SCORE (Swift COronavirus Therapeutics REsponse), a small EU-funded consortium of 8 partner organisations who also contribute to CARE, has successfully delivered pre-clinical proof of concept in six potential assets, published 40 papers to disseminate findings, and built a valuable SARS-CoV-2 specific toolset to aid further research

Within the 30-month timeframe of the project, under the leadership of Dr. Ed Schmidt (SCORE project manager; left) and Prof. Eric Snijder (SCORE coordinator; right), the SCORE partners already published 36 peer-reviewed scientific publications in leading scientific journals and four further publications submitted to pre-print repositories like BioRxiv, with acknowledgement of SCORE support. 

In addition to these scientific successes, the SCORE consortium identified and developed a number of antiviral compound lines which will be optimized, validated and developed further after the completion of the SCORE project. These future activities will include the development of the compound series 06 and 08 within the CARE consortium, the entry inhibitors (HR2), the main protease inhibitor 13b-K, the repurposed antiviral drug Suramin and nucleotide analogue AT-9010.

Additional achievements include the development of an extensive toolbox, the generation of a reverse genetics platform and reporter gene-expressing viruses, the development of multiple animal models, and the in-depth functional characterization of specific viral proteins/functions, including the Spike protein, the RNA polymerase complex, coronavirus replication organelles, the nsp14 exoribonuclease, and the nsp14 N7-methyltransferase. Enzymatic assays were developed for a variety of important drug targets and studies into the mechanism-of-action of various compounds have been initiated.

What is the relevance to CARE?

The aims of the SCORE consortium were very much in line with the aims of CARE and able to demonstrate how small flexible consortia can establish an early response and early screening for antiviral drugs, and development of essential assays and preclinical models. Now that SCORE is finished, it benefits from CARE’s longer duration, allowing the continuation of some of its work such as the development of Series 08 compounds within CARE.

The benefits of having partners-in-common

SCORE comprised a multidisciplinary team of scientists from eight organisations with complementary expertise, coordinated by Dr. Ed Schmidt (SCORE project manager), and Prof. Eric Snijder (SCORE coordinator). All partner organisations are also part of the CARE consortium, as listed below:

• Leiden Universitair Medisch Centrum (LUMC, The Netherlands)
• Université d’Aix Marseille (AMU, France)
• Katholieke Universiteit Leuven (KUL, Belgium)
• Universiteit Utrecht (UU, The Netherlands)
• Eidgenössisches Departement des Innern (EDI-IVI, Switzerland)
• Universität zu Lübeck (UzL, Germany)
• Helmholtz-Zentrum für Infektionsforschung (HZI, Germany)
• Janssen Pharmaceutica (Janssen, Belgium)

This commonality of partnership across CARE and SCORE enabled sharing of resources and knowledge, and optimizing the distribution of work, which included the transfer of several SCORE hits to the CARE pipeline for further development. It also allowed the transfer of established assays and other technologies from SCORE into CARE such as the employment of small-animal models which were established within SCORE.

The legacy of SCORE: introducing PanViPrep

A new project, PanViPrep, received confirmation of funding 4 August 2023. This will enable the work of SCORE to continue, targeting coronaviruses plus four other virus families. The abstract is below

PANVIPREP abstract: Antiviral drugs will be key in the management of future virus outbreaks. For each viral family with epidemic/pandemic potential, stockpiles of potent drugs are needed that can be deployed when a new pathogen emerges. Such broader-acting drugs (targeting conserved viral functions) are needed as of “day one” of an outbreak, for treatment and prophylaxis (e.g. in HCW and frail patients). In combination with quarantine measures, such drugs will delay (global) spread, allowing time for vaccine-development. Since the 2003 SARS outbreak, PANVIPREP’s core partners have successfully collaborated in leading European antiviral drug research projects. This provides a solid scientific basis in combination with translational drug discovery expertise. The team includes virologists, biochemists, structural biologists, medicinal chemists and pharmacokinetics experts. Previously developed know-how and toolboxes will be a major asset to achieve immediate impact. PANVIPREP aims to greatly expand the antiviral portfolio and identify novel druggable targets of high-risk RNA viruses. Hits will be identified through (i) phenotypic antiviral screening of compound libraries (ii) structure-based drug design, (iii) in silico screening, supported by the latest machine-learning methods. We will deliver 25 to 50 high-quality, broad(er)-spectrum (pan-genus/pan-family) hit molecules/hit series. Two of these will be developed to the early lead stage, including proof of concept in animal infection models. Remaining hits will serve as chemical tool-compounds to explore mechanisms of action thereby identifying novel druggable targets in RNA virus replication. This in turn will accelerates target-based drug design efforts. The workflow will integrate best practices in antiviral drug discovery with a range of methodological innovations, including AI-based methods, thus renovating and accelerating the antiviral hit discovery pipeline for future use and contributing to pandemic preparedness.

For more information, please contact:

Dr. Ed Schmidt (SCORE project manager): e.d.l.schmidt@lumc.nl

Prof. Eric Snijder (SCORE coordinator): e.j.snijder@lumc.nl

Further reading:

https://www.score-cov.eu/Article/Home

https://health.ec.europa.eu/events/broad-spectrum-anti-viral-therapeutics-key-tool-pandemic-preparedness-and-response-2022-11-22_en

SCORE was funded by the European Union’s Horizon 2020 research and innovation programme. It started in April 2020 and closed in October 2022.

CARE’s Young Researchers – Introducing Emmely Treffers, Postdoctoral Researcher, LUMC

Read about how Emmely’s work in proteomics of SARS-CoV-2 infected systems is growing our knowledge of how virus and host interact, in order to find novel ways to disrupt viral life cycle or counteract potential pathogenic host responses.

CARE (Corona Accelerated R&D in Europe) is the largest European research initiative addressing the challenges of COVID-19. It comprises 38 partners, from both industry and academia, in a set-up of eight multidisciplinary work-packages (WPs). In this series, we highlight the work of some of the young researchers involved in CARE as part of their PhD or postdoctoral work. Here, we learn how this opportunity has benefited Emmely, while simultaneously benefiting CARE and its ambition to help society defeat COVID-19 and future pandemics.

What experience did you have working on a Public Private Partnership before joining CARE? 

I had no experience working on a PPP before I joined CARE, but several of my colleagues have been involved in other PPPs in the past.

Why did you decide to get involved in CARE?

I decided to get involved in CARE because the SARS-CoV-2 pandemic had just started and I wanted to contribute scientifically by increasing the understanding of what happens in infected cells. CARE seemed a great opportunity to quickly get started.

How did your involvement in CARE come about?

I became involved in CARE because I had previously used (phospho)proteomics to study viral infection and in work package 5 we wanted to study protein abundance and post-translational modifications during SARS-CoV-2 infection. During my own PhD project I had worked in the Molecular Virology group and Proteomics group in the LUMC and could help the PhD student that was hired on the project to get started.

Tell us about the work you have been doing in the CARE consortium

My role in the CARE consortium involves proteomics of SARS-CoV-2 infected systems in work package 5. We are interested in changes in protein expression and changes in post-translational modifications such as phosphorylation and ubiquitination in response to infection. We started by optimizing SARS-CoV-2 infection in human bronchial epithelial cells growing on an air-liquid interface and in Calu-3 cells. These cells were infected and harvested at different time points post SARS-CoV-2 infection. We are currently validating hits from the proteomics experiments to determine their relevance during infection.

What highlights can you share from your time in the CARE consortium so far?

Some highlights from my time in CARE include learning how to work safely in a biosafety level 3 laboratory so I can perform the SARS-CoV-2 infection experiments for our proteomics and follow-up studies. It was a great feeling when we successfully completed the first large scale experiment.

Why does this work matter?

This work matters because understanding how the virus and host interact can help us to find novel ways to disrupt the viral life cycle or counteract host responses that might be linked to pathogenesis.

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

Challenges I have experienced include the optimization of the SARS-CoV-2 infection of the human bronchial epithelial cells. These cells are grown in inserts that contain a membrane bottom which allows the cells to grow into a bronchial epithelium on an air-liquid interface. Nutrients can pass through the membrane when the insert is placed in a well with growth medium, but there is no liquid on top of the cells. Because post-translational modifications are not very abundant it is necessary to enrich for them before mass spectrometry and this requires a larger amount of protein as starting material than regular proteomics. At first we wanted to use large inserts so we could harvest more protein, but when we studied the cells with microscopy it turned out that the number of cells that became infected in the centre of the inserts was very low. Eventually, we discovered that it was better to decrease the size of the inserts and pool several inserts for each sample. This resulted in a very large pile of plates that needed to be infected for the final experiment!

There were also pandemic specific challenges like shortages in laboratory materials which sometimes made it difficult to plan ahead when it was uncertain when materials would be delivered. Fortunately, most of the materials that we need are now available again or we’ve been able to find suitable replacements.

Further reading

Emmely is currently working on her first CARE publication. However, she has shared some links to publications in related research for our information:

Alphavirus proteomics papers:

https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/pmic.201400581

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011179

Protein-stimulated ribosomal frameshifting in arteriviruses:

https://www.pnas.org/doi/10.1073/pnas.1211145109

https://www.pnas.org/doi/10.1073/pnas.1321930111

https://academic.oup.com/nar/article/44/12/5491/2457549

https://www.sciencedirect.com/science/article/pii/S0021925817506717

CARE’s Young Researchers – Introducing Grace Beirne, PhD student, KU Leuven

Read about how Grace’s work in System Dynamics Modelling will help optimize the set-up of future consortia

CARE (Corona Accelerated R&D in Europe) is the largest European research initiative addressing the challenges of COVID-19. It comprises 38 partners, from both industry and academia, in a set-up of eight multidisciplinary work-packages (WPs). In this series, we highlight the work of some of the young researchers involved in CARE as part of their PhD or postdoctoral work. Here, we learn how this opportunity has benefited Grace, while simultaneously benefiting CARE and its ambition to help society defeat COVID-19 and future pandemics.

What experience did you have working on a Public Private Partnership before joining CARE? 

I had no experience of a public private partnership before joining CARE. As a PhD student, I am early in my career journey. I have experience in academia and experience working in public organisations, but I have no prior involvement with industry partners.

Doing my PhD research as part of the CARE consortium has been a really unique opportunity to get exposure to the industry perspective and understand public and private perspectives better, and how to combine these perspectives, in the context of this collaboration.

Tell us about the work you have been doing in the CARE consortium

My role in the CARE consortium involves building a system dynamics model of the health system surrounding the antiviral drug development in the CARE consortium.

I’m a PhD candidate in the Access-To-Medicines Research Centre at KU Leuven, Belgium, and we’re based in the faculty of business and economics. Our research team uses systems thinking to construct and analyse health systems with a human-centered focus, utilising a transdisciplinary approach.

My research aims to quantify and understand the impact of what’s being done in the CARE consortium by using systems thinking and system dynamics modelling methods.

We start with qualitative inputs. We use model building workshops and interviews to understand the mental models of all relevant stakeholders. We build a conceptual model based on the shared mental models of all stakeholders. We hold model validation interviews and workshops to confirm that the models, built from these initial inputs, correctly represent the reality. Once the interconnections and variables of the model are validated by all stakeholders, we can quantify the model. The quantified model can then be used to simulate, analyse and compare different scenarios.

What is System Dynamics? Click here to find out more

What highlights can you share from your time in the CARE consortium so far?

The care annual meetings have been great opportunities to connect and come together with the many members of this huge consortium and discuss our research. These opportunities to come together in person to share ideas have been really beneficial for our research.

Most of the data collection for our model is via online workshops and interviews. These are already very interesting and useful opportunities to understand the research being done by all the different partners in the consortium. All of the partners we interview are willing to share such interesting and valuable insights already, but the annual meetings, where we have been able to connect in person, has contributed to an extra level of understanding.

Why does this work matter?

This work matters because understanding what’s working well and being able to quantify what could be done differently or better is extremely valuable for designing future consortia or drug development initiatives.

The quantitative system dynamics model can be used to show what’s currently working well in the CARE consortium and can be used to simulate different scenarios to show counterfactuals of how the consortium could have been organised differently.

This can be used for optimising the functioning of the current consortium and the organisation of future consortia. This can promote better pandemic preparedness, since it can help to design new consortia faster and more efficiently in response to future pandemics or epidemics. This work can also be leveraged to inform more efficient and fast drug development generally, to overall improve patient outcomes.

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

The biggest challenge I’ve encountered in this research is tackling the extremely broad scope of the research and model. The consortium is a huge collaboration of almost 40 different public-private partners. There are so many different things being done in this consortium, so measuring, understanding, and modelling all of it has been very challenging.

Understanding this system is challenging and complex, but luckily, many CARE partners are willing to make time to participate in our interviews, share their learnings and insights and explain very clearly the core aspects of their roles in the consortium. This cooperation and willingness to collaborate, makes our research so much more feasible and relevant.

Currently, a big challenge that we’re working through is trying to quantify the more behavioural variables relating to consortium design, such as willingness to collaborate, trust, perceived success etc.. The method we use, system dynamics, is a tool that allows/facilitates the quantification of soft variables like these, so this gives a really good starting point. Currently it’s a learning process of applying these methods to the context of the consortium, but we know we can count on the CARE partners to engage in future workshops to help validate and strengthen our findings.

How have you benefited from your involvement in CARE?

I have benefited greatly by having access to such expertise and so many industry experts. The diversity of partners and the huge range of capabilities within the consortium provides a perfect pool of stakeholders to use as inputs in a system dynamics model.

Not only are there many skilled partners in the consortium, but the high willingness of partners to engage in our research and share their knowledge has been extremely beneficial.

Both the expertise in the consortium and the willingness of these experts to collaborate have been invaluable in helping me understand the health system of antiviral drug development and has helped me to improve my skills in system dynamics modelling.

CARE  – Committed to the COVID-19 cause

In May 2023, the World Health Organisation announced that the COVID-19 pandemic “is now an established and ongoing health issue which no longer constitutes a public health emergency of international concern (PHEIC)”, so should we still CARE?

When CARE was initiated, the world was reacting to a rising pandemic which claimed many lives globally, disrupted economies, upset personal lives and so on, due to the pervasive SARS-CoV-2 virus. Over the course of the life of the CARE consortium, we have seen many variants which have challenged our approaches and had varying effects on the severity of the disease, and we have also seen the pandemic peak and thankfully decline through the introduction of vaccines and increasing immunity in the global population.

The decline has now reached a point where the WHO deems COVID-19 to be an “established and ongoing health issue” rather than a public health emergency of international concern. COVID-19 is now expected to manifest as mini-waves rather than seasonal surges, and furthermore, it has left a legacy in the form of long COVID which will need to be managed for the many people affected. Availability of more potent antivirals may assist in preventing or mitigating the long term consequences of SARS-CoV-2 infection.

In parallel with this reality, we are starting to see organisations who quickly mobilised resources to help address the COVID-19 challenge in 2020, reprioritise core business efforts. So – does CARE still have something to offer? The key point is that the WHO deems the current position to be an “established and ongoing health issue”. There are also certain populations (such as immunocompromised individuals) for whom there is still an unmet need for COVID-19 prophylaxis and treatment. We also know that the virus continues to mutate, which may alter effectiveness of current approved treatments.

The emergency may be over, but we still need to be prepared. That is why CARE continues to stay true to its commitment to pandemic preparedness and its expert academic and industry teams continue to move forward in their endeavours, generating and applying new knowledge while responding to the everchanging context.

In the remaining two years of the CARE consortium, we anticipate bringing one or more variant agnostic medicines to the clinic, optimise other potential broad spectrum novel treatments that can be used in future pandemics, as well as continuing to share our findings as we progress.

So, CARE does care, and continues to strive to make a meaningful contribution to the world’s defences against the SARS-CoV-2 virus, as well as pandemics of the future.

CARE presentation at 9^th ESWI Influenza conference in Valencia

Are you going to the 9th ESWI Influenza conference in Valencia next week? If so, you will have the opportunity to learn about a new SARS-CoV-2 inhibitor that is targeting the membrane protein. Do not hesitate to attend this presentation by CARE partner KU Leuven.

Title of the presentation: A novel SARS-CoV-2 Inhibitor targeting the membrane protein with activity in a SCID mouse model.

Presenter: Manon Laporte

Session name: SCS12 – Antiviral and immune therapy (Auditorium 1)

Date/time: Tuesday, 19 September 2023, 5pm CET