Community Research and Development Information Service - CORDIS

H2020

IF-EBOla Report Summary

Project ID: 666102
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - IF-EBOla (Control of the Ebola Oubreak by both innovative Ultrasensitive Detection of EBOV and therapy)

Reporting period: 2014-11-01 to 2015-10-31

Summary of the context and overall objectives of the project

Our proposal has been strategically designed to efficiently respond to critical needs required to control the current EBOV outbreak from spreading. The work will involve two of the main EVD outbreak sites (Sierra Leone, Guinea) and an endemic EBOV area, the DRC. MDs, public health authorities and virus experts working on site will extend their collaboration to companies and institution to form a consortium of outstanding complementary partners, sharing their innovative technological approaches for a common goal. Our proposal includes 2 phases: (I) an urgent-response phase and (II) a long-term preparedness phase. Phase I seeks to: (a) deploy ultra-mobile autonomous laboratories to
be close to patients and treatment centers, to process (b) a unique technology to concentrate and clean viruses from complex human or animal samples ready to be processed for (c) ultrasensitive viral detection by optimized molecular diagnostics. In order to disrupt transmission chains, our ultrasensitive EBOV diagnostics will mainly focus on close contacts and convalescent patients that are most often asymptomatic or mildly symptomatic and are therefore potential silent transmitters. This will be extremely useful to the chain of decisions leading to the isolation of EBOV+ patients or the release of EBOV- convalescents. II includes: an experimental therapeutic approach and patient profiling to understand the EVD and cure parameters: (a) with the authorization of local ethical committees, early-detected patients (including caregivers) would benefit from early and innovative EC-WHO-strongly supported experimental passive-immune therapy based on neutralizing anti-EBOV polyclonal F(ab’)2 fragments; (b) To better understand the immune response against Ebola and the effect of the therapy, pre and post-treated patients will be followed and characterized at 3 different levels: immune (transcriptomes); infectious (other than EBOV, DNA arrays and NGS), and Ebola quasiespecies (sequence fingerprints).

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

"To carry out this project we have constructed a Work Plan with 6 Work Packages as follows from WP1 to WP6:
WP1 “Coordination, planning, management and reporting” (IRD/AK): IRD with the support of AK will ensure the general management of the project (legal and budget administration), management of technical and financial reporting and EC delivering, coordination of partners, project activities and external institutional relations.
WP1-State of Play (SOP): IRD ha began to work with AK from the beginning of the year 2015. In addition, we have experienced the setting up of the very first amendment of the whole H2020 to include AK among the partners of the IF-EBOLA consortium.

WP2 “Preparation of therapeutic antibodies” (Fab’entech): Production of antibodies and doses for the clinical study. In Q3-Q4 2015 (see below), the first doses could be available in case of emergency and/or major threat of disease expansion, under special access protocol and/or open clinical trial, assuming some regulatory fast-tracking and shared risks (preliminary timings to be confirmed). Accelerated scenario (pending request and approval of regulatory authorities such as EMA ). Given the emergency to answer to the current Ebola epidemic, an accelerated scenario of development could be designed. Depending on the horse’s hyperimmunisation response and the level of specific antibody concentration in collected horse plasmas, we could propose to launch the purification step of a first clinical batch directly after the in vitro proof of concept (POC) by May 2015, allowing the product availability by Q3 2015 (6 to 9 months of development) for emergency cases and clinical trial (timing to be confirmed). However, development and production accelerated planning need to be validated by EMA (on‐going official discussions with them). Especially, this approach would need regulatory fast‐tracks such as rolling submission or/and potential regulatory acceptation with on‐going results based for example on platform data approach and commitments (to be discussed) or/and special access/consideration. The equine plasma will be purified into a clinical/industrial batch according to the validated process developed by Sanofi Pasteur. This process consists of the purification of antibodies into specific polyclonal immunoglobulins in a GMP environment (strictly the same as the one used for Sanofi Pasteur anti‐rabies products and the one used for the already developed Fab’entech products), allowing their use for human injection and consisted in the first potential commercial / use vials. This step also includes the development and validation of a GMP ELISA test for the pharmaceutical release of the product and a stability study of the clinical batch.
WP2-SOP: Fabentech has been generating all the deliverables of this Work Package #2, corresponding to the horse anti-EBOV antibody (F(ab’)2) production and their efficiency control, including the in vitro and in vivo in non-human primates (BSL4 Lyon) neutralization assays. These preliminary experiments have shown that these antibodies can improve the virus-associated physiopathology in treated animals, including at least one of the monkeys that was cured with no detectable viremia. To improve the condition of use, new experiments in animals are programmed (BSL4, Winnipeg, Canada) next trimester. In the new program of the action, we will improve the characterization of these F to generate compassioned GMP lots. Since the WHO declared that EVD epidemic has stopped in all the affected West African countries and since Dr Line Matissen, Chief Program officer for the EBOLA outbreak 2014 suggested us to re adapt the project, we are very keen readapt the project and will do a list of suggestions, such as a pilot trial in humans to see the level of protection that they will generate. This could be useful to protect health care personnel.

WP3 “Field organization, patient Management & Ethical regulations” (Metabiota): this procedure including ethical rules and patient rights will be conducted under the close supervision of Metabiota Inc. including a strong interaction with Ministry of Health, WHO guidelines. Local Medical officers, medical practioners from every Health concerned facility will be part of the consultation and; when needed, social mobilization (contact-tracing) and community counseling (available treatment, palliative or curative).
WP3-SOP: Metabiota has been working with all the fieldwork issues. Since the epidemic landscape has changed and the Sierra Leone Government samples use’s policy has been changed too, we have seen our action be significantly delayed (almost 1-year delay). We have got the approved ethical agreement last August. Now we are waiting for the imminent release of the SLA (service level agreement) to carry out some experiments and ship samples to different places to carry out different works (see WP5). We are trying to extend to Sierra Leone A This WP will be adapted to a new program of the action as well.

WP4 “Clinical study: treatment of patients” (Fab’entech): one trial will be set up in 1 or 3 sites mainly (Metabiota, INMI) focused on patients with early diagnostic at the very beginning of the infection low-symptomatic or asymptomatic (IRD). If the treatment improves the vital prognostic and drastically the viral load, the patient release will be done after 3 or 4 consecutive negative EVOB diagnostic.
WP4-SOP: This WP will be not done due to epidemic changes. We are proposing a deviation to the phase two with complementary work to improve the characterization of horse anti-EBOV F(ab’)2,
WP5 “Homeostatic Profiling in pre- and post –treated individuals“(IRD): This WP’s aim is to rapidly set up the best concentration method of EBOV from different kind of samples (serum, plasma, urine saliva etc) for optimized (OIB) RT-PCR conditions to detect EBOV (IP, UM) in close contacts and convalescents individuals. RT-PCR alternative ultra-rapid methods will be assayed. The evolution of diagnosed patients the Homeostatic profiles (immune, infectious, EOBV adversity) of these early EBOV diagnosed patients will be followed up. They will be compared borderline patients including self cured convalescents and post treatment versus rapid progressors and healthy individuals. Three profiling of characterization will be done (i) immune (IP, IRD, OIB, & BGU), (ii) infectious (OIB, BGU, IRD) & (iii) EVOB quasiespecies (OIB, IP).
WP5-SOP: We have done preliminary experiments to fine tune conditions of capture EBOV from clinical samples and have shown that the ligand ApoH-coated magnetic beads is able to efficiently grab EBOV from clinical samples at least via the gp1. This work will be tuned in Sierra Leone with different human retrospective samples (Low viral load or first negative PCR) and from samples from survivors (looking for residual viral loads). We have generated a huge amount of metagenomic analyses indicating the circulating of EBOV quasispecies, which a majority of them are genetically close to the EBOLA Zaire Makona EM095B isolate. These metagenomic analyses from mores 77 million reads have also revealed that Lassa sequences are highly present (14%) among EBOV-infected patients, in addition to nosocomial bacteria and current local infections such HIV, MTB, malaria. Comparative studies will be run to assess the humoral and cellular immune responses in survivors. Some preliminary data are being generated from survivors infected in Sierra Leone but living outside of the country. The first results are very interesting showing data that could help to design therapies and adapted vaccines. Here all the deliverables has been done, even if they need to be completed because most of the results are preliminary. These data will be completed with the study of RNA expression analyses as soon as we work with high-quality samples from the field. The main aspects of the fieldwork will start in January 15, 2016, adapting the program to a needed deviation to initial program.

WP6 “Dissemination, communication and outreach” (AK/IRD) will act in order to increase the outreach and impact of the project through the wide dissemination of its objectives, activities and outputs.
WP6-SOP: We (Absiskey) have been communicating with the European Commission, media, scientific community, by presenting our data in four international meetings: Gordon Conferences in Ventura California, USA, March 8-13 2015, 7th Filovirus international meeting, March 25, Washington DC, USA, Fighting EBOLA, May 2015, Institut Pasteur Paris, France and EBOLA Tofo, Mozambique September 2015."

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

a. Impact in reinforcing competitiveness

Different impacts of IF-EBOLA action has been considered and delayed for reasons already mentioned in different sections of this document. We are working on the maintaining a majority of them and since changes have appeared, we propose to complete the previous Work Plan with complementary studies (see deviations on section 5 of the technical of the 1-year reporting period document B).
To improve the current Ebola diagnostic that stays one of pivotal unmet needs and one of our main priorities. Indeed, the diagnostic of EBOV at the very early stages of the disease is always needed to apply supportive and specific treatment as soon as possible (when the viral load is low) before the symptoms become too important. This could certainly improve both the isolations of patients to avoid the virus spillover and the treatment efficacy. We have begun some fine tune conditions, to this, we need high-quality (well preserved) samples in different BSL4 labs of the consortium (UM, IP, and KGH in Sierra Leone, and soon in Free Town with INMI) - that are presently running now and we have scheduled experiments in January 2016 in Sierra Leone. We are extending the use of ApoH method to concentrate to EBOV-associated co-infections.
The NGS –metagenomic analyses have revealed that EBOV Zaire (Makona EM095B) is the dominant genome at 85% among the circulating EBOV quasispecies. WE need to validate with new sequencing form different type of patients (death or survivors) to see if we observe different fingerprints according to the Rigel algorithm developed by OIB. This is crucial to check the designed primers to detect low viral loads at the very beginning of the infection or residual viral loads in survivors. These sequences have also permitted to design a chip array to help multiple detection of EBOV and co-infections. Metagenomic analyses have stressed the considerable amount of 14% of Lassa co-infections among the EBOV–infected patients. These findings and improvements will certainly have different impacts on the management of the epidemics and on the individual treatment.
The development of Fab’entech anti-Ebola polyclonal Immunoglobulin is among the few potential treatments officially identified and supported by the international community, in particular WHO and EMA. Such a project will accelerate the demonstration of the product interest and efficacy and then support the development of the company by offering the product to WHO/United nations for the low income countries, as well as a treatment for exposed personnel such as health care workers, army, NGOs, civilians etc… This study will support additional procurement of the products by governments as well as NGO institutions, and private institutions. Generated revenues will also help the company to further develop new products to target other infectious diseases such as Lassa fever which is still a major concern in Africa, Hendra/Nipah, Crimea-Congo-Hemorrhagic fever ‘CCCHF, etc.
The project as a result of fruitful collaboration between IF-EBOLA partners will spreading the original concept into the European research community will speed up applications of our technology not only in diagnosis, but also in microbiological science and in pharmaceutical industry generating another substantial European added-value in terms of the capacity to set up conceptual and technological platforms as part of preparedness strategies to face (re)emerging diseases.

b. Impact on solving societal problems

The unprecedented development of this Ebola outbreak has strongly impacted economic growth in affected countries encompassing both the direct cost of medical care and the reduction in years of healthy life expectancy and productivity because of early death and chronic illnesses. This, in return, leads to a reduction to business and infrastructure investment, social cooperation and social stability. We expect that the use of the products generated from this project will be paramount for the development of enhanced diagnostic methods and thus contribute to a better diagnosis and prognosis of virus associated infectious diseases. Therefore, the overall project is expected to help in solving major societal questions associated to this infectious agent.

IF-EBOLA is offering a complete preparedness platform of technological and conceptual approaches and strategies including as diagnostic detecting low viral loads, homeostasis immune profiling and monitoring as well as a potential early post-exposure treatment, polyclonal immunoglobulin can prevent the disease development (as it is well established for other diseases such as Rabies Tetanus, etc.) and thus reduce time in the hospital, virus spread and mortality.
With the SMEs involved, a dissemination of this technology to larger industry and to the scientific community is planned, with its preferential partners naturally in Europe.

c. Overall innovation aspects

The described technologies of our platform have a highly technological and innovative profile. There are many new and exciting avenues of exploration, each with great potential for biotechnological exploitation. These new directions will take us far beyond the existing state-of-the-art leading to:
 The follow-up of the infection according to ApoH capacity to bind pathogen particles will allow a more efficient development pathways for new therapies and vaccines, as well as other novel products of the new technologies, Ultrasensitive detection thanks to ApoH-sample pretreatment will allow accurate & ultrarapid POC IVD that will make part of preparedness for a next future epidemics as well as for bio-security and defense;
 The development of specific polyconal immunoglobulin doesn’t exist today, they will use a well-established technology, but will support the investment in a brand new dedicated facility that will be built in Lyon (France) for addressing emerging infectious diseases, using state-of- the art single use technologies;
 Good laboratory practices will be carefully implemented at the different stages of our intervention by properly training the health workers involved in the project;
 Laboratory workers will be supervised and trained by senior head of the laboratory (TOT have been initiated out of the country for the head of the local laboratories. Trainees will be use as trainer in country to assure laboratory safety and other tasks related to the laboratory (sampling, safe storage, appropriate data recording, location, sex, age, etc); Devices has been implemented in country and certain labs of the consortium to insure the proper technology development and transfer.
 Together, providing the concerned countries with modern and efficient equipment and training local people to perform diagnosis techniques for infectious diseases will help the country authorities in controlling the EVD epidemic. In a second time, the acquired capacities will contribute to improve surveillance and preparedness of all infectious diseases with potential impact on population health.

Related information

Record Number: 186336 / Last updated on: 2016-07-11
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