Inserm VRI-led research reveals predictors of severe disease and long COVID symptoms

The CARE partner Inserm-VRI has recently published two articles pertaining to severe SARS-CoV-2 infected patients from the French COVID cohort. The first article delves into the severity of SARS-CoV2 infection, to identify markers associated with the extent of severity of SARS-CoV2 infection. The second article characterized gene expression and cellular markers related to the persistence of symptoms post a severe infection.

Identifying COVID-19 patients who are at high risk of worse prognosis after severe disease is challenging. Inserm-VRI studied the blood of 61 patients who were hospitalized with severe COVID-19 and compared it to healthy people. They found that certain immune cells were abnormal, and there were many markers of inflammation. They identified a specific neutrophil activation marker, called CD177, which is present in high levels in the sera of severe COVID-19 patients and could predict which patients might develop severe disease. More importantly, measuring CD177 over time allowed them to identify patients with poor prognosis from those who will recover. These findings suggest that neutrophil activation is a hallmark of severe COVID-19 disease, and CD177 assessment could help identify patients at high risk for severe disease. Click here for the publication.

After recovering from severe COVID-19, some people may still experience prolonged symptoms. The CARE partner Inserm-VRI investigated the immune system dysfunction that causes these long-lasting symptoms. They analyzed the blood of severe COVID-19 patients at 1, 3 and 6 months after leaving the hospital and found abnormalities that persisted up to 6 months after discharge. These included high levels of markers of inflammation, changes in certain types of immune cells, a decrease in antibodies against the virus, and changes in gene expression related to blood clotting. They also identified a set of genes associated with thrombotic events in the acute phase of infection. The fact that these abnormalities persisted for up to six months, even in patients who were no longer experiencing symptoms, suggests that continued monitoring and preventive measures may be necessary. Click here for the publication.

One new CARE deliverable is  now publicly available on CARE webpage “Resources“

How far has CARE progressed with its anti-coronavirus small molecule development?  Read about screening cascades for hit discovery and the hit development programmes currently ongoing in CARE in the latest Portfolio report (D3.12).

CARE latest annual project summary is  now publicly available on CARE webpage “Resources“

Do you wish to know more about the progress made by the CARE project? Read the summary for the third year of the project, presenting CARE’s main results achieved after three year of research (March 2023).

About CARE’S Scientific and Ethics Advisory Board

What is the SEAB?

SEAB stands for Scientific and Ethics Advisory Board. It is an independent group, appointed by the CARE Steering Committee (SCOM) that can provide objective feedback on the activities and plans of the consortium in order to ensure its obligations are fulfilled.

Who is in the SEAB?

It is a group comprising two ethics and three scientific experts. Of the scientific experts below, Professor Manabe is also a clinician.

What role does the SEAB play?

 The SEAB’s role is to advise the project as a whole on scientific and technical development as well as ethics aspects, to support with decision making. They are expected to meet annually, which takes place during the CARE Annual Meeting. The group are also invited by the CARE SCOM to provide non-binding feedback and advice to the CARE General Assembly and CARE SCOM at this time.

We asked some of the SEAB members for their views about CARE’s progress, plans and relevance to society today

How relevant is CARE today?

 Prof. Janet Mifsud (JM): The subject may not be as urgent as it was when it was originally funded, however the unique collaborations, insights and technologies developed over these last few years in the CARE project have a much wider and important impact in the scientific arena. CARE also has the capacity to act as a fulcrum in the long-term visibility and foresight of what is being developed and researched for future pandemics.

Prof Yuka Manabe (YM): CARE could become a model for accelerating pandemic response and preparedness; academia has many innovative ideas that can be accelerated to impactful products if paired with industry partners who understand quality, reproducibility and commercialization.

Prof. Raffaele De Francesco (RDF): The World Health Organization (WHO) declared COVID-19 to be no longer a global health emergency in May 2023 however, the attention paid to COVID-19 should remain very high. New variants of the virus are constantly emerging, and some of these variants may be more transmissible or severe than previous variants. In this scenario, the activities of the Care consortium remain highly relevant.

What are your observations of the programme over the past three years?

 JM: It is clear that there has been a great deal of progress in CARE since inception. We have observed greater data sharing, interaction and communication between the work packages. While there are less lead compounds than anticipated in CARE, the repurposing work and working with compounds from outside the consortium and combination drugs offers promising alternative strategies.

YM: after a predictable period of framework development for how to engage, there has been measurable growth of CARE with increasing productivity and better cross fertilization across work packages.

RDF: CARE has made significant progress towards its goal to develop new drugs to fight Covid-19 and future pandemics, through building a very strong network that has the potential to make a major impact. The Consortium has shown how academia and industry can work together effectively to accelerate drug discovery and development.

What hopes do you have for the remaining period of CARE?

JM: CARE is offering very interesting integrative work in the systems biology approach from the molecular to clinical approaches which will be key and may have a great impact in the clinical trial developments. In the last few years of CARE, there is very interesting ancillary work planned such as the interactions related to the regulatory aspect with EMA with data from GDPR and ethics studies. The consortium systems modelling is also novel and may have a wider impact on other consortium and such IMI funding models. In my opinion this should be of interest to the Innovative Health Initiative (IHI) Steering Committee for to enable CARE learnings to be applied or adapted for other viral work.

YM: I hope that the funders continue to realize the value of seeing the collaboration through and considering how this vibrant network can be leveraged for future work. There have been many basic science discoveries in addition to novel and robust pipelines built to test new compounds. Expanding the work from just Europe to low- and middle-income countries in future iterations would also be welcome.

RDF: I hope and expect to see additional groundbreaking discoveries as well as substantial progress of existing candidates, eventually leading to the development of new important therapeutic and preventive agents.

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.