The faces behind the CARE work-packages – Panthéa Tzourio, WP8 Task Lead

CARE (Corona Accelerated R&D in Europe) is the largest European research initiative addressing the challenges of COVID-19. It is no surprise that it is designed in a comprehensive, yet agile, structure to fulfill the 38 partners’ shared key goals: (1) to identify therapeutics for the current pandemic, (2) to identify antiviral therapies for future outbreaks and (3) to increase the understanding of the pathophysiology of COVID-19. In a set-up of eight work-packages (WPs), the scientists and management at CARE carry out the project activities that have so far resulted in valuable learnings about the COVID-19 and how it might be defeated.  

Work Package 8 comprises a number of discrete consortium coordination and management task areas, such as data management and ethics. Here, we go behind the scenes through brief interviews with WP8 task leaders to hear insights on what makes their work so special, as well as their challenges and hopes.

WP8 – Data Management

The CARE work-package 8 (WP8) Data Management team focuses on the implementation, operation and administration of two databases, including a Labkey data management platform to host immunological test data from WP5 and clinical trials data from WP7 in order for the Inserm SISTM team to perform statistical analysis. WP8 Data Management Task Lead, Panthéa Tzourio (SISTM, Inserm) shares her views on this work of the CARE project.

What has your team delivered so far and what are you still working on during the remaining time in CARE? 

SISTM is a data sciences team based in Bordeaux directed by Pr. Rodolphe Thiébaut, specialising in developing appropriate statistical and modelling tools to describe the immune response to infections and vaccines using clinical and various complex biological datasets. SISTM is involved at several levels in CARE: statistical analysis of immune data for Work Package 5 (WP5), clinical trial methodology support for Work Package 7 (WP7) and data management in a dedicated data warehouse system in Work Package 8 (WP8).

Our main activity so far has been to manage the implementation, operation and administration of a Labkey Data management platform to host of Immunological test data from WP5 and Clinical trials conducted in WP7 in order for the SISTM team to perform statistical analysis. To reach this goal, we contributed to the preparation of the CARE Data Management Plan (DMP). This document, created during the preliminary phase of the project, is a living document outlining and describing the research data management pipeline and of course, requesting updates when either the data to be transferred or the repository system evolves.

In the case of Labkey, we expanded the data platform capacities by upgrading to a Primary edition of Labkey to better address specific research requirements. This included the direct connection between the data present in Labkey with the RStudio server analysis environment (in full GDPR compliancy) and the capacity to store and share the bio-statistical R analysis results and visualizations with the research team members within the study project secure environment in Labkey.

We also acquired and set-up integrated analyzing modules for lab experimental data file e.g. Nab, Elisa, Elispot, Luminex, Flow Cytometry. Those updates lead to modifications of the initial DMP submitted to IMI for approval.

We are glad to say that LabKey is ready to work with CARE data and we have already uploaded the French COVID 19 cohort data in our Labkey platform, analyzed the data and published the results (Levy et al., 2021). We have also created in-house statistical methods (differential gene expression analysis, intra-cellular staining analysis etc.) for which we developed a set of integrated visualization tools. At this stage, our work for CARE continues with the development of data visualization tools, refinement of statistical methods and obviously the maintenance of the data warehouse. We are fully ready to receive the data from the laboratories involved in WP5 investigations and the data from clinical trials.

What have you personally learned so far through the experience of working in CARE?

As the IT project manager in SISTM, CARE was my first experience in a research project of this magnitude. I really find it enriching to see the commitment of so many teams and industries to collaborate and advance the research in anticipation of future pandemics. Of course, competition is still present, but it was really nice to see how the IMI funding scheme really helped defining a common ground on which to build up new knowledge and paths for the future developments.

What has surprised you about working on the CARE project? 

As I said above, the magnitude of the project and the quality of the profiles involved are impressive. It is amazing that such a “big machine” like the CARE consortium, representing a variety of countries, public or private organizations works and even better: is delivering. I can say I am very glad to be part of this adventure.

What makes the work for CARE special for you and your team?

 For SISTM, which has been involved almost since the beginning of the pandemic in the analysis and modeling of COVID data, CARE is the opportunity to work with the best representatives of the scientific and industrial community and thus keep contributing to the global effort. On a more personal note, I like the idea to keep the research and innovation focused on future COVID outbreak risks: providing more tools to avoid the need to pay such a heavy toll ever again.

What are the biggest challenges you have encountered with respect to your task activities? (and how did you overcome them?)

 Without hesitation, I would say the biggest challenge we encountered in our activities was linked to the data management of some patients’ clinical and biological data collected during the COVID pandemic that we received from a variety of sources.

For most of these transferred data, we were not associated with the initial design of data or the initial protocol and as can be understood, during the pandemic crisis the hospitals collected in haste and did not have time or resources to harmonize their practices. This led to the creation of heterogeneous cohorts with missing data or discrepancies on files structures, common variable nominations, data column formats, etc…

This is why with this experience in mind, whenever possible we now try to take an upstream approach, and participate to the protocol designs so to understand or propose the proper structure for the different data to collect and define the proper information to put in the Data Transfer Agreement.

Although, this is a rather current practice in the industry, where the different services are integrated, there is still some room for improvement in academic structures, but this is definitely something on which we are making progress!

The faces behind the CARE work-packages – Craig Fenwick, WP4 academic Lead

CARE (Corona Accelerated R&D in Europe) is the largest European research initiative addressing the challenges of COVID-19. It is no surprise that it is designed in a comprehensive, yet agile, structure to fulfill the 38 partners’ shared key goals: (1) to identify therapeutics for the current pandemic, (2) to identify antiviral therapies for future outbreaks and (3) to increase the understanding of the pathophysiology of COVID-19. In a set-up of eight work-packages (WPs), the scientists and management at CARE carry out the project activities that have so far resulted in valuable learnings about the COVID-19 and how it might be defeated.  

Over the course of the project, we have seen some changes in the leadership of the eight work packages, and will once again go behind the scenes through brief interviews with our newest work package leaders to hear insights on what makes their work so special, as well as their challenges and hopes.

WP4 – Generation and characterization of monoclonal antibodies against SARS-CoV-2 and related coronaviruses 

The CARE work-package 4 (WP4) focuses on the generation and characterization of monoclonal antibodies against SARS-CoV-2 and related coronavirus. The EFPIA Lead of WP4, Craig Fenwick (Centre Hospitalier Universitaire Vaudois) shares his views on the work in WP4 of the CARE project.

What makes the work for CARE special for you and your WP team? 

 The interdisciplinary team of highly talented members makes it a pleasure to work with partners in industry and academia to combat this ever-evolving and important infectious disease that brought the world to a standstill. Although the most dangerous phase of the pandemic has passed for most, the WP4 team members are highly motivated and committed to developing new broadly active antibodies and therapeutic strategies that could benefit the elderly and those in our population with immunodeficiencies who are unable to mount a protective immune response following vaccination. These at-risk individuals may have primary hereditary immunodeficiencies or secondary immunodeficiencies resulting from external factors that compromise the immune response, including the use of immunosuppressive medications by individuals including organ transplant recipients, infections by certain viruses, or specific cancer therapies. These antibodies may also serve as a preparedness therapeutic against a future coronavirus outbreak with pandemic potential.

What are or were the biggest challenges within WP4? (and how did you overcome them?)

 The greatest challenge that we and others have faced in the discovery of anti-COVID therapeutic antibodies has been the rapid evolution of the virus toward more infectious and immune response evading variants. Potent antibodies active against all circulating viruses at the time have been discovered by our groups on several occasions, only to have their neutralizing effect abolished by the next emerging variant. We are overcoming these challenges by identifying highly rare antibodies that bind to conserved regions of the virus that can’t easily mutate to evade neutralization without compromising the fitness of the virus, making it poorly transmissible from person to person.

What have you personally learned so far through the experience of working in CARE? 

 The urgency of the pandemic really galvanized the team into a highly collaborative and supportive network where we considered all the necessary milestones between basic research, discovery and preclinical profiling to move promising candidates forward quickly and as efficiently as possible. Many of the different team members contributed to minimizing the various bottlenecks in the research to have the best possible chance of success.

The faces behind the CARE work-packages – Richard Zwaal, WP1 EFPIA Lead

CARE (Corona Accelerated R&D in Europe) is the largest European research initiative addressing the challenges of COVID-19. It is no surprise that it is designed in a comprehensive, yet agile, structure to fulfill the 38 partners’ shared key goals: (1) to identify therapeutics for the current pandemic, (2) to identify antiviral therapies for future outbreaks and (3) to increase the understanding of the pathophysiology of COVID-19. In a set-up of eight work-packages (WPs), the scientists and management at CARE carry out the project activities that have so far resulted in valuable learnings about the COVID-19 and how it might be defeated.  

Over the course of the project, we have seen some changes in the leadership of the eight work packages, and will once again go behind the scenes through brief interviews with our newest work package leaders to hear insights on what makes their work so special, as well as their challenges and hopes.

WP1 – Anti-coronavirus drug discovery in phenotypic virus-cell-based assays 

The CARE work-package 1 (WP1) dedicates its efforts to identify small molecule therapeutic candidates against the current SARS-CoV-2 and potentially other variants of concern using the infectious virus. For this, the CARE scientists take a close look at how the virus can be inhibited in cell culture using drugs that could potentially qualify for repurposing, small molecule libraries and biologicals. The EFPIA Lead of WP1, Richard Zwaal (Johnson & Johnson) shares his views on the work in WP1 of the CARE project. 

Taking over the WP1 leadership, what accomplishments are you building on?  

Over the course of the project, our top-notch scientists have done an amazing job working tirelessly to identify and develop new anti-coronaviral molecules. Excitingly, these are hitting new targets, expanding our armaments against the current and future strains of coronavirus. The excellent interaction between WP1 and the other work packages has also proven critical to progressing the different chemical series that we are advancing. 

What will change with your new role as part of the WP1 leadership?  

As we are moving into the final chapter of the CARE consortium, it will be important to prioritize our remaining efforts on advancing the internally developed chemical series as far as possible along the discovery pipeline.. 

What have you personally learned so far through the experience of working in CARE?  

It is hard to believe that it has already been four years since the CARE project began. COVID-19 came out of nowhere and its rapid spread across the globe instigated a challenging and intense battle with many unexpected twists and turns. Unfortunately, we, and others, quickly found out that repurposing of existing drugs did not give us the golden bullet we needed, and we had to set out for de novo drug discovery programs. Now the public health emergency has been declared over, interest is slowly waning. Yet, COVID-19 is still very much around us (with 10,000 coronavirus deaths reported to WHO in December alone), so it is important to keep pushing forward, broadening our antiviral weaponry and preparing for patient populations that are still vulnerable for current SARS-CoV-2 infections.

What aspects will you be focusing on in your new role as co-lead of WP1?

The last year of a project always seems to fly by. We will be preparing for reaching the final milestones and deliverables, and will need to be thinking about extending our collaborations and partnerships beyond the current project.

With a new academic lead also in place for WP1, Johan Neyts, how will the two of you work together sharing the WP1 leadership?

Johan is a world-renowned authority in virology and I am really looking forward to working with him to achieve our project goals. I will do my best to ensure that we continue to build on the great work that has been done. I believe that with all the combined expertise in WP1, we can still make significant progress in this field.

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New potent bisubtrate inhibitors of SARS-CoV-2 nsp14 N7-Methyltransferase 

The CARE partner Aix-Marseille University (AMU), in collaboration with other research groups, has published two articles pertaining to the development of new bisubstrate inhibitors against the SARS-CoV-2 nsp14 (N7-guanine)-methyltransferase (N7-MTase). This enzyme, which catalyses the transfer of the methyl group from the S-adenosyl-L-methionine (SAM) cofactor to the N7-guanosine cap, plays a key role in the translation of viral RNA into proteins.

As a first step, AMU designed and synthetized nucleoside-derived inhibitors with the goal to improve interactions with the SARS-CoV-2 N7-MTase nsp14. In a biochemical assay, seven out of the 39 compounds showed remarkable double-digit nanomolar inhibitory activity against the N7-MTase nsp14. The three most potent inhibitors significantly stabilized nsp14 and the best inhibitor demonstrated high selectivity for nsp14 over human RNA N7-MTase.

Structure-Activity Relationship studies reveal an effective bisubstrate structure of the inhibitors, which occupy both the SAM-binding site and the cap RNA substrate binding site of the enzyme. Moreover, based on docking studies, the particular scaffold of these compounds interacts with two key conserved residues – Arg310 and Phe426 in SARS-CoV nsp14 – of the catalytic pocket that has been identified as critical for N7-MTase nsp14 activity and consequently for SARS-CoV-2 replication. Click here for the publication or here for a repository access.

As a second step, a structure-guided drug design approach was applied to design a new series of inhibitors with the aim of increasing the interaction with the SAM binding pocket. 26 novel adenosine mimetics were synthesized with eight of them inhibiting the N7-MTases of coronaviruses with subnanomolar to nanomolar activity, while sparing the cognate human N7-MTase. Moreover, the best compounds inhibit SARS-CoV, SARS-CoV-2 and MERS-CoV nsp14 N7-MTase activity, three viruses which share a similar structure organisation of the nsp14 protein. Click here for the publication. The activity of the developed compounds remains at a moderate level in infected cells at this stage. We are currently analyzing the delivery of the compounds into cells, and work on the synthesis of prodrugs is also currently underway.

These promising results strengthen the emerging status of the N7-MTase nsp14 as a valid target for antiviral rational-designed pancoronavirus inhibitors.

Preparing for future pandemic: outputs and progress resulting from a European Commission (EC) sponsored workshop in November 2022

While Covid-19 is no longer deemed to be a pandemic, the risk of future pandemics remains. Application of lessons learned during our collective recent experience is vital to being in a stronger position to handle this situation again.

Members of the CARE consortium were among the participants of a workshop held a year ago, organized by the EC’s Directorate-General for Research and Innovation (DG-RTD) and the European Health Emergency Preparedness and Response Authority (HERA) to explore the opportunities and challenges of providing globally available broad spectrum antiviral therapeutics as a tool for pandemic preparedness.

Given the evolving and unpredictable nature of the coronavirus, the delegates of the workshop recommended inclusion of broad-spectrum antiviral therapeutics as a key tool of pandemic preparedness. The workshop which was set up with input from Dr. Ed Schmidt and Prof. Eric Snijder (LUMC), and Johan Neyts (KUL) from CARE was also attended by Marnix Van Loock (Janssen).

Why broad spectrum antiviral therapeutics?

Broad-spectrum antiviral therapeutics in cocktail or combination formats to limit drug resistance, can potentially target broader viral families or groupings in an initial outbreak, crucially buying time for more targeted therapies to be developed and tested in parallel, by containing the spread of the (novel) virus in the early stages and limiting the impact of the pandemic on the health system. The reassurance of knowing there is a swift therapeutic response to an arising future epidemic is important for society, having experienced the impact Covid-19 had on so many lives and economies globally.

Key recommendations from the workshop

To make this a reality requires measures to support rapid global drug development including effective collaborations though global and harmonized research infrastructures, adequate and flexible manufacturing capacities, fast and efficient global clinical trials, clear regulatory frameworks for broad spectrum antivirals (as current regulatory pathways only provide approval for a specific viral disease) and sufficient and flexible funding.

In this context, public-private partnerships such as CARE are an important tool to mobilize the expertise needed in an emergency response and to enable sustainable funding. Moreover, the importance of basic research to understand pathogens was highlighted as it is the foundation for the research done in response to an epidemic or a pandemic.

Since the workshop took place almost 12 months ago, a new series of calls for proposals was launched by HERA on broad-spectrum antivirals with various projects being approved in 2023. One of them is the Panviprep consortium, which will start on 1 January 2024 and in which all eight partners of the SCORE consortium (who are also all CARE partners) together with seven additional partners, will develop antiviral drugs against a range of pandemic viral threats.

How does this relate to CARE?

 CARE is heavily involved in broad-spectrum antiviral development as part of its preparedness track. These recommendations lend weight to the ongoing antiviral discovery and preclinical work being undertaken today in CARE across numerous work packages.

For more information

November 2022 meeting outputs: https://op.europa.eu/s/y449