Therapeutics For Ebola Virus Disease: 19 August 2022

Therapeutics for Ebola virus disease
19 August 2022
Therapeutics for Ebola virus disease
19 August 2022
Therapeutics for Ebola virus disease, 19 August 2022
ISBN 978-92-4-005574-2 (electronic version)

ISBN 978-92-4-005575-9 (print version)
© World Health Organization 2022
Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.
org/licenses/by-nc-sa/3.0/igo).
Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any
use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work,
then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along
with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The
original English edition shall be the binding and authentic edition”.
Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization
(http://www.wipo.int/amc/en/mediation/rules/).
Suggested citation. Therapeutics for Ebola virus disease, 19 August 2022. Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO.
Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris.
Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing,
see https://www.who.int/copyright.
Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine
whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component
in the work rests solely with the user.
General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of
WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on
maps represent approximate border lines for which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature
that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty
of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising
from its use.
Design and layout: L’IV Com Sàrl

iii
Contents
Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv
Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi
Executive summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Methods: how this guideline was created. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Recommendations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.1 Recommendation for mAb114 and REGN-EB3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.2 Recommendation for remdesivir. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.3 Recommendation for ZMapp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4. How to access and use this guideline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5. Uncertainties and future research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Annex 1. Neutralizing monoclonal antibody mAb114 for Ebola virus disease (EVD):
guidance for health care workers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Annex 2. Neutralizing monoclonal antibody cocktail REGN-EB3 for Ebola virus

disease (EVD): guidance for health care workers.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
iv
Acknowledgements
The World Health Organization (WHO) would like to thank the collaborative efforts of all those involved
to make this process rapid, efficient, trustworthy and transparent.
Clinical Co-Chairs: Richard Kojan (ALIMA, Democratic Republic of the Congo); Robert Fowler
(University of Toronto, Canada).
Methods Chair: Gordon Guyatt (McMaster University, Canada).
Guideline Development Group (GDG) members: Aasim Ahmad (National Bioethics Committee,
Pakistan); Cindy Albertson (Samaritan’s Purse, United States of America [USA]); Séverine Caluwaerts
(Médecins Sans Frontières, Belgium); A Modet Camara (ALIMA, Guinea); Ian Crozier (Frederick
National Laboratory, USA); Hilde De Clerck (Médecins Sans Frontières, Belgium); Susanna Dunachie
(University of Oxford, United Kingdom of Great Britain and Northern Ireland [United Kingdom]);
William A Fischer (University of North Carolina, USA); Bushra Jamil (Aga Khan University, Pakistan);
Patricia Kabuni (Kinshasa University Clinic, Democratic Republic of the Congo); Charline Kahambu
Ngorombi (Ministry of Health, Democratic Republic of the Congo); Maurice Kakule (Mangodomu
Reference Health Centre, Democratic Republic of the Congo); Marie-Claire Kolié (ALIMA, Guinea);
Sulaiman Lakoh (Ministry of Health and Sanitation, Sierra Leone); Hans-Jörg Lang (ALIMA, Germany);
J Soka Moses (Ministry of Health, Liberia); Isekusu Mpinda Fiston (Ministry of Health, Democratic
Republic of the Congo); Philippe Mukumbayi Mulumba (Institut National de Recherche Biomédicale,
Democratic Republic of the Congo); Srinivas Murthy (University of British Columbia, Canada); Sorie
Samura (National Emergency Medical Services, Sierra Leone).
A list of GDG members with accompanying biographies can be found on the WHO Health Care
Readiness and Clinical Unit website: WHO Guideline Development Group for Therapeutics for Ebola
Virus Disease1.
Systematic review team: Rachel Couban (McMaster University, Canada); Ya Gao (Lanzhou
University, China); Long Ge (Lanzhou University, China); Qiukui Hao (McMaster University, Canada);
Jinhui Tian (Lanzhou University, China); Yunli Zhao (West China Hospital, Sichuan University, China).
Guideline core GRADE2 team: The guideline core GRADE team reviewed the systematic review
and GRADE tables and prepared materials for the GDG and wrote the final guideline. Lisa Askie
(Scientist, Methods Lead, Methods and Standards Team, Quality Assurance Norms and Standards,
Science Division, WHO); Janet Diaz (Lead, Clinical Management, Health Care Readiness, Geneva,
WHO); Robert Fowler; Gordon Guyatt; Qiukui Hao; Richard Kojan; Marta Lado (Clinical Management,
Health Care Readiness, Geneva, WHO); Daniel Youkee (Clinical Management, Health Care Readiness,
Geneva, WHO).
WHO Steering Committee: Julienne Anoko (Focal Point, Risk Communication and Community
Engagement, WHO Regional Desk for Health Emergencies, Dakar); Lisa Askie; Mercedes Bonet
(Sexual and Reproductive Health and Research, Geneva, WHO); Alejandro Javier Costa (Health
Emergencies Operations, Geneva, WHO); Vanessa Cramond (Clinical Management, Health Care
1
https://www.who.int/publications/m/item/who-global-guideline-development-group-for-therapeutics-for-ebola-virus-disease
2
Grading of Recommendations Assessment, Development and Evaluation.
Acknowledgements v
Readiness, Geneva, WHO); Janet Diaz; Luca Fontana (Health Emergencies Operations, Geneva,
WHO); Pierre Formenty (Team Lead, Viral Haemorrhagic Fevers; Health Emergency Interventions,
Health Emergencies Programme, Geneva); Patrice Kabongo (Case Management, WHO African
Region); Rashidatu Fouad Kamara (Case Management Lead, WHO African Region); Krutika Kuppalli
(Clinical Management, Health Care Readiness, Geneva, WHO); Marta Lado; Lorenzo Moja (Essential
Medicines List, Geneva, WHO); Maurice Nzogu (Clinical Management, Health Care Readiness,
Geneva, WHO); Andreas Reis (Health Ethics and Governance Unit, Geneva, WHO); Pryanka Relan
(Clinical Management, Health Care Readiness, Geneva, WHO); Julie Viry (Clinical Management,
Health Care Readiness, Geneva, WHO); Victoria Willet (Infection Prevention and Control, Health
Care Readiness, Geneva, WHO); Daniel Youkee.
External reviewers: Lori Dodd (National Institutes of Health, USA); Tom Fletcher (Liverpool School of
Tropical Medicine, United Kingdom); Sabue Mulangu (Institut National de Recherche Biomédicale,
Democratic Republic of the Congo); Jerome Pfaffman (United Nations Children’s Fund). Professor
Andrew Owen (University of Liverpool, United Kingdom) reviewed the mechanism of action sections
for the four therapeutics.
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 declarations of interests (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.
Funding source: This guideline was funded with Unitaid funds.

vi
Abbreviations
Anti-IL-6 anti-interleukin-6
Anti-TNF anti-tumor necrosis factor
ALT/AST alanine aminotransferase/aspartate aminotransferase
CI confidence interval
CFR case fatality rate
CT value cycle threshold value
DOI declaration of interests
EBOV Ebola virus
EOI Expression of Interest
EVD Ebola virus disease
GDG Guideline Development Group
GRC Guideline Review Committee
GRADE Grading of Recommendations Assessment, Development and Evaluation
HIV human immunodeficiency virus
ICEMAN Instrument to assess the Credibility of Effect Modification Analyses
IL-6 interleukin-6
NMA network meta-analysis
NP nucleoprotein
PALM Pamoja Tulinde Maisha (Together Save Lives) (in Kiswahili)
PICO population, intervention, comparator, outcomes
RBD receptor binding domain
RCT randomized controlled trial
RT-PCR real-time polymerase chain reaction
SD standard deviation
WHO World Health Organization

vii
Executive summary
Clinical question: What is the role of virus-specific therapeutics in the treatment of patients with
Ebola virus disease (EVD), caused by Ebola virus (EBOV; Zaire ebolavirus)?
Context: The limited evidence base for therapeutics for EVD was augmented by the publication of
the Pamoja Tulinde Maisha (PALM) randomized controlled trial (RCT) in 2019, which compared ZMapp
with three investigational agents: remdesivir, REGN-EB3 and mAb114. This guideline reviews the existing
evidence and provides recommendations for use of EBOV-specific therapeutics in patients with EVD.
Target audience: Health care providers caring for patients with EVD and policy-makers involved in
EVD preparedness and response.
Methods: A systematic review and meta-analysis of RCTs of therapeutics for EVD was conducted.
Recommendations based on the synthesized evidence were made by the GDG using GRADE
methodology.
New recommendations: The GDG made the following recommendations:

Strong recommendation for treatment with mAb114 or REGN-EB3 for patients with real-
time polymerase chain reaction (RT-PCR) confirmed EVD and for neonates of unconfirmed
EVD status, 7 days or younger, born to mothers with confirmed EVD;
Conditional recommendation against treatment with remdesivir for patients with RT-PCR
confirmed EVD;
Conditional recommendation against treatment with ZMapp for patients with RT-PCR
confirmed EVD.
Availability: Access to these therapeutics is challenging and pricing and future supply remain
unknown, especially in resource-poor areas. Without concerted effort, access will remain limited, and
it is therefore possible that this strong recommendation could exacerbate health inequity. Therefore,
given the demonstrated benefits for patients, these recommendations should act as a stimulus to
engage all possible mechanisms to improve global access to these treatments.
About this guideline: This guideline from WHO incorporates the latest high-quality evidence and
provides new recommendations on EBOV-specific therapeutics for EVD. The GDG typically evaluates
a drug when WHO judges sufficient evidence is available to make a recommendation. While the
GDG takes an individual patient perspective in making recommendations, it also considers resources
implications, acceptability, feasibility, equity and human rights. This guideline was developed
according to standards and methods for trustworthy guidelines.
Nomenclature: To facilitate comprehension, this guideline maintained the therapeutic names as

they were described in the relevant RCTs and other peer-reviewed publications.
Name used in RCTs mAb114 REGN-EB3 remdesivir ZMapp

Molecular name ansuvimab atoltivimab, maftivimab, 2G4, 4G7, 13C6
remdesivir
and odesivimab-ebgn
Commercial name Ebanga™ Inmazeb™ Veklury™ ZMapp™
1
1. Introduction
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 Taï 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 case fatality remains high, with a pooled case fatality rate (CFR) of
60% (95% confidence interval [CI]: 47–73%) in outbreaks from 2010–2020 (3). In recent years, several
outbreaks of EVD have occurred in Africa; including the prolonged 2013–2016 EVD outbreak in West
Africa; the 2018–20, 2020, 2021 outbreaks in the Democratic Republic of the Congo; and the 2021
outbreak in Guinea (4).
Following the publication of an RCT demonstrating superior efficacy of two EVD therapeutics, in
comparison with the ZMapp control arm (5), WHO proposed to develop a new guideline. This is a
new guideline written to accompany the optimized supportive care for EVD standard operating
procedures (6, 7). This guideline aims to summarize high-quality evidence for EVD therapeutics and
make recommendations for their use.
2
2. 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 online3.
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 [PICO]); 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)
Population
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.
3
https://www.who.int/publications/m/item/who-global-guideline-development-group-for-therapeutics-for-ebola-virus-disease
2. Methods: how this guideline was created 3
Table 1. Population subgroups and pre-specified direction of effect
Subgroups Categories Risk of mortality by category Postulated direction of effect

Age Paediatric/adult/older age Paediatric and older age = Paediatric and older age =
≤ 5 years, 5–59 years, ≥ 60 years higher risk of mortality reduced treatment effect
Prior EVD vaccination Vaccination within 10 days, Vaccination within 10 days = Vaccination within 10 days =
> 10 days higher risk of mortality reduced treatment effect
Day of illness (duration ≤ 5 days, > 5 days Longer duration of illness Duration > 5 days = reduced
of symptoms prior to (> 5 days) = higher risk of treatment effect
treatment) mortality
Pregnancy Per trimester Pregnancy = higher risk of Pregnancy = reduced treatment
mortality effect
Disease severity as EVD-nucleoprotein (NP) value as Higher disease severity = higher More severe disease = reduced
specified by GDG proxy for viraemia risk of mortality treatment effect
Creatinine Lower EVD-NP CT value
Liver function (AST/ALT) < 22 = higher risk of mortality
ALT: alanine aminotransferase; AST: aspartate aminotransferase; CT: cycle threshold.
Intervention
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.
Comparator
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.
Outcomes
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.
4 Therapeutics for Ebola virus disease, 19 August 2022
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.
Table 2. Outcome prioritization scores of GDG participants and EVD patients
Outcome All respondents GDG and WHO EVD patients All rank GDG rank EVD
n=35, mean Steering n=10, mean patients
(SD) Committee (SD) rank
n=25, mean
(SD)
Duration of admission 7.3 (1.7) 7.08 (1.7) 7.6 (1.6) 4 4 5
Mortality 8.7 (0.9) 8.8 (0.5) 8.2 (1.4) 1 1 1
Time to symptom resolution 6.8 (1.8) 6.8 (1.9) 6.8 (1.6) 8 7 11
Serious adverse effects 7.1 (1.7) 7.2 (1.3) 7.0 (2.5) 6 3 10
Adverse maternal outcomes 7.5 (1.5) 7.4 (1.2) 7.6 (2.1) 2 2 4
Time to viral clearance 6.5 (2.1) 6.4 (1.9) 6.8 (2.7) 9 9 12
Mental health outcomes 6.4 (1.8) 6.0 (1.4) 7.2 (2.6) 10 10 8
Adverse perinatal outcomes 6.9 (1.7) 6.8 (1.5) 7.2 (2.4) 7 8 7
Interruption of treatment 5.9 (2.6) 5.8 (2.6) 6 (2.7) 13 12 13
Viraemia through disease course 6.3 (2.7) 5.8 (2.7) 7.5 (2.4) 12 13 6
Functional status post EVD 7.2 (1.6) 6.8 (1.6) 8.1 (1.5) 5 6 3
Risk of onward transmission 7.3 (2.0) 6.9 (1.9) 8.2 (1.9) 3 5 2
Future fertility outcomes 6.3 (2.1) 6.0 (1.9) 7.1 (2.3) 11 11 9
Mean outcome prioritization score 6.93 (2.0) 6.78 (1.9) 7.3 (2.2) — — —
These steps led to the generation of a final PICO, displayed in Table 3.
Table 3. Final research question (PICO)
Population All patients with confirmed EVD of any disease severity

Intervention Antiviral agents, neutralizing monoclonal antibodies, convalescent plasma.
Anti-inflammatories, corticosteroids, anti-TNF, IL-6 receptor blockers, blood products, endothelial stabilization agents
(Fx06), interferon, antimalarials, antifibrinolytics.
Comparator Standard care
Outcomes Mortality, adverse maternal outcomes, duration of admission, risk of onward transmission, serious adverse effects,
functional status post EVD, adverse perinatal outcomes, time to symptom resolution, time to viral clearance.
Potential 1. Age ≤ 5 years, 6–17 years, 18–59 years, ≥ 60 years
subgroups of 2. Prior EVD vaccination
interest 3. Disease severity (CT value ≤ 22 vs > 22)
4. Pregnancy
5. Day of illness on admission
2. Methods: how this guideline was created 5
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: https://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.
6
3. Recommendations
Results of the systematic review
The full results of the search strategy and the protocol can be found here DOI: https://doi.org/10.1016/
S2666-5247(22)00123-9 (13). Two RCTs were found which met the inclusion criteria. PREVAIL II published
by Davey et al. in 2016 (18), and the PALM trial published by Mulangu et al. in 2019 (5). The two trials
investigated four therapeutics, ZMapp (a triple monoclonal antibody agent), remdesivir (a nucleotide
analogue RNA polymerase inhibitor), mAb114 (a single human monoclonal antibody derived from
an Ebola survivor) and REGN-EB3 (a coformulated mixture of three IgG1 monoclonal antibodies).
PREVAIL II
PREVAIL II was an RCT of ZMapp vs standard of care. Patients were stratified according to baseline
EBOV-NP 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 multiple sites, two in Liberia, seven in Sierra Leone,
one in Guinea, and one 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%. Death occurred in
13 of 35 patients who received the current standard of care alone, and in 8 of 36 patients who also
received ZMapp.
PALM
PALM, was a randomized trial of ZMapp vs three other EBOV-specific therapeutics, conducted in
the Democratic Republic of the Congo in 2018 to 2019. Patients were assigned in a 1:1:1:1 ratio to
receive ZMapp, remdesivir, mAb114, or REGN-EB3. Patients of any age, including pregnant women,
were eligible if they had a positive result on RT-PCR. Neonates < 7 days of unconfirmed EVD status
were also eligible if they were born to a mother with documented EVD. Patients were stratified
according to baseline PCR CT value for the virus (≤ 22 vs > 22). The primary end-point was 28-day
mortality. A total of 681 patients were enrolled, from 20 November 2018 to 9 August 2019. 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).
3. Recommendations 7
3.1 Recommendation for mAb114 and REGN-EB3
Strong recommendation for
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 ).
Remarks
• 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).
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
Evaluation4.
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.
Justification
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.
4
https://extranet.who.int/pqweb/news/1st-invitation-manufacturers-therapeutics-against-ebola-virus-disease-submit-expression
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
Summary
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.
Fig. 1 Network plot of indirect comparison of mAb114 compared with standard care via ZMapp
REGN-EB3
Remdesivir
mAb114
Standard care
ZMapp
Outcome Study results and Absolute effect estimates Certainty of the evidence Plain language
Timeframe measurements (Quality of evidence) summary
Standard care mAb114
Mortality Relative risk: 0.42 395 166 Moderate mAb114 probably reduces
(absolute effect (CI 95% 0.19–0.93) per 1000 per 1000 Due to serious imprecisiona mortality compared with
estimated from standard care when using
Follow up based on indirect the lowest baseline risk
lowest baseline evidence Difference: 229 fewer per 1000
risk) estimate.
(CI 95% 320 fewer–28 fewer)
Mortality Relative risk: 0.42 660 277 Moderate mAb114 probably reduces
(absolute effect (CI 95% 0.19–0.93) per 1000 per 1000 Due to serious imprecisionb mortality compared with
Follow up based on indirect the highest baseline risk
highest baseline evidence Difference: 383 fewer per 1000
risk) estimate.
(CI 95% 535 fewer–46 fewer)
Serious adverse Risk difference: 0.016 Difference: 16.0 more per 1000 Very low Whether mAb114 increases
events (CI 95% 0.061–0.93) (CI 95% 61.0 fewer–93.0 more) Due to serious risk of bias and very serious adverse events
serious imprecisionc compared with standard
Based on indirect evidence care is very uncertain.
Time to viral Measured by days: 8.68 7.54 Low mAb114 may have little or
clearance Scale: Lower better Mean Mean Due to very serious imprecisiond no effect on time to viral
clearance compared with
Follow up based on indirect standard care.
evidence Difference: MD 1.14 lower
(CI 95% 4.09 lower–1.81 higher)
a
Imprecision: serious. Small number of patients in the standard care versus ZMapp comparator informing this indirect comparison;
b
c
Risk of bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias. Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias;
imprecision: very serious. Wide confidence intervals;
d
Imprecision: very serious. Wide confidence intervals.
PICO
Intervention: REGN-EB3
Summary
Evidence summary
The evidence for REGN-EB3 compared with standard care was informed by the PALM and PREVAIL
II studies. The indirect comparison of REGN-EB3 with standard care via ZMapp is shown below. For
patients with confirmed EVD, the GRADE summary of findings table (see Fig. 2) shows the relative
and absolute effects of REGN-EB3 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 REGN-EB3 and standard care is shown below.
Fig. 2 Network plot of direct comparison of REGN-EB3 with standard care via ZMapp
REGN-EB3
Remdesivir
mAb114
Standard care
ZMapp
Standard care REGN-EB3
Mortality Relative risk: 0.4 395 158 Moderate REGN-EB3 probably reduces
(absolute effect (CI 95% 0.18–0.89) per 1000 per 1000 Due to serious imprecisiona mortality compared with
Follow up based on indirect Difference: 237 fewer per 1000 the lowest baseline risk
lowest baseline evidence
risk) (CI 95% 324 fewer–43 fewer) estimate.
Mortality Relative risk: 0.4 660 264 Moderate REGN-EB3 probably reduces
(absolute effect (CI 95% 0.18–0.89) per 1000 per 1000 Due to serious imprecisionb mortality compared with
Follow up based on indirect Difference: 396 fewer per 1000 the highest baseline risk
highest baseline evidence
risk) (CI 95% 541 fewer–73 fewer) estimate.
Serious adverse Risk difference: 0.016 Difference: 16.0 more per 1000 Very low Whether REGN-EB3
events (CI 95% 0.061–0.93) (CI 95% 61.0 fewer–93.0 more) Due to serious risk of bias and very increases serious adverse
serious imprecisionc events compared with
Based on indirect evidence standard care is very
uncertain.
Time to viral Measured by days: 8.68 8.38 Low REGN-EB3 may have little
clearance Scale: Lower better Mean Mean Due to very serious imprecisiond or no effect on time to viral
Follow up based on indirect Difference: MD 0.30 lower standard care.
evidence
a
b
c
d
PICO
Intervention: REGN-EB3
Comparator: mAb114
Summary
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
REGN-EB3
Remdesivir
mAb114
Standard care
ZMapp
mAb114 REGN-EB3
Mortality Relative risk: 0.96 166 159 Low There may be little or no
(absolute effect (CI 95% 0.71–1.29) per 1000 per 1000 Due to very serious imprecisiona difference between REGN-
estimated from EB3 and mAb114 when
Based on data from Difference: 7 fewer per 1000 using the lowest baseline
lowest baseline 329 participants in 1 study
risk) (CI 95% 48 fewer–48 more) risk estimate.
Mortality Relative risk: 0.96 277 266 Low There may be little or no
(absolute effect (CI 95% 0.71–1.29) per 1000 per 1000 Due to very serious imprecisionb difference between REGN-
estimated from EB3 and mAb114 when
Based on data from Difference: 11 fewer per 1000 using the highest baseline
highest baseline 329 participants in 1 study
risk) (CI 95% 80 fewer–80 more) risk estimate.
Serious adverse Risk difference: 0.000 Difference: 0.0 fewer per 1000 Moderate There is probably little or
events (CI 95% 0.012–0.012) (CI 95% 12.0 fewer–12.0 more) Due to serious risk of biasc no difference between
REGN-EB3 and mAb114 in
Based on data from serious adverse events.
329 participants in 1 study
Time to viral Measured by days: 7.54 8.38 Moderate REGN-EB3 probably has
clearance Scale: Lower better Mean Mean Due to serious imprecisiond little or no difference on
time to viral clearance
Based on data from Difference: MD 0.84 higher compared with mAb114.
a
Imprecision: very serious. Wide confidence intervals;
b
c
d
Imprecision: serious. Wide confidence intervals.
3.1.1 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
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 antibody-
dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis and antibody-dependent
complement deposition are also implicated in activity of REGN-EB3.
3.2 Recommendation for remdesivir
Conditional recommendation against
We suggest against treatment with remdesivir for patients with RT-PCR confirmed EVD
(conditional recommendation against ).
Remark
This recommendation only applies to EVD caused by Ebola virus (EBOV; Zaire ebolavirus).
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.

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.

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.

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.

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.
Justification
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.
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.
PICO
Intervention: Remdesivir
Summary
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.
Fig. 4 Network plot of indirect comparison of remdesivir to standard care via ZMapp
Remdesivir REGN-EB3
mAb114
Standard care
ZMapp
Standard care Remdesivir
Mortality Relative risk: 0.64 395 253 Very low Whether remdesivir
(absolute effect (CI 95% 0.29–1.39) per 1000 per 1000 Due to extremely serious reduces mortality
estimated from imprecisiona compared with standard
Follow up based on indirect care is very uncertain when
lowest baseline evidence Difference: 142 fewer per 1000
risk) using the lowest baseline
(CI 95% 280 fewer–154 more) risk estimate.
Mortality Relative risk: 0.64 660 422 Very low Whether remdesivir
(absolute effect (CI 95% 0.29–1.39) per 1000 per 1000 Due to extremely serious reduces mortality
estimated from imprecisionb compared with standard
Follow up based on indirect care is very uncertain when
highest baseline evidence Difference: 238 fewer per 1000
risk) using the highest baseline
(CI 95% 469 fewer–257 more) risk estimate.
Serious adverse (Risk difference: 0.022 Difference: 22.0 more per 1000 Very low Whether remdesivir
events (CI 95% 0.056–0.099) (CI 95% 56.0 fewer–99.0 more) Due to serious risk of bias and very increases serious adverse
serious imprecisionc events compared with
Based on indirect evidence standard care is very
uncertain.
Time to viral Measured by days: 8.68 8.41 Low Remdesivir may have little
clearance Scale: Lower better Mean Mean Due to very serious imprecisiond or no effect on time to viral
Follow up based on indirect standard care.
evidence Difference: MD 0.27 lower
a
Imprecision: extremely serious. Wide confidence intervals;
b
c
Risk of bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias;
d
3.2.1 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).
3.3 Recommendation for ZMapp
Conditional recommendation against
We suggest against treatment with ZMapp for patients with RT-PCR confirmed EVD (conditional
recommendation against ).
Remark
This recommendation only applies to EVD caused by Ebola virus (EBOV; Zaire ebolavirus).
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.

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.

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.

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.

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.
Justification
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.
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.
PICO
Intervention: ZMapp
Summary
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
REGN-EB3
Remdesivir
mAb114
Standard care
ZMapp
Outcome Study results and Absolute effect estimates Certainty of the Plain language
Timeframe measurements evidence summary
Standard care ZMapp (Quality of evidence)
Mortality Relative risk: 0.6 395 237 Very low Whether ZMapp reduces mortality
(absolute effect (CI 95% 0.28–1.26) per 1000 per 1000 Due to extremely serious compared with standard care is very
estimated from imprecisiona uncertain when using the lowest
Based on data from 71 Difference: 158 fewer per 1000 baseline risk estimate.
lowest baseline participants in 1 study
risk) (CI 95% 284 fewer–103 more)
Mortality Relative risk: 0.6 660 396 Very low Whether ZMapp reduces mortality
(absolute effect (CI 95% 0.28–1.26) per 1000 per 1000 Due to extremely serious compared with standard care is very
estimated from imprecisionb uncertain when using the highest
Based on data from Difference: 264 fewer per 1000 baseline risk estimate.
highest baseline 71 participants in 1 study
risk) (CI 95% 475 fewer–172 more)
Serious adverse Risk difference: 0.028 Difference: 28.0 more Very low Whether ZMapp increases serious
events (CI 95% 0.046–0.102) (CI 95% 46.0 fewer–102.0 more) Due to serious risk of adverse events compared with
Based on data from bias and very serious standard care is very uncertain.
71 participants in 1 study imprecisionc
Time to viral Measured by days: 8.68 8.43 Low ZMapp may have little or no effect on
clearance Scale: Lower better Mean Mean Due to very serious time to viral clearance compared with
imprecisiond standard care.
Based on data from Difference: MD 0.25 lower
Duration of Measured by days: 15.73 13.71 Low ZMapp may reduce the duration of
admission Scale: Lower better Mean Mean Due to serious risk of admission compared with standard
bias, and very serious care.
Based on data from Difference: MD 2.02 lower
50 participants in 1 study imprecisione
a
b
c
d
e
Imprecision: serious. Wide confidence intervals.
3.3.1 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 antibody-
dependent 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).
20
4. How to access and use this

guideline
How to access the guideline
WHO website in PDF format: this is a full read out of the MAGICapp content for those
without reliable web access.
Health Care Readiness - Clinical Unit and Ebola Virus Disease: these resources were
created by the Clinical Unit, Health Care Readiness, Geneva, WHO.
The PDF can also be downloaded directly from MAGICapp (see cogwheel top right).
MAGICapp in online, multilayered formats5: this is the fullest version of the guideline, as
detailed below.
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.
5
https://app.magicapp.org/#/guidelines
4. How to access and use this guideline 21
Dissemination
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.
22
5. 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).
Therapeutics
What is the optimal dosage of mAb114 and REGN-EB3? Are fractionated doses of
neutralizing monoclonal antibodies more efficacious? If any, what is the optimal Fc effector
function/characteristics for EBOV-specific antibodies?
What is the association (if any) between the use of neutralizing monoclonal antibodies and
clinical sequelae or viral persistence in EVD survivors?
Are there significant interactions between neutralizing monoclonal antibodies targeting the
EBOV-GP and EVD vaccines incorporating EBOV-GP when administered concurrently?
Does combination therapy with a neutralizing monoclonal antibody plus another agent
reduce mortality compared with the use of single monoclonal antibody therapy?
Is there a potential risk of viral resistance caused by selective pressure of neutralizing
monoclonal antibodies?
Is there a role for neutralizing monoclonal antibodies for post-exposure prophylaxis for high-
risk exposures?
Which novel therapeutics have the most promising breadth of pan filovirus activity? Which
novel therapeutics are the most effective in terms of penetration into immune-privileged
sites?
Optimized supportive care

Can a bundle of optimized supportive care and therapeutics reduce the CFR in the
highest risk patients? What is the optimal composition of bundled care for EVD?
How can optimized supportive care for all EVD patients be implemented, especially at the
beginning of an outbreak?
What renal replacement interventions are most effective and feasible for patients with
EVD?
What is the influence of co-existing or super infection with endemic pathogens (for
example, malaria, HIV), on disease course and outcomes?
Rapid diagnostic tests

How can rapid diagnostic tests for EVD complement existing testing strategies?
Can rapid diagnostic tests identify EVD patients earlier and reduce delays to treatment?
5. Uncertainties and future research 23
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.
24
References
1. Kuhn JH, Adachi T, Adhikari NKJ, Arribas JR, Bah IE, Bausch DG et al. New filovirus disease classification and nomenclature.
Nat. Rev Microbiol. 2019;17(5):261-263.
2. Jacob ST, Crozier I, Fischer WA, Hewlett A, Kraft CS, Vega M-ADL et al. Ebola virus disease. Nat Rev Dis Primers. 2020;6(1):13.
3. Kawuki J, Musa TH, Yu X. Impact of recurrent outbreaks of Ebola virus disease in Africa: a meta-analysis of case fatality
rates. Public Health. 2021;195 89-97.
4. Ebola virus disease factsheet. Geneva: World Health Organization; 2021.
5. Mulangu S, Dodd LE, Davey RT, Tshiani Mbaya O, Proschan M, Mukadi D et al. A randomized, controlled trial of Ebola virus
disease therapeutics. New Engl J Med. 2019;381(24):2293-2303.
6. Optimized supportive care for Ebola virus disease: clinical management standard operating procedures. Geneva: World
Health Organization; 2019.
7. Lamontagne F, Fowler RA, Adhikari NK, Murthy S, Brett-Major DM, Jacobs M et al. Evidence-based guidelines for supportive
care of patients with Ebola virus disease. Lancet. 2018;391(10121):700-708.
8. WHO handbook for guideline development. Geneva: World Health Organization; 2014.
9. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P et al. GRADE: an emerging consensus on rating
quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-6.
10. Therapeutics for Ebola virus disease. Guideline Development Group meeting, 17 November 2021. Geneva: World Health
Organization; 2021 (https://www.who.int/publications/m/item/meeting-report-of-the-first-gdg-meeting-for-therapeutics-
for-ebola-virus-disease-%28evd%29, accessed 1 August 2022).
11. Disease Outbreak News (DONs). Geneva: World Health Organization; 2022 (https://www.who.int/emergencies/disease-
outbreak-news, accessed 1 August 2022).
12. Schandelmaier S, Briel M, Varadhan R, Schmid CH, Devasenapathy N, Hayward RA et al. Development of the Instrument
to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses.
CMAJ. 2020;192(32):E901-E906.
13. Gao Y, Zhao Y, Guyatt G, Fowler R, Kojan R, Ge L, Tian J, Hao Q. Effects of therapies for Ebola virus disease: a systematic
review and network meta-analysis. Lancet Microbe. 2022 DOI: https://doi.org/10.1016/S2666-5247(22)00123-9.
14. Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A et al. Going from evidence to recommendations. BMJ.
2008;336(7652):1049-51.
15. Andrews JC, Schünemann HJ, Oxman AD, Pottie K, Meerpohl JJ, Coello PA et al. GRADE guidelines: 15. Going from evidence
to recommendation-determinants of a recommendation’s direction and strength. J Clin Epidemiol. 2013;66(7):726-35.
16. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles
and summary of findings tables. J Clin Epidemiol. 2011;64(4):383-94.
17. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J. GRADE guidelines: 3. Rating the quality of evidence.
J Clin Epidemiol. 2011;64(4):401-6.
18. Davey RT, Nordwall J, Proschan MA. Trial of ZMapp for Ebola virus infection. New Engl J Med. 2017;376(7):700-701.
19. Hargreaves A, Brady C, Mellors J, Tipton T, Carroll MW, Longet S. Filovirus neutralising antibodies: mechanisms of action
and therapeutic application. Pathogens. 2021;10(9):1201.
20. Tshiani Mbaya O, Mukumbayi P, Mulangu S. Review: insights on current FDA-approved monoclonal antibodies against
Ebola virus infection. Front Immunol. 2021;12:721328.
21. Hoenen T, Groseth A, Feldmann H. Therapeutic strategies to target the Ebola virus life cycle. Nat Rev Microbiol.
2019;17(10):593-606.
22. Vandvik PO, Brandt L, Alonso-Coello P, Treweek S, Akl EA, Kristiansen A et al. Creating clinical practice guidelines we can
trust, use, and share: a new era is imminent. Chest. 2013;144(2):381-389.
23. Agoritsas T, Heen AF, Brandt L, Alonso-Coello P, Kristiansen A, Akl EA et al. Decision aids that really promote shared decision
making: the pace quickens. BMJ. 2015;350:g7624.
24. Guidelines for the management of pregnant and breastfeeding women in the context of Ebola virus disease. Geneva:
World Health Organization; 2020 (https://apps.who.int/iris/handle/10665/330851, accessed 1 August 2022).
25. Essential Items Estimator Tool (Ebola); 2022 (https://essentialitemsestimator.com/, accessed 1 August 2022).
25
Annex 1
Neutralizing monoclonal antibody mAb114 for Ebola virus disease (EVD):
guidance for health care workers
Neutralizing monoclonal antibody

mAb114 for Ebola virus disease (EVD)
mAb114 is also known by the commercial name Ebanga™ and molecular Guidance for health care workers
name ansuvimab.
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.
CLINICAL INDICATIONS
• All patients with RT-PCR confirmed EVD caused by
Zaire ebolavirus, including children, pregnant women,
breastfeeding women and older people.
• Neonates < 7 days, without EVD RT-PCR confirmation,
born to mothers with RT-PCR confirmed EVD.
Patients should receive mAb114 as soon as possible after
confirmation of RT-PCR diagnosis of EVD.
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.
2-8 °C
COVID-19 STORAGE
Prior to reconstitution After reconstitution
C
Store refrigerated at 2 °C to 8 °C (36 °F to 46 °F)
G in the
2-8 °C The maximum storage time for reconstituted solution in the
M
original carton to protect from light. Do not freeze. vial and the diluted solution in the IV bag is 4 hours.
COVID-19
Do not shake. • If the infusion is stopped for any reason, it can be restarted
Con the same patient as long as the time from dilution to
2-8 °C -0 °C Mrestarting and completing the infusion remains within 4 hours.
G
COVID-19
• If the timeframe has been exceeded the remaining dosage
Expiry Casirivimab 600 mg +required for600the
imdevimab mgpatient shouldinfusion
for intravenous be calculated,
(total dose new vials
1200 mg)
The expiration date for the product is available
C Size of prefilled infusion viabag
a product- Preparing prepared, diluted
casirivimab andthen administered
imdevimab and the
Casirivimab
using individual excess
vialsa 600 diluted
mg + imdevimab 600 mg for intr
G
specific website which is frequently
M updated. Access the
Casirivimab
-0 °C 600 mg + imdevimab
Intodruga600 should
prefilled
Size
0.9%be
mg for intravenous
safely
infusion
sodium
of prefilled disposed.
(total dose
chloride or 5%
infusion
1200
Drugs
mg)
dextrose
bag should
infusion bagnot
injectbe moved
Preparing casirivimab and imde
Size of prefilled infusion bag Preparing casirivimab and imdevimab using individual vialsa
website using the QR code provided on the product. from
Into a prefilled high-risk
0.9% sodium to5%low-risk
chloride or zones
dextrose infusion for temporary storage.
bag inject
1
2
Into a prefilled 0.9% sodium chlo
1
50 mL
DOSAGE 250 mLAND ROUTE
3 3
100 mL
1 1
150 mL 5 mL 5 mL
4 4
2 2
50 mL
3 3 5 ml 5 ml
100 mL 150 mL 5 mL 5 mL
4 4
250 mL
5 ml 5 ml
-0 °C
The dose of mAb114 for adult and paediatric patients is 50 mg/kg (or 1 mL/kg) reconstituted with sterile water for injection,
50 mL
Casirivimab Casirivimab
Imdevimab Imdevimab
further diluted and administered as a single intravenous (IV) 5infusion over (use60 minutes. 100 mL
mL of casirivimab two 6-mL
5 mL of (use
5 mL of imdevimab casirivimab 150
vials of casirivimab OR 5-mL of one
two 6-mL vials(use
mL
20-mL vial) AND
two 6-mL
of imdevimab 250of mL
OR 5-mL
vials ofofone
OR 5-mL one 20-mL vial) AND
casirivimab
20-mL vial)
5 mL
5 mL of imdevimab (use two 6-mL vials of imdevimab OR 5-mL of one 20-mL vial)
EXAMPLE: Patient weighting 50 kg
• Recommended dose is 2500 mg mAb114 OR 50 mL of mAb114. Casi
• The dosage requires 7 vials. 50 kg =
5 mL of casirivimab (use two 6-m
x 7 vials
• Insert in each of the vials: 7.7 mL50of
mL sterile water for injection using a sterile 5 mL of imdevimab
2-8 °C (use two 6-m
1
2
3
4
100 mL 150 mL
5 l
7.7 mL
m
6
10-mL syringe and an 18-gauge needle. Holding horizontally, angle the needle
10
250 mL
7 8
9
8 7
9
6
5
10 ml 4
COVID-19
3
2
1
1
down at an approximate 45° angle,50 mL above the lyophilized powder. Slowly inject
2
3
4
100 mL 150 mL 45°

5
7.7 mL
6
the diluent along the wall of the vial and without any air 250
to avoid foaming and
C
mL
7
8
9
10 ml
G
M
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 Sterile water 10 seconds
START
take up to 20 minutes 10
-0 °C
• The total of the mAb114 vials should be 50 mL and should be added to 50 mL
10
20
30
20
40
50
500 mL
30
60 hour minute
70
40
80
of dilution solution (0.9% sodium chloride 150 mLor Ringer’s lactate) to make a total of
90 ml
50
100
250 mL
110
120
150 mL50 mL
130
100 mL
140
150 ml
100 mL diluted infusion solution. 150 mL 7.7 mL

250 mL
.
• Invert 10 times (do not shake).

hour minute
REGN-EB3
Invert
Invert10
10times
times 1 hour
10
10
20
• Infuse the 100 mL of diluted infusion solution over 60 minutes.

30
20
40
50
500 mL
30
60
70
40
80
90 ml
50 hour minute
150 mL
100
250monoclonal
mL
110
Neutralizing antibody mAb114 for Ebola virus disease

150 mL(EVD)
120
130
140
150 ml
2 August 2022
© World Health Organization 2022. Some rights reserved.
.
hour minute
This work is available under the CC BY-NC-SA 3.0 IGO licence. REGN-EB3 FINISH
WHO reference number: WHO/EVD/therapeutics/mAb114/Poster_A/2022.1
Preparation and administration of

mAb114 for Ebola virus disease (EVD)
ers 1. CALCULATE
CALCULATE DOSE 2. RECONSTITUTE
DOSE 2. DILUTE 3. ADMINISTER
3. DILUTE4.4.MONITOR
ADMINISTER 5. MONITOR
1. CALCULATE DOSE
• Weigh the patient.
• Calculate the dose as per Table 1.
TABLE 1. mAb114 dose, number of vials required, volume of dilution solution to add to
mAb114, final infusion solution volume
Total diluted infusion solution

add to reconstituted mAb114

Volume of dilution solution to

(mL) (mAb114 and dilution

Volume of mAb114 (mL)

Body weight (kg)
Body weight (kg)
Body weight (kg)

Number of vials
Number of vials
Number of vials
solution)
solution)
solution)
(mL)
(mL)
(mL)
1 1 1 5 6 36 36 5 50 86 71 71 9 100 171
2 2 1 10 12 37 37 5 50 87 72 72 9 100 172
3 3 1 10 13 38 38 5 50 88 73 73 10 100 173
4 4 1 10 14 39 39 5 50 89 74 74 10 100 174
5 5 1 10 15 40 40 5 50 90 75 75 10 100 175
6 6 1 10 16 41 41 6 50 91 76 76 10 100 176
7 7 1 10 17 42 42 6 50 92 77 77 10 100 177
8 8 1 10 18 43 43 6 50 93 78 78 10 100 178
9 9 2 10 19 44 44 6 50 94 79 79 10 100 179
10 10 2 10 20 45 45 6 50 95 80 80 10 100 180
11 11 2 25 36 46 46 6 50 96 81 81 11 100 181
12 12 2 25 37 47 47 6 50 97 82 82 11 100 182
13 13 2 25 38 48 48 6 50 98 83 83 11 100 183
14 14 2 25 39 49 49 7 50 99 84 84 11 100 184
15 15 2 25 40 50 50 7 50 100 85 85 11 100 185
16 16 2 25 41 51 51 7 100 151 86 86 11 100 186
17 17 3 25 42 52 52 7 100 152 87 87 11 100 187
18 18 3 25 43 53 53 7 100 153 88 88 11 100 188
19 19 3 25 44 54 54 7 100 154 89 89 12 100 189
20 20 3 25 45 55 55 7 100 155 90 90 12 100 190
21 21 3 25 46 56 56 7 100 156 91 91 12 100 191
22 22 3 25 47 57 57 8 100 157 92 92 12 100 192
23 23 3 25 48 58 58 8 100 158 93 93 12 100 193
24 24 3 25 49 59 59 8 100 159 94 94 12 100 194
25 25 4 25 50 60 60 8 100 160 95 95 12 100 195
26 26 4 50 76 61 61 8 100 161 96 96 12 100 196
27 27 4 50 77 62 62 8 100 162 97 97 13 100 197
28 28 4 50 78 63 63 8 100 163 98 98 13 100 198
29 29 4 50 79 64 64 8 100 164 99 99 13 100 199
30 30 4 50 80 65 65 9 100 165 100 100 13 100 200
31 31 4 50 81 66 66 9 100 166
32 32 4 50 82 67 67 9 100 167
33 33 5 50 83 68 68 9 100 168
34 34 5 50 84 69 69 9 100 169
35 35 5 50 85 70 70 9 100 170
Preparation and administration of mAb114 for Ebola virus disease (EVD)

2 August 2022
This work is available under the CC BY-NC-SA 3.0 IGO licence.
WHO reference number: WHO/EVD/therapeutics/mAb114/Poster_B/2022.1
Casirivimab 600 mg + imdevimab 600
Sizemg for intravenous
of prefilled infusion bag infusionPreparing
(total dose 1200and
casirivimab mg)imdevimab using individual vialsa
Into a prefilled 0.9% sodium chloride or 5% dextrose infusion bag inject
Into a prefilled 0.9% sodium chloride or 5% dextrose infusion bag inject 1
2
Annex 1. mAb114 1
2
27
50 mL
3 3
100 mL 150 mL 5 mL 5 mL
4 4
250 mL
5 ml 5 ml
1 1
2 2
50 mL
3 3 Casirivimab Imdevimab
100 mL 150 mL 5 mL 5 mL
4 4
5 mL of casirivimab (use two 6-mL vials of casirivimab OR 5-mL of one 20-mL vial) AND
250 mL
5 ml 5 ml
Preparation and administration of mAb114Casirivimab Imdevimab

for Ebola virus disease (EVD) Guidance for health care workers
5 mL of casirivimab (use two 6-mL vials of casirivimab OR 5-mL of one 20-mL vial) AND
2. RECONSTITUTE 1
• Prepare mAb114 in a clean dedicated space50inmLa low-risk

100 mL zone.
2
3
4
5
150 mL 7.7 mL
6
250 mL
7
• Wash hands per protocol.

8
9
10 ml
l
m
10
9
• Remove mAb114 vials from refrigerator and allow them to reach room temperature.
8
7
6
5
4
3
2
1
• 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.
45° 2-8 °C
• Insert the needle tip into the mAb114 vial. Holding horizontally, angle the needle down at an
1
2
3 COVID-19
50 mL 100 mL approximate 45° angle, above the lyophilized powder. Slowly inject the sterile water for injection
4
5
150along
mL the wall of the vial and without any air to avoid
7.7 mL
6
250 mL
7
foaming and bubbles.

8
9
10 ml
10
10
20
30
C
20
40
G
• Swirl gently (do NOT shake) for approximately 10 seconds; then set the vial down to rest for at
50
500 mL
30
M
60
70
40
80
90 ml
50
least 10 seconds. Repeat until the powder is dissolved.150 mLThis 250

may mLtake up to 20 minutes.
100
110
120
150 mL
130
140
150 ml
• Check the reconstituted solution for discolouration or visible particles; if present do NOT administer and discard the vial.
REGN-EB3 -0 °C
3. DILUTION
Following reconstitution, mAb114 must be further • Inject mAb114 into the dilution solution to reach total
diluted prior to IV infusion. diluted infusion solution volume.
• Select an appropriate amount of dilution solution, either: • Invert the IV bag 10 times
− 0.9% sodium chloride or to ensure thorough mixing.
10
10
20
30
− Ringer’s lactate solution.

20
Do not shake.
40
50
500 mL
30
60
70
40
80
• Withdraw and discard the quantity of solution from • Label the IV bag with the
90 ml
50
150 mL
100
250the
mLIV bag until you reach the appropriate volume of
110
120
150 mL patient’s name, date of birth,

130
140
150 ml
dilution solution (Table 1, column 4) with an 18–20 gauge weight in kg, dose of
1–1.5” needle and an appropriately sized syringe, using mAb114 included and date
standard aseptic technique. REGN-EB3and time of drug expiration.
• Withdraw the calculated volume of reconstituted Note: For paediatric patients use a 10-mL syringe and
mAb114 from the vial(s). infusion pump.
4. ADMINISTER
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 20-25 °C
prior to administration.
HCG
• Administer the diluted infusion solution over 60 minutes,
Remember the
via infusion pump (for paediatric patients < 20 kg it is FIVE
C RIGHTS
preferable) or manually through an intravenous giving set of drugT administration:
containing a sterile 1.2 micron polyether sulfone (PES)
ATION RIGH
TP
filter membrane, DEHP-free, latex-free. DIC AT
ME S
If manually: drip rate = (total volume (mL) / minutes) x drop factor*
IEN
HT
RIG
* Check the giving set packaging! -0 °C

• Record the time and date the infusion was started. IV
SC
mg
OSE
5 ml
RIG H T
• Flush the line at the end of the infusion.

2
1 1
2
Oral
4
HT D
5 ml
− If a syringe pump was used, then remove the syringe and flush
ROU
IIIIIIIIIIII
RIG
III II
II I
II
II
IIIIIIIIIIII
III
IIIIIIIIIIII
the line with 2–5 mL of IV solution.

TE
III
II
II
I II
II III
IIIIIIIIIIII
− If an infusion bag was used, replace the empty bag and flush the line RIG HT TI M E
START
by infusing at least 25 mL of IV solution, to ensure complete product administration. START
5. MONITOR START hour
hour
minute
minute
• Monitor patient symptoms and vital signs: heart rate,

blood pressure, respiratory rate and oxygen saturation:
hour minute
.
hour minute
START
hour minute
− immediately before infusion

− 15 minutes after starting the infusion
.
hour minute
hour minute
− at the end of the infusion

.
hour minute
hour minute
− if any clinical deterioration during the infusion, hour

.
minute
take vital signs more frequently and assess hour
hour
hour
.
. minute
minute
minute
the patient clinically. FINISH

. FINISH
hour minute
Preparation and administration of mAb114 for Ebola virus disease (EVD) FINISH
hour minute
2 August 2022
This work is available under the CC BY-NC-SA 3.0 IGO licence. .

hour minute
FINISH
Preparation and administration of mAb114 for Ebola virus disease (EVD) Guidance for health care workers
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 infusion-
associated events.
IF SIGNS OR SYMPTOMS OF A CLINICALLY SIGNIFICANT HYPERSENSITIVITY REACTION OR ANAPHYLAXIS
OCCUR, IMMEDIATELY DISCONTINUE THE INFUSION AND INITIATE APPROPRIATE MEDICATIONS, SUPPORTIVE
THERAPY AND AIRWAY MANAGEMENT.
INFUSION REACTION GUIDE

Suggestions only – not meant to replace existing clinical guidelines or alter clinical judgment.
INFILTRATION FEVER HYPERTENSION OTHER SEIZURES ANAPHYLAXIS ALLERGIC
SYMPTOMS: REACTION
(Watch for pain, SHIVERING
swelling, tightness HYPOTENSION
around injection OEDEMA
site; skin cooling/ PERIPHERAL
blanching; leakage NEUROPATHY
at insertion site)
1. STOP infusion
38 °C – 39 °C Mild Mild Brief, no loss of
1. Continue 1. Continue 1. Continue consciousness
2. Discontinue IV
infusion, monitor infusion, monitor infusion, monitor 1. Continue
site, bandage,
vital signs vital signs vital signs infusion, monitor
apply heat OR
patient
cold if available 2. Administer
paracetamol
3. Insert new
peripheral IV
39 °C – 40 °C BP > 140/90 Moderate Self limiting Moderate Moderate
1. Reduce infusion (OR increase 1. Reduce infusion seizure 1. STOP infusion 1. Reduce infusion
rate by 50% of diastolic rate by 50% 1. STOP infusion. 2. Administer IV rate by 50%
2. Monitor until pressure 2. Monitor until 2. Monitor vital diphenhydramine 2. Administer IV
temperature is > 20 mmHg) symptoms are signs q 15 min 3. Notify site diphenhydramine
< 39 °C, then 1. Reduce infusion reduced to mild for 15–30 min. physician as 3. Administer
resume regular rate by 50% 3. Resume regular 3. If vital signs soon as possible IV fluids
rate increase 2. Monitor BP infusion schedule are stable and 4. Continue to 4. Monitor patient q
3. Administer every 15 min seizure does not administer 15 minutes until
paracetamol per until BP is recur, resume regular IV fluid symptoms are
schedule < 140/90, then regular infusion 5. Monitor vital reduced to
resume regular schedule signs q 15 min Grade 1 or below,
infusion schedule until reaction then resume
subsides and regular infusion
patient stabilizes schedule
> 40 °C BP > 160/100 Severe Persistent Severe
1. STOP infusion (OR increase 1. STOP infusion seizures 1. STOP infusion
2. Continue to of diastolic 2. When symptoms 1. STOP infusion 2. Assess and
administer pressure are reduced to 2. Assess and secure airway
regular IV fluid, > 30 mmHg) mild, resume secure airway 3. Administer IM
paracetamol 1. STOP infusion infusion rate 3. Continue to epinepherine
3. External cooling 2. Administer BP at 50% administer regular 4. Supplemental
measures medications if 3. Monitor at IV fluid, diazepam oxygen
(if available) available 50% rate for 4. Monitor vital 5. Volume
4. When 3. When BP is 15–30 min signs every resuscitation:
temperature is reduced 4. If reaction does 15 min until 1–2 L IV as
< 39 °C, resume < 140/90, not re-occur, seizures subside needed
infusion rate resume infusion resume regular and patient 6. For broncho-
at 50% rate at 50% infusion schedule stabilizes spasm resistant Patien
5. Monitor at 50% 4. Monitor at 50% 5. When stable, to IM epinephrine,
rate for 15–30 rate for 15–30 resume infusion give salbutamol
min with vital min with vital at 50% previous via nebulizer, • Re
signs q 15 min signs q 15 min rate or inhaler
6. If reaction does 5.If reaction does 6. Monitor for 7. IV diphen-
• Th
not re-occur, not re-occur, 15–30 min with hydramine • Ins
resume regular resume regular vital signs every 8. Monitor vital
infusion schedule infusion schedule 15 min signs q 15 min
18
7. If seizures do not until reaction the
re-occur, resume subsides and foa
regular infusion patient stabilizes
schedule the
• Th
REPORT: Access the website using the QR code provided on the product.
(0.
Preparation and administration of mAb114 for Ebola virus disease (EVD) • Inv
2 August 2022
© World Health Organization 2022. Some rights reserved. • Inf
29
Annex 2
Neutralizing monoclonal antibody cocktail REGN-EB3 for Ebola virus disease
(EVD): guidance for health care workers
Neutralizing monoclonal antibody cocktail

REGN-EB3 for Ebola virus disease (EVD)
REGN-EB3 is also known by the commercial name INMAZEB™ and molecular names Guidance for health care workers
atoltivimab, maftivimab, odesivimab.
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.
CLINICAL INDICATIONS
• All patients with RT-PCR confirmed EVD caused by Zaire
ebolavirus, including children, pregnant
women, breastfeeding women and older people.
• Neonates < 7 days, without EVD RT-PCR confirmation,
born to mothers with RT-PCR confirmed EVD.
Patients should receive REGN-EB3 as soon as possible
after confirmation of RT-PCR diagnosis of EVD.
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
• 50 mg of maftivimab per kg
2-8 °C
• 50 mg of odesivimab per kg
diluted and administered as a single intravenous (IV) infusion. COVID-19
Volume of REGN-EB3 needed (mL) = body weight (kg) x 3

C
Number of vials of REGN-EB3 needed = volume of REGN-EB3 / 14.5 G 2-8 °C
M
STORAGE COVID-19
Prior to dilution C
2-8 °C G
Store REGN-EB3 vial refrigerated at 2 °C to 8 °C (36 °F to 46 °F) -0 °C M
in the original carton to protect from light. Do not freeze or shake. COVID-19
After dilution TABLE 1. StorageC conditions depending

The maximum duration between preparation of the diluted on the different
G dilution solutions
-0 °C
M
REGN-EB3 to completion of administration to the patient Dilution solution Storage conditions
depends on the dilution solution used and the storage 0.9% sodium chloride Store at room temperature up to
conditions within the times in table one. 25 °C for no more than 8 hours
or refrigerated at 2 °C to 8 °C
• If the infusion is stopped for any reason, it can be restarted -0 °C for no more than 24 hours.
as long as the time from dilution to completing the infusion 5% dextrose solution or Store at room temperature up to
remains within the time stated in table one. Ringer’s lactate solution 25 °C for no more than 4 hours
or refrigerated at 2 °C to 8 °C
• If the timeframe has been exceeded the remaining dosage for no more than 4 hours.
required for the patient should be calculated, new vials
Expiry
prepared, diluted then administered and the excess diluted
The expiration date for the product is available via a
drug should be safely disposed. Drugs should not be moved product-specific website, which is frequently updated
from high-risk to low-risk zones for temporary storage. (www.regeneron.com).
Neutralizing monoclonal antibody cocktail REGN-EB3 for Ebola virus disease (EVD)
2 August 2022
WHO reference number: WHO/EVD/therapeutics/REGN-EB3/Poster_A/2022.1
Preparation and administration of

REGN-EB3 for Ebola virus disease (EVD)
ers 1. CALCULATE DOSE 2. DILUTE 3. ADMINISTER 4. MONITOR
1. CALCULATE DOSE
• Weigh the patient.
• Calculate the dose as per Table 2.
TABLE 2. Dose, number of vials, total diluted infusion volume and infusion time of REGN-EB3
solution (REGN-EB3 and

Volume of dose REGN-

Infusion time of diluted

dilution solution) (mL)

Total diluted infusion

Dose of REGN-EB3
Dose of REGN-EB3
Dose of REGN-EB3
Body weight (kg)
Body weight (kg)
Body weight (kg)

infusion solution
infusion solution
infusion solution
Number of vials
Number of vials
Number of vials
EB3 (mL)
EB3 (mL)
EB3 (mL)
(mg)
(mg)
(mg)
1 50 3 1 15 4 hours 35 1750 105 8 250 2 hours 69 3450 207 15 500 2 hours
33 1650 99 7 250 2 hours 67 3350 201 14 500 2 hours
34 1700 102 8 250 2 hours 68 3400 204 15 500 2 hours
Note: The recommended infusion volume ensures the final concentration of the diluted solution is between 9.5 mg/mL to 23.7 mg/mL
Preparation and administration of REGN-EB3 for Ebola virus disease (EVD)

2 August 2022
WHO reference number: WHO/EVD/therapeutics/ REGN-EB3/Poster_B/2022.1
Annex 2. REGN-EB3 31
Preparation and administration of REGN-EB3 for Ebola virus disease (EVD) Guidance for health care workers
2. DILUTION
• Prepare REGN-EB3 in a clean dedicated space in the • Withdraw and discard solution from the
low-risk zone. IV bag equal to the calculated volume of REGN-EB3
• Wash hands per protocol. in mL required, using appropriately sized syringe and
21-gauge needle following standard aseptic techniques.
• Remove vials from the refrigerator and allow them to
reach room temperature. • Add the calculated volume of REGN-EB3 required to the
IV bag of dilution solution.
• Check there is no discolouration in the content of any vial.
• Invert the IV bag 10 times to ensure thorough mixing.
• Select type of dilution solution and volume required
Do not shake.
(Table 2), either:
− 0.9% sodium chloride • Label the IV bag with the patient’s name, date of birth,
− 5% dextrose (recommended solution for neonates) or weight in kg, dose of REGN-EB3 included and date/time
− Ringer’s lactate solution. of drug expiration.
3. ADMINISTER
• Introduce yourself to the patient and explain that you • Record the time and date the infusion was started.
are planning to administer the medication. • Flush the line at the end Remember the
• Do not mix with or administer with other of the infusion. FIVE RIGHTS
medicinal products. − When the infusion bag is of drug administration:
almost empty, hang a
• Allow the diluted infusion solution to reach room ATION RIGH
TP
DIC AT
temperature prior to administration. 250-mL 0.9% sodium ME
chloride flush bag or
IEN
HT
• Administer the diluted infusion solution via infusion
RIG
T
pump (for paediatric patients < 20 kg it is preferable) inject at least an
or manually through an IV giving set containing a sterile additional 50 mL of IV
SC
mg
OSE
5 ml
in-line or add-on 0.2-micron filter. Casirivimab 600 mg + imdevimab 0.9% of sodium chloride
RIG H T
4
1 1
2
600 mg for intravenous infusion (total Oraldose 1200 mg)

3
HT D
Casirivimab 600 mg + imdevimab 600 mg intofor
theintravenous
IV infusioninfusion
bag. (total dose 1200 mg)
5 ml
• Select the appropriate infusioninfusion

rate. bag
ROU
Size of prefilled Preparing casirivimab and imdevimab using individual vialsa IIIIIIIIIIII
RIG
III II
II I
II
II
IIIIIIIIIIII
III
If manually: drip rate = (total volume (mL) / minutes) Into a prefilled 0.9% sodium chloride or 5% dextrose
IIIIIIIIIIII
TE
Casirivimab 600 mg + imdevimab 600 mg for intravenous infusion (totalinfusion
dose 1200 bag mg)
inject
III
II
II
I II
II III
IIIIIIIIIIII
x drop factor* Size of prefilled infusion bag Preparing casirivimab and imdevimab using individual vialsa
RIG HT TI M E
* Check the giving set packaging! 1
1
2 1
1
50 mL 2 3 2 3
100 mL
50 mL 150 mL 5 mL 5 mL
3 4 3 4
100 mL 250 mL 5 mL 5 mL
5 ml 5 ml
150 mL
4 4
4. MONITOR
1 1
250 mL
5 ml 2
52 ml
50 mL START
3 3
100 mL 150 mL 5 mL 5 mL
4 4
250 mL
5 ml 5 ml
• Monitor patient symptoms and vital signs: heart rate, Casirivimab Imdevimab
Casirivimab Imdevimab
blood pressure, respiratory rate and oxygen saturation: 5 mL of casirivimab (use two 6-mL vials of casirivimab OR 5-mL of one 20-mL vial) AND
Casirivimab Imdevimab
hour minute
5 mL5ofmLcasirivimab (use two

of imdevimab (useSTART6-mL vials of casirivimab
two 6-mL vials of imdevimab OROR
5-mL of one
5-mL 20-mL
of one AND
vial)vial)
20-mL
− immediately before infusion 5 mL 5ofmL
imdevimab (use(use
of casirivimab twotwo
6-mL vials
6-mL of of
vials casirivimabOR
imdevimab OR5-mL of one
5-mL of one20-mL
20-mLvial)
vial)
AND
− 15 minutes after starting the infusion .
− 1 hour into the infusion

hour minute
hour minute
START
− at the end of the infusion

− if any clinical deterioration during the infusion, take vital START
.
hour minute
hour minute hour minute
signs more frequently

50 mL and assess the patient clinically.
1
2
3
FINISH
4
100 mL
1
2 1 5
150 mL 7.7 mL
3 2 6
50 mL 250 mL
3 7
50 mL
4 .
100 mL
. .
4 8
100150
mLmL 150 mL
5 5 9
7.77.7
mLmL
hour minute 6 hour minute hour minute
6hour 10 ml
minute
250 mL250 mL
7 7
8 8
9 9
10 ml 10 ml
EXAMPLE hour
.
minute
hour
.
minute hour minute
Patient weighting 50 kg FINISH

50 kg =
• Recommended dosage is 2500 mg of atoltivimab, 2500 mg of START .
11 vials
hour minute
hour minute
maftivimab and 2500 mg of odesivimab OR 150 mL of REGN-EB3. FINISH

• The dosage requires 11 vials of REGN-EB3.
hour minute
10
. 10 10
20
• Take an IV bag of 500 mL of dilution solution (0.9% sodium

10
20 30
hour minute 30 20
40
20
40 50
500 500
mL mL
10 50 30
30 60
10
20 60
FINISH
70
40
30 70
40
chloride, Ringer’s lactate 150

or150
5% mLdextrose solution).
20 80 80
40 90 ml
90 ml
50 50
50
mL 500 mL
30 100 100
250 mL
60
250 mL
110 110 .
70
40 120 120
80
150 mL
130
150 mL
130 hour minute
• Withdraw and discard 150150

mL mL 250of
mLthe solution with an
90 ml 140
50 140
100 150 ml 150 ml
110
120
150 mL
130
140
appropriately sized syringe and 21-gauge needle following

150 ml
REGN-EB3
REGN-EB3
standard aseptic techniques. hour minute
REGN-EB3 Invert 10 times

• Inject 150 mL of REGN-EB3 into the infusion solution to have a
total infusion solution of 500 mL .
• Invert 10 times (do not shake).

hour minute
• Infuse the 500 mL of diluted infusion solution over 2 hours. 2 hoursFINISH

2 August 2022
Preparation and administration of REGN-EB3 for Ebola virus disease (EVD) Guidance for health care workers
HYPERSENSITIVITY AND INFUSION REACTIONS

Hypersensitivity reactions including infusion-associated events have been reported during and post-infusion
with REGN-EB3. The most common adverse events (incidence ≥ 20%) are pyrexia, chills, tachycardia, tachypnoea
and vomiting. The rate of infusion of REGN-EB3 may be slowed or interrupted if the patient develops any signs of infusion-
associated events.
IF SIGNS OR SYMPTOMS OF A CLINICALLY SIGNIFICANT HYPERSENSITIVITY REACTION OR ANAPHYLAXIS
OCCUR, IMMEDIATELY DISCONTINUE THE INFUSION AND INITIATE APPROPRIATE MEDICATIONS, SUPPORTIVE
THERAPY AND AIRWAY MANAGEMENT.
INFUSION REACTION GUIDE

Suggestions only – not meant to replace existing clinical guidelines or alter clinical judgment.
INFILTRATION FEVER HYPERTENSION OTHER SEIZURES ANAPHYLAXIS ALLERGIC
SYMPTOMS: REACTION
(Watch for pain, SHIVERING
swelling, tightness HYPOTENSION
around injection OEDEMA
site; skin cooling/ PERIPHERAL
blanching; leakage NEUROPATHY
at insertion site)
1. STOP infusion
38 °C – 39 °C Mild Mild Brief, no loss of
1. Continue 1. Continue 1. Continue consciousness
2. Discontinue IV
infusion, monitor infusion, monitor infusion, monitor 1. Continue
site, bandage,
vital signs vital signs vital signs infusion, monitor
apply heat OR
patient
cold if available 2. Administer
paracetamol
3. Insert new
peripheral IV
39 °C – 40 °C BP > 140/90 Moderate Self limiting Moderate Moderate
1. Reduce infusion (OR increase 1. Reduce infusion seizure 1. STOP infusion 1. Reduce infusion
rate by 50% of diastolic rate by 50% 1. STOP infusion. 2. Administer IV rate by 50%
2. Monitor until pressure 2. Monitor until 2. Monitor vital diphenhydramine 2. Administer IV
temperature is > 20 mmHg) symptoms are signs q 15 min 3. Notify site diphenhydramine
< 39 °C, then 1. Reduce infusion reduced to mild for 15–30 min. physician as 3. Administer
resume regular rate by 50% 3. Resume regular 3. If vital signs soon as possible IV fluids
rate increase 2. Monitor BP infusion schedule are stable and 4. Continue to 4. Monitor patient q
3. Administer every 15 min seizure does not administer 15 minutes until
paracetamol per until BP is recur, resume regular IV fluid symptoms are
schedule < 140/90, then regular infusion 5. Monitor vital reduced to
resume regular schedule signs q 15 min Grade 1 or below,
infusion schedule until reaction then resume
subsides and regular infusion
patient stabilizes schedule
> 40 °C BP > 160/100 Severe Persistent Severe
1. STOP infusion (OR increase 1. STOP infusion seizures 1. STOP infusion
2. Continue to of diastolic 2. When symptoms 1. STOP infusion 2. Assess and
administer pressure are reduced to 2. Assess and secure airway
regular IV fluid, > 30 mmHg) mild, resume secure airway 3. Administer IM
paracetamol 1. STOP infusion infusion rate 3. Continue to epinepherine
3. External cooling 2. Administer BP at 50% administer regular 4. Supplemental
measures medications if 3. Monitor at IV fluid, diazepam oxygen
(if available) available 50% rate for 4. Monitor vital 5. Volume
4. When 3. When BP is 15–30 min signs every resuscitation:
temperature is reduced 4. If reaction does 15 min until 1–2 L IV as
< 39 °C, resume < 140/90, not re-occur, seizures subside needed
infusion rate resume infusion resume regular and patient 6. For broncho-
at 50% rate at 50% infusion schedule stabilizes spasm resistant
5. Monitor at 50% 4. Monitor at 50% 5. When stable, to IM epinephrine,
rate for 15–30 rate for 15–30 resume infusion give salbutamol
min with vital min with vital at 50% previous via nebulizer,
signs q 15 min signs q 15 min rate or inhaler
6. If reaction does 5.If reaction does 6. Monitor for 7. IV diphen-
not re-occur, not re-occur, 15–30 min with hydramine
resume regular resume regular vital signs every 8. Monitor vital
infusion schedule infusion schedule 15 min signs q 15 min
7. If seizures do not until reaction
re-occur, resume subsides and
regular infusion patient stabilizes
schedule
REPORT: Access the website using the QR code provided on the product.

2 August 2022
For further information, contact:
World Health Organization
20, Avenue Appia
CH-1211 Geneva 27
Switzerland
www.who.int

Therapeutics For Ebola Virus Disease: 19 August 2022

Uploaded by

Copyright:

Available Formats

Therapeutics For Ebola Virus Disease: 19 August 2022

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Therapeutics For Ebola Virus Disease: 19 August 2022

Uploaded by

Copyright:

Available Formats

Therapeutics for Ebola virus disease

ISBN 978-92-4-005574-2 (electronic version)

© World Health Organization 2022

Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris.

Design and layout: L’IV Com Sàrl

Executive summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

2. Methods: how this guideline was created. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

4. How to access and use this guideline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

5. Uncertainties and future research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Annex 2. Neutralizing monoclonal antibody cocktail REGN-EB3 for Ebola virus

Methods Chair: Gordon Guyatt (McMaster University, Canada).

Funding source: This guideline was funded with Unitaid funds.

Anti-TNF anti-tumor necrosis factor

ALT/AST alanine aminotransferase/aspartate aminotransferase

CFR case fatality rate

CT value cycle threshold value

DOI declaration of interests

EBOV Ebola virus

EOI Expression of Interest

EVD Ebola virus disease

GDG Guideline Development Group

GRC Guideline Review Committee

GRADE Grading of Recommendations Assessment, Development and Evaluation

HIV human immunodeficiency virus

ICEMAN Instrument to assess the Credibility of Effect Modification Analyses

NMA network meta-analysis

PALM Pamoja Tulinde Maisha (Together Save Lives) (in Kiswahili)

PICO population, intervention, comparator, outcomes

RBD receptor binding domain

RCT randomized controlled trial

RT-PCR real-time polymerase chain reaction

WHO World Health Organization

New recommendations: The GDG made the following recommendations:

Nomenclature: To facilitate comprehension, this guideline maintained the therapeutic names as

Name used in RCTs mAb114 REGN-EB3 remdesivir ZMapp

2. Methods: how this guideline was

Step 2: Finalizing the research question (population, intervention, comparator, and

Table 1. Population subgroups and pre-specified direction of effect

Subgroups Categories Risk of mortality by category Postulated direction of effect

Outcome prioritization results

Table 2. Outcome prioritization scores of GDG participants and EVD patients

These steps led to the generation of a final PICO, displayed in Table 3.

Table 3. Final research question (PICO)

Population All patients with confirmed EVD of any disease severity

Step 3: Evidence synthesis and GRADE

Step 4: Final recommendations

The following key factors informed transparent and trustworthy recommendations:

3.1 Recommendation for mAb114 and REGN-EB3

Strong recommendation for

Certainty of the evidence

Values and preferences

Resources and other considerations

Acceptability and feasibility

mAb114 prescribing information

Dosage and route of mAb114

For detailed information on dosing, see Annex 1.

REGN-EB3 prescribing information

Dosage and route of REGN-EB3

For detailed information on dosing, see Annex 2.