Essential medicines and health products

Ebola vaccines, therapies, and diagnostics

Questions and Answers

6 October 2015

This Q&A provides answers to questions about clinical trials and evaluations of potential vaccines, therapies, and diagnostics for Ebola virus disease. Additional questions and answers about the epidemiology of the disease, as well as infection prevention and control, clinical treatment, and recommendations for travel, can be found at: http://who.int/csr/disease/ebola/faq-ebola/en/

VACCINES

Is there a vaccine to protect against Ebola virus disease?

At this time, there are no vaccines to protect against EVD licensed for use in humans. Clinical trials for several candidate vaccines are in various phases and a safe and effective vaccine is hoped for by the end of 2015.

Which vaccines are in development?

Results from Phase I clinical trials for two vaccine candidates – ChAd3-ZEBOV, developed by GlaxoSmithKline (GSK) in collaboration with the US National Institute of Allergy and Infectious Diseases (NIAID), and VSV-EBOV, developed by NewLink Genetics and Merck Vaccines USA in collaboration with the Public Health Agency of Canada – were obtained in January. Both vaccine candidates have been shown to be safe and well tolerated in humans. The results from the trials were published in the New England Journal of Medicine.

Currently, Phase II and Phase III clinical trials for VSV-EBOV are underway in Guinea (Ebola ça suffit!) and Sierra Leone (STRIVE). The data from the Guinea Phase II Front Line Worker and the Phase III ring vaccination trials will be reviewed in the coming weeks by the trial Data Safety and Monitoring Board (DSMB). The Board will determine if sufficient data has been compiled to reach a conclusion on efficacy. A Phase II/III study (PREVAIL) in Liberia was started, but due to zero cases of EVD until recently, the trial is in the process of being extended to Guinea.

Johnson & Johnson, in association with Bavarian Nordic, has developed a 2-dose vaccination approach for Ebola using different vaccines for the first and second doses. This approach is known as heterologous prime-boost. The two vaccine candidates are known as Ad26-EBOV and MVA-EBOV. Results from Phase I evaluation in humans are available.

Novavax, a biotech company in the US, has developed a recombinant protein Ebola vaccine candidate based on the Guinea 2014 Ebola virus strain and has completed a Phase I human clinical trials in Australia.

An additional vaccine candidate has recently finished early stage human clinical testing in China.

The Russian Federal Ministry of Health is developing a recombinant influenza candidate Ebola vaccine, as well as other approaches. The recombinant influenza candidate is scheduled to start Phase I trials in the second half of 2015. Other products in development include an oral adenovirus platform (Vaxart), an alternative vesicular stomatitis virus candidate (Profectus Biosciences), an alternative recombinant protein (Protein Sciences), a DNA vaccine (Inovia) and a recombinant rabies vaccine (Jefferson University) among others.

Which vaccines are being tested and where?

Product / Company

Phase

Trial Location

Dates

ChAd3-ZEBOV

GlaxoSmithKline and PHAC

Phase I

By VRC at NIH, USA

September 2014

By Oxford University in the UK

By CVD in Mali

October 2014

At the University of Lausanne, Lausanne, Switzerland

rVSV-ZEBOV

NewLink Genetics and Merck Vaccines USA

Phase I

By WRAIR in the US

October 2014

By NIAID in the US

By CTC North GmbH in Hamburg, Germany

November 2014

At Albert Schweitzer Hospital in Lambarene, Gabon

At the University of Geneva, Geneva, Switzerland

At the IWK Health Center, Halifax, Canada

By KEMRI Wellcome Trust in Kilifi, Kenya

December 2014

Ad26-EBOV and MVA-EBOV

Johnson & Johnson and Bavarian Nordic

Phase I

By University of  Oxford in the UK and NIAID, USA

January 2015

TBD, Kenya

  Second half of 2015

TBD, Uganda

TBD, United Republic of Tanzania

Recombinant protein Ebola vaccine candidate

Novavax

Phase I

Australia

February 2015

ChAd3-ZEBOV

GlaxoSmithKline and PHAC

Phase II

TBD, Cameroon

Second half of 2015

TBD, Ghana

TBD, Mali

TBD, Nigeria

TBD, Senegal

VSV-EBOV

NewLink Genetics and Merck Vaccines USA

Phase III

By WHO, Médecins Sans Frontiéres (MSF) and Government of Guinea in

Conakry, Guinea

April 2015 –

Ring vaccination trial design.

As of 17 July, 103 rings comprising approximately 4 000 volunteers have been vaccinated.

VSV-EBOV

Phase III

By Médecins Sans Frontiéres (MSF),  WHO and Government of Guinea in Conakry, Guinea

March 2015 – A vaccine trial for front line workers only. As of 19 June, more than 800 volunteers have been vaccinated. The target number is 1 200.

ChAd3-ZEBOV

GlaxoSmithKline and PHAC

and

VSV-EBOV

NewLink Genetics and Merck Vaccines USA

Phase II/III

By US NIH and MOH Liberia in

Monrovia, Liberia

March 2015 –

Randomized control trial design

As of 30 April, Phase II enrollment of 1 500 volunteers in Liberia was completed.

VSV-EBOV

NewLink Genetics and Merck Vaccines USA

Phase III

By US CDC and MOH Sierra Leone in

Freetown, Sierra Leone

April 2015 –

Cluster based, non-blinded, individually randomized trial design.

As of 18 June, approximately 6 000 frontline workers had been enrolled with half of them vaccinated.

 

Pre-clinical trials

Pre-clinical trials are carried out in laboratories and animals and aim to: 1) determine whether a vaccine works as intended and 2) to identify any harmful effects.

Clinical trials

Phase I trials involve 20 to a few hundred healthy individuals and examine safety and immune response. They also identify commonly-occurring adverse reactions.

Phase II trials involve several hundred to a few thousand people and determine the optimum vaccine composition for achieving protection while ensuring safety.

Phase III trials involve thousands to tens of thousands of people and examine the vaccine's ability to prevent a disease as intended. They also provide further safety information.

Post-licensure monitoring or formal Phase IV trials involve the target population. These surveillance activities identify, through spontaneous reporting systems to health authorities, less common adverse events, events which could occur after a long time, or events that may occur in specific subgroups of the target population.

Which other treatments, therapies, or devices are available or being evaluated?

CONVALESCENT BLOOD AND PLASMA

Transfusion of convalescent whole blood and plasma has been prioritized for use as an investigational therapy. Convalescent whole blood donated by EVD recovered patients was currently being administered in some Ebola treatment centres in Sierra Leone. Trials using convalescent plasma are underway in Liberia and Guinea.

Product / Company

Phase

Trial Location

Status

Convalescent plasma

Phase II/III

At MSF Ebola Treatment Centre, Donka Hospital, Conakry, Guinea

Managed by ITM Antwerp and 15 partners; funded by the European Commission and the Wellcome Trust

As of 19 June, 101 patients were treated with convalescent plasma.

Convalescent plasma

Phase II/III

Liberia

Managed by ClinRM and Duke University; funded by the Bill and Melinda Gates Foundation (BMGF).

Before Liberia was declared Ebola free on 9 May, convalescent plasma transfusions had been administered on a compassionate basis. Due to zero cases of Ebola until recently, the study in Liberia was discontinued.

Convalescent plasma

Phase II/III

Sierra Leone

Managed by the University of Liverpool, in collaboration with 15 other partners; funded by the Wellcome Trust and BMGF.

As of 5 October, 3 patients have been treated with Convalescent plasma and 88 donations have been successfully collected. The first use of an apheresis machine was completed and resulted in the successful collection of 750 ml of plasma.

 

Assessments of national capacities for ensuring the safety of blood products outside of clinical trial settings and plans for recovery and strengthening of national blood transfusion services in the affected countries are being developed.

DRUGS AND MEDICINES

Of the pre-existing medicines that were considered for re-purposing to treat Ebola, several are either being tested or considered for testing in patients with EVD or have already been used in patients with EVD. A few other therapies have also been considered for use in treatment, but have been deemed not to be appropriate for further investigation. Of the novel products, like FX06 and Zmab, some have shown initial promise in models and a few have been administered to a small number of Ebola patients on a compassionate basis. However, these cases are too few to permit any conclusion regarding safety and efficacy. Several drugs have also been used in clinical settings without prior review by WHO, including amiodarone, atorvastatin + irbesartan +/- clomiphene.

The drugs have been evaluated by the WHO Science and Technical Advisory Committee on Emergency Ebola Interventions (STAC-EE) and categorized as follows:

  • Drugs already under evaluation in formal clinical trials in West Africa.
  • Drugs that have been prioritized for testing in human efficacy trials, but for which such trials are not yet underway.
  • Drugs that have already been given to patients for compassionate reasons or in ad hoc trials.
  • Drugs that demonstrate promising anti-Ebola activity in-vitro or in mouse models, but for which additional data should be generated prior to proceeding to clinical trials.
  • Drugs that had been prioritized or considered for prioritization and have now been deprioritized based on new data or more detailed analysis of old data.

Product / Company

Phase

Trial Location

Description

Favipiravir

Fujifilm/Toyama, Japan

Phase II

By INSERM in

Guinea: Conakry, Guéckedou, Macenta, Nzérékoré

Used to treat influenza.

Clinical trials began in December 2014. Preliminary data presented in February 2015 does not permit a firm conclusion regarding efficacy and more data is required; trial continues.

The drug has been administered to around 200 patients who received 9 days of oral treatment. There is no control group.

The trial is at ETUs in Gueckedou, Nzerekore, Donka, and Conakry and is led by INSERM with funding from the European Commission.

The EU has announced preliminary findings from these trials which show the antiviral may be effective in treating patients with early stage EVD. In adults and adolescents with a low to moderate viral load, the case fatality rate was 15% (vs 30%, historically). WHO is taking a cautious interpretation given the lack of concurrent controls in the study.

TKM-100802 (siRNA)

Tekmira, Canada

Phase II

By Oxford University in

Kerry Town, Sierra Leone

siRNA – a short RNA sequence that cleaves Ebola RNA in cells and prevents virus multiplication. Treats 100% of infected monkeys.

A clinical trial started in early March 2015 in Port Loko, Sierra Leone, led by Oxford University with funding from the Wellcome Trust.

The trial was halted on 19 June on the grounds of having met one of the clinical endpoints. Continuing enrolment was not likely to demonstrate an overall therapeutic benefit.

ZMapp

MappBio USA

Phase II

By NIAID in

Liberia, Sierra Leone and the United States of America

Cocktail of three monoclonal antibodies with neutralizing activity against Ebola virus in animal models. Treats 100% of infected non-human primates (NHP). The product has been used on several patients under compassionate use.

A multi-country, multisite randomized controlled trial opened to enrollment in Liberia and the United States in February 2015 and in Sierra Leone in March 2015. Enrollment is ongoing – currently, more than 35 patients have been enrolled.

No data on efficacy is available yet.

Preparations to extend this trial to Guinea (in collaboration with INSERM) are in progress.

MIL-77

MabWorks, China

Phase I

 

Cocktail of three monoclonal antibodies with the same sequence as the monoclonals in Zmapp, yet made in CHO cells.

Efficacy in monkeys comparable to Zmapp.

To date, used in two expatriated patients under compassionate use.

IND for Phase I filed in China.

Prioritized for use on Ebola patients in condition of not interfering with the clinical assessment of efficacy of Zmapp.

BCX-4430

Biocryst, USA

Phase I

By Quotient Clinic in the UK

Broad-spectrum direct-acting nucleoside analogue.

Phase I safety trial is underway. No efficacy trial is planned until safety data have been analysed.

Interferons

Phase II

By Guinea MOH in

Coyah, Guinea

Approved for treatment of HepB and C and multiple sclerosis.

Guinean authorities, in collaboration with Canadian scientists, launched a clinical study of an interferon in Ebola-infected patients. Due to risks of symptom exacerbation, enrollment limited to patients with recent symptom onset. To date, 9 patients have been enrolled in the trial.

Amiodarone

Observational

At the Lakka & Goderich ETU in

Sierra Leone

Used to treat cardiac dysrhythmia.

Was used compassionately in approximately 80 patients in Sierra Leone and reportedly reduced case fatality ratio when compared with local historical norms. The statistical significance of this result is not known due to variations in case fatality rates across sites and over time.

This treatment is no longer being used.

Atorvostatin + Irbesartan +/- Clomiphene

Sierra Leone

Approved for cholesterol control / hypertension / infertility, respectively.

Apparently used to treat some patients in Sierra Leone, however, there has been no confirmation from the treatment centres that such studies took place, and no clinical data on the patients are available. Therefore, no conclusion on utility, safety or efficacy is possible.

FX06

Peptide for use in treating vascular leakage.

Administered compassionately to two patients. No conclusions can be drawn yet.

Zmab

Non-GMP experimental monoclonal antibody product with no plans for GMP production.

Administered on a compassionate basis to a few patients when other products are not available.

Amodiaquine

 

Médecins Sans Frontiéres (MSF)

Antimalarial products were provided to all patients entering Ebola treatment centres. When MSF switched from an antimalarial containing lemefantrine to one containing amodiaquine, the case fatality rates dropped.

It is not known if this is due to efficacy of amodiaquine against Ebola or to toxicity of lemefantrine in patients with EVD.

Brincidofovir

Chimerix, USA

Phase II

By Oxford University at the

ELWA 3 Clinic, Monrovia, Liberia

An antiviral used to treat CMV.

Clinical trial halted and abandoned; the drug has been deprioritized for use in Ebola treatment.

 

An analysis of available data from compassionate use of several therapeutic options in patients with Ebola in Europe did not lead to interpretable findings, due to polytherapy and non-standardized data collection.

WHO has also begun prioritizing the anti-malarial drug amodiaquine for testing in non-human primates. The use of this drug has been observed, in some populations, to be temporally associated with a reduction in case fatality rate. Although studies in mice show no therapeutic potential, empirical data warrant further investigation. Studies are being initiated to explore its prophylactic potential.

WHO is working with all relevant stakeholders on each of the potential therapies and vaccines to continue to accelerate identification, verification, development, and, if safety and efficacy are found, deployment.

A list of drugs that have been categorized and prioritized for consideration for testing or use in patients infected with Ebola has been published.

DIAGNOSTICS

How is Ebola virus disease (EVD) diagnosed?

The symptoms for EVD are similar to the onset of many diseases, including influenza and malaria. The best way to diagnose whether someone with suggestive symptoms is infected with EVD is by taking a body sample, such as blood, and sending it to a laboratory that is properly equipped to handle potential Ebola specimens. In some cases, this may be a biosafety level (BSL) 3 or 4 laboratory in a neighbouring city or country. In field situations, mobile laboratories can be established in order to reduce the time between transport of the specimens and return of results. In the case of EVD, the delay caused by the need to transport specimens creates significant logistical problems with the management of potential but unconfirmed cases of EVD.

Have any new diagnostics been approved for use in the current Ebola outbreak?

Product / Company

Description

RealStar® Filovirus Screen PT-PCR Kit 1.1

Altona Diagnostics GmbH, Germany

In vitro diagnostic test that detects filovirus-specific RNA in human plasma using the QIAamp® Viral RNA Kit for RNA extraction. The assay is designed to detect all filoviruses.

ReEBOV Antigen Rapid Test Kit

Corgenix, USA

This is an antigen test based on detection of the Ebola matrix protein VP40 rather than nucleic acid.

Liferiver™ Ebola Virus (EBOV) Real Time RT-PCR Kit

Shanghai ZJ Bio Tech Co. Ltd., China

In vitro diagnostic test, based on real-time PCR technology intended for the detection of all highly pathogenic members of Ebolavirus: Zaire ebolavirus (ZEBOV), Sudan ebolavirus (SUDV), Taï Forest ebolavirus (TAFV) and Bundibugyo ebolavirus (BDBV) in blood, serum, plasma (non-heparin anticoagulant).

Xpert® Ebola Assay

Cepheid, Sweden

The assay is a cartridge based (all reagents contained in the cartridge) that is used with the GeneXpert systems platforms that can accommodate other assays such as HIV viral load, TB, HIV qualitative and many more.

It is a real-time reverse transcription polymerase chain reaction (RT-PCR) assay but with no front end manipulation required (extraction and amplification take place in the cartridge itself) so less prone to contamination and better suited for staff without formal laboratory training. 100 times more sensitive than the benchmark assay (Altona).

 

New WHO guidance on “Selection and use of Ebola in vitro diagnostic (IVD) assays” has been published.

Recently, a field study of 4 rapid diagnostic tests (RDTs) was performed in Sierra Leone. Data analysis is expected to be completes by 10 July and may influence WHO’s future guidance to countries.

What other devices or equipment are available for treatment of EVD?

Integral to the safe and effective treatment of EVD is the need for appropriate personal protective equipment and essential medicines for providing supportive care to persons with Ebola. A list of equipment and medicines can be found below.

What are the ethical considerations for use of unregistered interventions?

On 11 August 2014, WHO convened an Ethics Panel to consider and assess the ethical implications of the potential use of unregistered interventions. The panel reached consensus that in the particular circumstances of this outbreak, and provided certain conditions are met, it is ethical to offer unproven interventions for which the safety and efficacy have not yet been demonstrated in humans as potential treatment or prevention. Key conditions relate to the evidence and ethical basis for the assessment of each intervention. There should be a strong scientific basis for the hypothesis that the intervention will be effective against EVD in humans: the unregistered interventions to be offered should have been demonstrated to be safe and efficacious in relevant animal models, and in particular, in non-human primates. In addition, use of such interventions should be based on the best possible assessment of risk and benefit from the information available at a given time.

Ethical criteria must guide the provision of such interventions and should include: transparency about all aspects of care; informed consent; freedom of choice; confidentiality; respect for the person; preservation of dignity; and involvement of the community. The panel advised that there is a moral obligation to collect and share all data generated, including from treatments provided for compassionate use. In addition, several areas where identified that need more analysis and discussion:

  • ethical ways to gather data while striving to provide optimal care under the prevailing circumstances;
  • ethical criteria to prioritize the use of unregistered experimental therapies and vaccines; and
  • ethical criteria for achieving fair distribution of therapies and vaccines in communities and among countries.
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Last update:

21 November 2015 00:35 CET