Overall Objectives
Research Program
Bilateral Contracts and Grants with Industry
Partnerships and Cooperations
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## Section: Partnerships and Cooperations

### European Initiatives

#### FP7 & H2020 Projects

The member of SISTM Team are involved in EHVA (European HIV Vaccine Alliance):

• EHVA: European HIV Vaccine Alliance: a EU platform for the discovery and evaluation of novel prophylactic and therapeutic vaccine candidates

Coordinator: Inserm/University of Lausanne. Other partners: EHVA consortium gathers 41 partners. Duration: 60 months. 01 /01 /2016 - 31 /12 /2020

With 37 million people living with HIV worldwide, and over 2 millions new infections diagnosed each year, an effective vaccine is regarded as the most potent public health strategy for addressing the pandemic. Despite the many advances in the under-standing, treatment and prevention of HIV made over the past 30 years, the development of broadly-effective HIV vaccine has remained unachievable. The EHVA international alliance, which includes academic and industrial research partners from all over Europe, as well as sub-Saharan Africa and North America, will work to discover and progress novel vaccine candidates through the clinic. EHVA fosters a multidisciplinary approach to the challenge of developing broadly effective HIV vaccines. EHVA’s program primary goals are:

• To develop a Multidisciplinary Vaccine Platform (MVP) for prophylactic and therapeutic HIV vaccines

• To move at least two novel prophylactic vaccine candidates to clinical development

• To identify immune correlates associated with control of HIV replication following immunological intervention

• To establish a strong scientific basis for further development of EHVA vaccine candidates in larger clinical trials

To this purpose, EHVA bring to the field 4 multidisciplinary research platforms representative of the latest advances in clinical trials and preclinical vaccine development. These four platforms cover all aspects of vaccine development from early-stage discovery to clinical trials.

• The Discovery Platform will work to disclose promising vaccine candidates based on the induction of T-cell and antibody responses (ie, neutralizing antibody and non-neutralizing antibody).

• The Immune-Profiling Platform will advance assays to predict the immunogenicity of potential vaccine candidates. The ability to generate a profile of a potential vaccine candidate, using models that emulate the immune system’s response, will assist with benchmarking novel and existing vaccine candidates.

• The Data Management/Integration and Down-Selection Platform is developed around the WP10 led by Rodolphe Thiébaut. SISTM provides here state-of-the-art statistical tools for the analysis and interpretation of complex data and algorithms for the efficient selection of vaccines.

• The Clinical Trial Platform includes pharmaceutical industry expertise for late stage development, a network of top European clinical centers for conducting large cohort studies, as well as relationships with leading scientists based in Africa. Future testing of EHVA vaccine in Sub-Saharan Africa is a research priority because it is the area of the world with the greatest number of people infected with HIV.

• IP-CURE-B: Immune profiling to guide host-directed interventions to cure HBV infections. Coordinated by Inserm (France), the project includes a total of 13 Beneficiaries: Centre Hospitalier Universitaire Vaudois (Switzerland), Karolinska Institutet (Sweden), Institut Pasteur (France), Universita degli studi di Parma (Italy), Fondazione IRCCS CA’ Granda – Ospedale maggiore policlinico (Italy), Universitaetsklinikum Freiburg (Germany), Ethniko Kai Kapodistriako Panepistimio Athinon (Greece), Fundacio Hospital Universitari vall d’Hebron (Spain), Gilead Sciences Inc. (USA), Spring Bank Pharmaceuticals, Inc (USA), European Liver Patients Association (Belgium), Inserm Transfert SA (France). Duration: 60 months. $01/01/2020-31/12/2024$

HBV infections, are a major global public health threat with over 257 million people worldwide chronically infected and over 887,000 deaths per year. 4.7 million people live with HBV in the European Union (EU) and European Economic Area (EEA). W.H.O. estimates that HBV causes almost $40%$ of the cases of hepatocellular carcinoma (HCC), which is the 2nd leading cause of cancer-related mortality worldwide. HBV kills nearly 900,0000 people around the world each year. The current prophylactic vaccine has no impact on established chronic infection.

The objective of the IP-CURE-B project is to develop novel curative concepts for chronic hepatitis B (CHB). Specific aims will be to: 1) improve the rate of functional cure of CHB by boosting innate immunity with immune modulators and stimulating adaptive immune responses with a novel therapeutic vaccine; ii) characterize immune and viral biomarker signatures for patient stratification and treatment response monitoring; iii) integrate biological and clinical data to model the best combination treatment for future trials; iv) model the effectiveness of novel curative therapies with respect to disease spectrum, patient heterogeneity, and constraints of National Health Systems.

The project organization combines: i) a Proof of Concept clinical trial of a combination of 2 novel compounds stimulating innate immunity; ii) a preclinical immune therapy platform in humanized mice combining immune-modulatory strategies to stimulate innate immunity, rescue exhausted HBV-specific T cells and generate anti-HBV adaptive responses; iii) extensive virologic and immune profiling to identify correlates of cure in patients, iv) the integration of large biological and clinical data-sets, v) a cost-effectiveness modelling of new therapeutic interventions, vi) project management, vii) results exploitation and dissemination.

In the IP-CURE-B project, SISTM coordinates WP6 Data science platform for data integration and statistical modeling which will provide powerful data management and statistical tools for the analysis and interpretation of the complex heterogeneous and high-dimensional data generated in the other WPs. For data management and data sharing, SISTM will leverage on a data warehouse system, based on Lab-key Server, the primary structure already established within the EU funded H2020 EHVA project. SISTM will develop and apply statistical methods for integrating data from several assay platforms to better describe and understand the mechanisms of the experimental products and to define predictive signatures of viral control and functional cure. Indeed, the immune system forms a sophisticated network of tissues, cells and molecules that interact in order to achieve viral control. Understanding how this complex network responds to interventions aimed at HBV functional cure requires the use and integration of data from multiple assay technologies. Two main strategies will be used: 1) statistical approaches to relate and down-select several high-dimensional data from the various assays in humanized mice and humans; 2) a modelling approach, taking into account biological knowledge and the results from the first step, to better capture and understand the non-linear relationships between the components of the immune system, viral control and their dynamics over time. Statistical and mechanistic models will be used, based on ordinary differential equation systems or other approaches. At the end of the process, if an adequate model is identified, this can be used to down-select immunomodulatory and vaccine regimens and make in silico predictions about optimized strategies or stratified treatment approaches. These approaches have been successfully applied in HIV immunotherapy trials and in vaccine trials by SISTM.

#### Collaborations in European Programs, Except FP7 & H2020

The members of SISTM are also involved in Innovative Medicine Initiative 2 (IMI2) projects which are all under the IMI Ebola+ program that was launched in response to the Ebola virus disease outbreak of 2014. SISTM is active in 3 projects which are all in collaboration with Janssen Vaccines & Preventions B.V. The overall aim of the EBOVAC program is to assess the safety, immunogenicity and efficacy of a novel 2-dose Ad26 + MVA prophylactic vaccine regimen against Ebola Virus Disease. In this context, the 3 projects develop as follows:

• EBOVAC1: Development of a Prophylactic Ebola Vaccine Using an Heterologous Prime-Boost Regimen.

Coordinated by London School of Hygiene & Tropical Medicine (United Kingdom). Other beneficiaries: Janssen a Pharmaceutical Companies of Johnson & Johnson, The Chancellor, Masters and Scholars of the University of Oxford (United Kingdom), Inserm (France), University of Sierra Leone (Sierra Leone). Duration: 84 months. 01 /12 /2014 - 30 /11 /2021.

EBOVAC1 is dedicated to the Phase I and III development of prime-boost vaccine based on Ad26.ZEBOV and MVA-BN-Filo. Phase I was conducted in the US, the UK and in Africa (Sierra Leone, Uganda, Kenya and Tanzania) for a total of 231 volunteers enrolled. Phase III was conducted in Sierra Leone in several phases leading to the successful enrolment of more than 2800 volunteers including around 500 children aged 1-17 years. In EBOVAC1, SISTM is modelling the immune response to the Ad26.ZEBOV and MVA-BN-Filo, using the data obtained in the project.

• EBOVAC2: Development of a Prophylactic Ebola Vaccine Using a 2-Dose Heterologous Vaccination Regimen: Phase 2.

Coordinated by Rodolphe Thiébaut with the following partners: Inserm (France), Labex VRI (France), Janssen Pharmaceutical Companies of Johnson & Johnson, London School of Hygiene & Tropical Medicine (United Kingdom), The Chancellor, Masters and Scholars of the University of Oxford (United Kingdom), Le Centre Muraz (Burkina Faso), Inserm Transfert (France). Duration: 72 months. 01 /12 /2014 - 30 /11 /2020.

EBOVAC2 main objective is to provide extensive and robust data on the safety and immunogenicity of the Ad26.ZEBOV and MVA-BN-Filo vaccine. This was designed by: 1. Carrying out translational studies to link vaccine elicited immune responses in humans to protection from Ebola in vaccinated non-human primates 2. Carrying out Phase II trials in African and European volunteers in approximately 6 countries, four in Africa and two in the EU with an overall target enrolment of approximately 1,500 subjects. Given the compressed nature of this development program, the Phase II studies were conducted in parallel with the planned Phase III study (EBOVAC1). The rationale for inclusion of European volunteers in Phase 2, in addition to the trials in Africa, is to allow for higher sensitivity in safety signal detection in populations with low incidence of febrile illnesses, to generate negative control specimens for assay development, to allow for inclusion of health care workers or military personnel that may be deployed to Ebola-endemic regions. 3. Evaluating the vaccine response in special population groups, such as children (ages 1-17 years), the elderly (ages 50-65) and individuals infected with HIV, to confirm safety and immunogenicity. The Phase II trials started as soon as preliminary safety data were available from Phase I trials. 4. Monitoring and characterizing immune response to the proposed vaccine through different set of analysis of the humoral and cellular response with different approaches (ICS, luminex, gene expression analysis, T and B cell activation assays, Virus neutralization assays...) leading to a unique set of data. In EBOVAC2, in addition to the coordination of the whole project, SISTM is involved in the statistical analysis of the results obtained by the VRI lab responsible for an important part of the exploratory work, but also in the integrative data analysis of these high dimension and complex data. A Labkey environment was established in SISTM for EBOVAC2 to facilitate the exchange and following treatment of the project data.

• EBOVAC3: Bringing a prophylactic Ebola vaccine to licensure.

Coordinated by the London School of Hygiene & Tropical Medicine (United Kingdom). Other beneficiaries: Janssen a Pharmaceutical Companies of Johnson & Johnson, Inserm (France), The University of Antwerpen (Belgium), University of Sierra Leone (Sierra Leone). Duration: 60 months. 01 /06 /2018 - 30 /05 /2023.

EBOVAC3 aims at supporting an essential part of the remaining clinical and manufacturing activities required for licensure in the European Union (EU) and the United States (US) for the candidate heterologous Ad26.ZEBOV and MVA-BN-Filo prophylactic vaccine regimen against Ebola virus disease. As a follow-up project, the IMI2 funded EBOVAC3 project, has started in June 2018. In this project, the vaccine strategy is further evaluated in specific populations in Africa (infants in Guinea and Sierra Leone; and front line workers in RDC). The project includes a work package on modelling, which is led by Rodolphe Thiébaut. Three workshop have been organized in Bordeaux (October 29th-30th, 2018), Arcachon (May 2nd-3rd, 2019) and Leiden (November 20th, 2019) to discuss and collaborate with the EBOVAC3 partners on the planned modelling work.

• PREVAC-UP: The Partnership for Research on Ebola VACcinations-extended follow-UP and clinical research capacity build-UP.

SISTM is also involved in PREVAC-UP, an EDCTP2 project in direct link with the research carried out on the Ebola vaccines.

Coordinated by Inserm (France). Other beneficiaries: CNFRSR (Guinea), CERFIG (Guinea), LSHTM (UK), COMAHS (Sierra-Leone), NIAID (USA), NPHIL (Liberia), USTTB (Mali), Centre pour le Développement des Vaccins (Mali), Inserm Transfert SA (France). Duration: 60 months. 01 /01 /2019 - 31 /12 /2023.

Human-to-human transmission of Ebola virus in West Africa was interrupted in 2016 but the risk of reemergence of the disease is real. Thus, efforts to develop a safe and effective vaccine against Ebola virus disease with a durable prophylactic effect in communities must continue. The PREVAC-UP project is built around the PREVAC consortium. The Partnership for Research on Ebola Vaccinations (PREVAC) is an international consortium including the French Institute of Health and Medical Research, the London School of Hygiene & Tropical Medicine, the US National Institutes of Health, health authorities and scientists from Guinea, Liberia, Mali and Sierra Leone, a non-governmental organization (Alliance for International Medical Action), and Merck, Johnson & Johnson and Bavarian Nordic companies. The PREVAC trial is a phase IIB, randomized, placebo controlled, multicentre trial evaluating the safety and immunogenicity over 12 months of three vaccine strategies in children and adults. Participants are randomized to one of five groups: (i) vaccination with Ad26.ZEBOV prime and MVA-BN-Filo boost, (ii) vaccination with rVSV$\delta$G-ZEBOV-GP prime and a boost of the same vaccine, (iii) vaccination with rVSV$\delta$G-ZEBOV-GP vaccine without boost, (iv) placebo group 1 and (v) placebo group 2. Preliminary phases started in Liberia and Guinea in March 2017; the main phase of the trial evaluating the five regimens will begin in Liberia, Guinea Sierra Leone and Mali in April 2018 with an enrolment targets of 1,400 adults and 1,400 children.

PREVAC-UP two primary objectives are to determine (i) the long-term immunogenicity and safety and (ii) durability of humoral and cellular immune responses of Ebola vaccine regimes over 60 months. We will also evaluate the effect of co-infections, such as malaria and helminths on the immune response to vaccination. An integrative statistical analysis of the immune response will be used under the coordination of SISTM to explore the mechanism of action of the vaccines and to identify early correlates of durable antibody induction. PREVAC-UP will also build on the extensive community mobilization efforts previously generated through PREVAC to provide a trans-national platform for social and health science research and training. Finally, this research proposal will expand and sustain capacity building and training of scientists in the four participant African countries. This program is expected to significantly impact Ebola prevention and control in adults and children in Africa. PREVAC-UP will also strengthen capacity for science relevant to the development and evaluation of new vaccines in sub-Saharian Africa.

In PREVAC-UP, SISTM leads the WP4 Utilisation of a system vaccinology approach using integrative statistical analyses and mechanistic modelling of the immune response to explore the interrelationship of immune response to Ebola vaccines. System vaccinology approach helps in better understanding and predicting the response to vaccines as demonstrated in the context of yellow fever, flu and many other vaccines. The idea is to integrate the massive data generated by high-throughput technologies (transcriptomics, flow cytometry, multiplex data) and population characteristics (sociodemographics and coinfections) to isolate the main markers/signatures associated to the vaccine response. Then, a mechanistic model of the response can be built and hopefully predict the individual long-term response. The PREVAC trial is a unique opportunity for setting up such an approach and apply it to the most advanced vaccine platforms against Ebola. The Inserm-SISTM team has produced several publications highlighting how within-host mechanistic models could play an important role in predicting vaccine efficacy and in improving treatment regimens, notably in HIV. The team has started to work on modelling the response to the Ad26.ZEBOV/MVA platform. In PREVAC-UP, it is expected that signatures and the mechanistic model itself will be different according to the type of vaccine as, specifically, the rVSV is a replicative vector. Two main outcomes are expected. One is a better understanding of the individual variability of the immune response and another is the prediction of the response with two specific aspects: after a new boost and on the long-term (5 years) for a new vaccinees. Identification and validation of an early correlate of later antibody responses would allow early prediction of whether an individual, or group of individuals is likely to be a poor responder and then to recommend subsequent interventions to test in this subset (such as change in vaccination strategy or additional boosts). Heterogeneity in antibody responses is expected within each group as it has been observed in former studies. In PREVAC-UP, information will be collected to inform the reason of this variability. Specific aspects will be explored such as the impact of malaria and various infectious agents on the immune response. Integrating such information in a mechanistic model of the immune response may help understanding the pathway leading to blunted response in vaccines and also to generate new hypotheses that could be biologically validated later on. Another important aspect of the modelling approach is the quantification of the impact of each potential factor helping to order the relative importance of various factors. In conclusion, this work is definitely at the confluence of the other work packages, integrating and ordering all the available information to understand and predict the effects of the promising vaccine strategy evaluated in the PREVAC trial.

#### Collaborations with Major European Organizations

• University of Oxford;

• London School of Hygiene and Tropical Medicine;

• University Hospital Hambourg (UKE);

• Heinrich Pette Institute for Experimental Virology, Hambourg;

• MRC, University College London;

• MRC Biostatistics Unit, University of Cambridge;

• The University of Antwerpen;

• University of Milan;

• University of Bergen.