known by the commercial name EbangaTM and molecular name ansuvimab.
Guidance for health care workers - Recommended dose is 2500 mg mAb114 OR 50 mL of mAb114.
2-8 C COVID-19 C G M -0 C 2-8 C COVID-19 C G M -0 C 2-8 C COVID-19 C G M -0 C Invert
- The dosage requires 7 vials.
- Insert in each of the vials: 7.7 mL of sterile water for injection using a sterile 10-mL syringe and an 18-gauge needle. Holding horizontally, angle the needle down at an approximate 45 angle, above the lyophilized powder. Slowly inject the diluent along the wall of the vial and without any air to avoid foaming and bubbles. Swirl them gently for 10 seconds and leave them to rest for 10 seconds until all the powder is dissolved. Repeat until the powder is dissolved. This may take up to 20 minutes - The total of the mAb114 vials should be 50 mL and should be added to 50 mL of dilution solution (0.9% sodium chloride or Ringer's lactate) to make a total of 100 mL diluted infusion solution. - Invert 10 times (do not shake).
- Infuse the 100 mL of diluted infusion solution over 60 minutes. Casirivimab 600 mg + imdevimab 600 mg for intravenous infusion (total dose 1200 mg)   - Prepare mAb114 in a clean dedicated space in a low-risk zone.

# kg =
- Wash hands per protocol.
- Remove mAb114 vials from refrigerator and allow them to reach room temperature.
- Check there is no discolouration in the content of any vial.
- Take 7.7 mL sterile water for injection using a sterile 10 mL syringe and an 18-gauge needle.
- Insert the needle tip into the mAb114 vial. Holding horizontally, angle the needle down at an approximate 45 angle, above the lyophilized powder. Slowly inject the sterile water for injection along the wall of the vial and without any air to avoid foaming and bubbles. - Swirl gently (do NOT shake) for approximately 10 seconds; then set the vial down to rest for at least 10 seconds. Repeat until the powder is dissolved. This may take up to 20 minutes. - Check the reconstituted solution for discolouration or visible particles; if present do NOT administer and discard the vial.
Following reconstitution, mAb114 must be further diluted prior to IV infusion.
- Select an appropriate amount of dilution solution, either:  0.9% sodium chloride or  Ringer's lactate solution. - Withdraw and discard the quantity of solution from the IV bag until you reach the appropriate volume of dilution solution (Table 1, column 4) with an 18-20 gauge 1-1.5" needle and an appropriately sized syringe, using standard aseptic technique. - Withdraw the calculated volume of reconstituted mAb114 from the vial(s).
- Inject mAb114 into the dilution solution to reach total diluted infusion solution volume. - Invert the IV bag 10 times to ensure thorough mixing. Do not shake. - Label the IV bag with the patient's name, date of birth, weight in kg, dose of mAb114 included and date and time of drug expiration.
Introduce yourself to the patient and explain that you are planning to administer the medication.
- Do not mix with or administer with other medicinal products.
- Allow the diluted infusion solution to reach room temperature prior to administration. - Administer the diluted infusion solution over 60 minutes, via infusion pump (for paediatric patients < 20 kg it is preferable) or manually through an intravenous giving set containing a sterile 1.2 micron polyether sulfone (PES) lter membrane, DEHP-free, latex-free. If manually: drip rate = (total volume (mL) / minutes) x drop factor  Check the giving set packaging! - Record the time and date the infusion was started. - Flush the line at the end of the infusion.
 If a syringe pump was used, then remove the syringe and ush the line with 2-5 mL of IV solution.  If an infusion bag was used, replace the empty bag and ush the line by infusing at least 25 mL of IV solution, to ensure complete product administration.
Preparation and administration of mAb114 for Ebola virus disease (EVD) Guidance for health care workers  Into a pre lled 0.9% sodium chloride or 5% dextrose infusion bag inject ize of pre lled infusion bag Preparing casirivimab and imdevimab using individual vials Casirivimab 600 mg + imdevimab 600 mg for intravenous infusion (total dose 1200 mg)

# HYPERSENSITIVITY AND INFUSION REACTIONS
Hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with mAb114. The most common adverse events (incidence  20%) are pyrexia, chills, tachycardia, tachypnoea and vomiting. The rate of infusion of mAb114 may be slowed or interrupted if the patient develops any signs of infusionassociated events. - All patients with RT-PCR con rmed EVD caused by Zaire ebolavirus, including children, pregnant women, breastfeeding women and older people.

# IF SIGNS OR
- Neonates < 7 days, without EVD RT-PCR con rmation, born to mothers with RT-PCR con rmed EVD.
Patients should receive REGN-EB3 as soon as possible after con rmation of RT-PCR diagnosis of EVD.
Both the REGN-EB3 and mAb114 are recommended for use in EVD. The two drugs should not be given together.
The choice of which monoclonal antibody to use depends on availability, including emerging information about effectiveness.

# AVAILABLE FORMULATION
A vial of REGN-EB3 (14.5 mL) contains:
- 241.7 mg (16.67 mg per mL) of atoltivimab - 241.7 mg (16.67 mg per mL) of maftivimab - 241.7 mg (16.67 mg per mL) of odesivimab.
Note: Each vial is used for only one patient, it must not be used for multiple patients.

# DOSAGE AND ROUTE
The recommended dosage of REGN-EB3 is 150 mg/kg (equivalent to 3 mL/kg):
- 50 mg of atoltivimab per kg
The expiration date for the product is available via a product-speci c website, which is frequently updated (www.regeneron.com).

# 2-8 C
COVID-19 C G M -0 C 2-8 C COVID-19 C G M -0 C 2-8 C COVID-19 C G M -0 C

# After dilution
The maximum duration between preparation of the diluted REGN-EB3 to completion of administration to the patient depends on the dilution solution used and the storage conditions within the times in table one.
- If the infusion is stopped for any reason, it can be restarted as long as the time from dilution to completing the infusion remains within the time stated in table one.
Into a pre lled 0.9% sodium chloride or 5% dextrose infusion bag inject Size of pre lled infusion bag Preparing casirivimab and imdevimab using individual vials Casirivimab 600 mg + imdevimab 600 mg for intravenous infusion (total dose 1200 mg) Into a pre lled 0.9% sodium chloride or 5% dextrose infusion bag inject Size of pre lled infusion bag Preparing casirivimab and imdevimab using individual vials Casirivimab 600 mg + imdevimab 600 mg for intravenous infusion (total dose 1200 mg)