COVID-19 : Inserm on all fronts

Science

The COVID-19 pandemic represents a health crisis unprecedented in its scale and impact on our lives. Caused by an emergent coronavirus, SARS-CoV-2, this disease has rallied researchers both across the world and here at Inserm. Our objectives are multiple:  understand the disease, improve its treatment, develop vaccines rapidly and anticipate future developments of the pandemic in order to protect people.

Over 660,000 confirmed deaths and around 17 million people infected worldwide! Such is the tragic human toll of the COVID-19 pandemic since SARS-CoV-2 appeared in China at the end of last year. And France has not been spared – far from it. According to Public Health France, by June 2020 over 166,000 people had contracted the disease and almost 30,000 had died from it since the epidemic began. In this context, “Inserm’s mission has never been so important,” states Éric D’Ortenzio1, physician-epidemiologist at Inserm and Scientific Coordinator of the REACTing Consortium – a key player in ­ fighting the pandemic. In the face of the pandemic, Inserm researchers have been unanimous in their response. “There has been huge mobilisation for research against COVID-19,” adds the epidemiologist. Inserm has contributed to over 450 scienti­fic publications on a disease which only a few months ago was unknown. That being said, numerous grey areas need to be elucidated in order to combat the virus effectively and bring an end to the pandemic. In this issue of our magazine, we give you an overview of the research conducted in France on SARS-CoV-2 and its disease, COVID-19.

Know your enemy

SARS-CoV-2 is a new member of the large family of coronaviruses, which generally cause colds or mild ‑ u-like illnesses that resolve spontaneously. However, since the start of the century, three lethal epidemics have been caused by emergent coronaviruses: SARS-CoV-1 in 2003, MERS-CoV in 2012, and SARSCoV-which appeared in China at the end of last year. The latter also highlyresembles its cousin, SARS-CoV-1. “The two viruses are 80%­ similar,” states Isabelle Imbert2, CNRS biologist and professor at Aix-Marseille University. Similar too are some of the mechanisms of infection. Both viruses use the same target to bind to human cells: the ACE2 receptor. Usually involved in regulating blood pressure, this protein is locatedb on the surface of certain cells present on the walls of the airways and also on those of the blood vessels and intestines. The virus binds to these receptors via the S protein (“spike” protein), which protrudes from its surface. “It is notably in terms of this protein that the two SARS-CoV strains differ,” notes the biologist. Once bound to the cells, the virus penetrates them, diverting their mechanisms in order to replicate in large numbers. These are the replication mechanisms that Imbert’s team is aiming to characterise and subsequently inhibit. Thanks to in vitro studies and in silico (computer) modelling, the researchers are hoping to specifically inhibit an enzyme essential to the replication of the virus, polymerase. “This would give us a treatment with few side effects because this enzyme activity is not found in humans,” continues Imbert. This project also convinced REACTing and the French National Research Agency (ANR), which are helping to fund it. In addition to the biological mechanisms of the infection, it is crucial to know the natural history of COVID-19, the disease caused by SARS-CoV-2. “This is the primary objective of the French COVID-19 observational cohort, which was set up as soon as the first cases started to emerge in France,” explains Yazdan‑ Yazdanpanah3, Head of Infectious Diseases at Bichat Hospital in Paris and member of the COVID-19 Steering Committee. This research began with a description of the first five patients diagnosed at Bichat at the end of January and revealed three very different types of clinical presentation: two cases with few symptoms and a favourable outcome, two cases that were initially reassuring but worsened after ten days, and one immediately serious form with multiple organ damage. Since the first cases were described, over 3,000 patients hospitalised across France for COVID-19 have enrolled in the cohort. “The data collected improve our understanding of the disease, its symptoms, and the response to treatment,” continues the specialist. Information that is all crucial in helping medical staff ­ fight COVID-19. In addition, this cohort has made it possible to create a biobank. “This biobank is used for basic and clinical research, declares Yazdanpanah. Making these samples available to researchers means that they can, for example, study the genome of the virus or its interactions with our immune system.­“

How the immune system responds to the virus varies widely from one individual to another. The majority of those infected with COVID-19 recover spontaneously. However, around 20% require hospitalisation – for very serious forms of the disease in quarter of cases. These generally involve acute respiratory insuf­ficiency and sometimes thrombosis: blood clots form in the veins, reducing the blood circulation and intensifying the respiratory problems. Observational cohorts such as French COVID-19 have identified several factors likely to promote the worsening of the disease. For example, pre-existing cardiovascular or respiratory disease, diabetes, chronic illness, and also obesity. Two studies coordinated by Inserm researchers in hospitals in Lille and Lyon con­firm a higher prevalence  of people with obesity in intensive care for COVID-19 than in the general population. Age also plays a key role in the serious forms of the disease. According to data compiled by Public Health France since 1 March, 72 is the median age of people admitted to French hospitals. And among those who died in French hospitals, 71% were aged 75 or over.

Towards robust therapeutic avenues

Without treatment that targets the virus directly, healthcare professionals have found themselves powerless in ­ fighting this disease that only a few months ago did not exist. In the face of this health emergency, the most rapid and effective strategy consists of repurposing existing drugs. “Molecules whose toxicity is known will rapidly be made available to patients,” confirms Bruno Lina4, head of the Inserm team at the International Centre for Infectiology Research (CIRI) in Lyon and member of the COVID-19 Steering Committee. This approach is also central to the research of the laboratory he heads up at CIRI. “We have developed a model of preclinical infection that is very close to human physiology, allowing us to test numerous drugs,” states the virologist. So far, “none of the molecules have shown noteworthy efficacy, but interesting signals have been revealed for some of them, such as the non-steroidal anti-inflammatory, naproxen”. These ­ ndings remain to be con­firmed on experimental models and in clinical practice. Studies have already been set up to evaluate the ef­ cacy of drugs that are potentially active against SARS-CoV-2. This is notably the case of Discovery, coordinated by Inserm within the framework of the REACTing consortium. This European clinical trial was set up in record time and began on 22 March. By early July, 763 hospitalised patients had enrolled out of the 3,200 envisaged Europe-wide. “The rate of enrolment is currently low,” acknowledges Lina. “The European component has taken time to set up, given the regulatory and funding issues and also a certain level of reticence,” adds Yazdan Yazdanpanah, President of the trial ’s steering committee. But the data has not been collected in vain, far from it. Discovery is an integral part of Solidarity, the World Health Organization (WHO) clinical trials consortium, which groups almost 5,500 patients from 21 countries and is evaluating the same molecules. These include – at least initially – the antiviral remdesivir, which is used to fight the Ebola virus. Then lopinavir and ritonavir – antivirals habitually used against HIV. This lopinavir/ritonavir combination has been evaluated alone and in association with  interferon beta-1a, an immunomodulator that reduces inflammation by limiting the action of certain chemical messenger emitted by our immune cells: proin inflammatory cytokines. And, ­ finally, hydroxychloroquine, an antimalarial highly-mediatised as a potential treatment for COVID-19 but whose interim analyses have shown lack of efficacy in reducing the mortality of hospitalised patients versus standard of care. As for the antivirals evaluated, the results should be available by the end of the summer. But “probably none of these molecules are very effective in reducing mortality because any positive effects would have been seen already,” laments Yazdanpanah. That is why Solidarity and Discovery, which were designed as adaptive trials, discontinued in July their testing of lopinavir/ritonavir with or without interferon beta. Discussions are underway as to the testing of new treatments – thanks to the high level of adaptability of these studies that makes it possible to constantly reassess the research protocols in order to take into account the most recent and robust international ­findings.

A group of drug repurposing clinical trials, Corimuno-19, is also ongoing in a cohort of patients with pneumonia caused by the virus. “Thanks to a protocol of multiple, randomised, controlled clinical trials nested withinn this cohort, we can evaluate several molecules at the same time, and as such accelerate research while maintaining a high level of methodological quality and patient safety,” states Pierre-Louis Tharaux5, Inserm Research Director and one of the project’s coordinators. Sponsored by the Paris public hospitals group (AP-HP) with the support of REACTing, Corimuno-19 is particularly focused on several immunomodulators. The aim is to ­ finnd out whether these drugs, which are notably prescribed in autoimmune diseases, can limit the immune system exacerbation that occurs in some hospitalised patients. This exacerbation, referred to as “cytokine storm,” leads to the excessive production of cytokines, which contributes to a rapid degradation in the health of the patient. For the time being, three molecules directed against cytokines or their cell receptor have been evaluated: sarilumab, tocilizumab, and anakinra. Around 700 patients from 30 clinical centres have taken part in these trials. “The results are in the final phase of validation, continues the researcher. They will make it possible to determine whether these molecules, particularly tocilizumab, reduce the risk of mortality for patients in respiratory distress as has been observed in several retrospective studies.” The Corimuno-19 project is also studying the efficacy and tolerability of anticoagulants and corticosteroids. These treatments are used to reduce the risk of thrombosis and inflammation, respectively – complications which appear to be linked to cytokine storm. These observational studies could back up the preliminary results of Recovery – a UK clinical trial on dexamethasone. This inexpensive and widely-available corticosteroid is considered to significantly reduce the mortality of patients with severe respiratory insufficiency. The last component of Corimuno-19, the Coriplasm trial, is aimed at evaluating the ef­ cacy of transfusing plasma from patients who have recovered from COVID-19. Their plasma contains antibodies directed against the virus. Transfusing them could help hospitalised patients to ­ ght the infection.

The use of antibodies is positioned to become an effective therapeutic approach pending the production of vaccines. Tens of research teams worldwide are trying to identify antibodies that could have a therapeutic action on the virus. An objective which is shared by the Inserm team of Hugo Mouquet6 at Institut Pasteur in Paris. “Using the blood samples of patients, particularly those from the French Covid-19 cohort, we have already been able to produce and characterise 60 ­human antibodies. These are specific to the S protein, one of the preferred targets of our immune system in its fight against SARS-CoV-2, explains Mouquet. Some of them are interesting because they present at low dose a neutralising activity that blocks the infection of the cells.” If these ­ findings are confirmed in experimental and clinical models, they could be produced in large quantities to treat the disease. While costly, these monoclonal antibodies [monoclonal because they recognise the one same part of an antigen, ed.] would also be likely to be prescribed on a preventive basis in order to protect the most exposed and/or the most vulnerable populations. In addition, knowledge acquired on the antibodies and the mechanisms of immune response could in time contribute to the development of more effective vaccines. Developing safe and effective vaccines is the best way of providing protection. About twenty vaccines are undergoing clinical evaluation worldwide even if only three of them are in Phase 3 – this last stage of validation used to con­firm the efficacy of a therapeutic or vaccine strategy on a large number of people. Furthermore, 130 vaccine candidates are also in development.

A vaccine – not quite there yet

In France, some thirty research teams have joined the race. The most advanced research is probably that being coordinated by Frédéric Tangy at Institut Pasteur, in which the idea is to use the attenuated measles vaccine as a vector for presenting SARS-CoV-2 antigens – coronavirus elements able to trigger an immune response sufficient to immunise us without making us ill. A Phase 1 clinical trial to verify the safety and tolerability of this vaccine has been envisaged for the end of the summer. At Inserm, twelve teams are involved in COVID-19 vaccine research projects. Three of them have recently received funding from France’s Ministry of Higher Education, Research and Innovation on the opinion of an expert committee coordinated by REACTing. The first project is being developed by Camille Locht7’s team at the Lille Infection and Immunity Centre, which is focusing on the whooping cough vaccine as a vector. The second is being developed by Yves Lévy8’s team at the Vaccine Research Institute (VRI) in Créteil, whose strategy consists of having monoclonal antibodies present antigens of the virus. Finally, the vaccine formula advocated by Patrice Marche9, Inserm Research Director at the Institute for Advanced Biosciences (IAB) in Grenoble, is based on particles composed of natural lipids. “These are lipid droplets the size of a virus that carry the antigens capable of inducing an immune system response,” explains the immunologist. This approach developed in conjunction with the Laboratory of Electronics and Information Technologies (LETI) of the French Alternative Energies and Atomic Energy Commission (CEA) has already proved itself with HIV antigens on experimental models. “The industrial process for the production of these particles is already in place and their quality control is straightforward, which represents two considerable advantages when it comes to rapidly producing a vaccine in an emergency situation, states Marche. It remains for us to prove that the antigens induce a protective immune response.” If successful, this second-generation vaccine candidate could begin clinical trials at the end of next year.

A future vaccine already under criticism?

There is no shortage of initiatives when it comes to developing SARS-CoV-2 vaccines and it is highly likely that one of them will arrive at completion as of next year. Beyond the questions of production and distribution, how would such a vaccine be received by the population? In an attempt to answer this question, a survey was conducted at the end of March on a sample of 1,012 adults representative of the French population. This research, coordinated by Inserm sociologist Patrick Peretti-Watel10, indicates that 26% of people in France would refuse a vaccine. “This proportion increases to 37% among the underprivileged social classes, which are already more exposed to infectious diseases than the rest of the population,” laments the researcher. Another worrying finding is that 36% of women under the age of 35 – who also play a crucial role in vaccinating children – would refuse the vaccine. This study shows division along political lines. According to its authors, these parameters must be taken into account by the public authorities in order to get as many people as possible onboard with future vaccination campaigns and to avoid political controversies – like those having tarnished the 2009 H1N1 influenza virus vaccine.

In the absence of vaccines and treatments, an effective solution for halting the spread of the virus has been lockdown. But its impacts have not been the same for everyone. Some people are more vulnerable to mental health problems, as the latest data from the Tempo cohort confirm. Coordinated by Maria Melchior11, Inserm Research Director at the Pierre Louis Institute of Epidemiology and Public Health, this cohort of 1,200 people studies mental health and addictive behaviours in young adults. The questionnaires that were sent to the participants during lockdown reveal that the proportion of those declaring financial difficulties had increased during this period of professional inactivity. And they are more subject to symptoms of anxiety and depression than those who affirm having no money problems. The study of social inequalities in health is also central to the research of Michelle Kelly-Irving12, Inserm Research Director at Toulouse III University. To find out the impact of the pandemic on these inequalities, the epidemiologist is coordinating an interdisciplinary research program named Epidemic. “Its first component is aimed at characterising the social determinants of the epidemic,” specifies Kelly-Irving. Some socio-professional categories are more exposed to the virus – not just healthcare professionals but also supermarket and delivery workers, for example. Conversely, executives present a lower risk of infection because they are generally able to workfrom home. These socio-professional variations also expose people differently according to sex.” Data from a sample of 20,001 volunteers representative ofthe French population, the COVID-19 Barometer – administered by polling institute IPSOS in partnership with datacovid.org –, indicate that women are over represented among those diagnosed with COVID-19. “We think that women, who are more present in paramedical and service industry roles, have had increased exposure to thevirus or easier access to testing.” The Epidemic project, funded by the ANR, also looks at the psychological impacts and socio-anthropological conditions of lockdown via an online survey and qualitative interviews, respectively.   

Anticipating a new epidemic

This research will enable us to improve how we prepare for any similar future health crises and their impact on the population, particularly under privileged social classes. “Our initial findings   suggest that a one-size-fits-all approach to lockdown creates or amplifies social inequalities in health. Could lockdown be done differently? According to income, housing type or region?” wonders the epidemiologist. By obliging most of us to stay home, lockdown has made it possible to break the chain of viral transmission, but this radical measure has drastically modi­ ed our social contacts. In order to ­ nd out how these have changed during and after lockdown, Lulla Opatowski13, Senior Lecturer at Versailles-Saint-Quentin-en-Yvelines University and epidemiologist at Institut Pasteur, has set up SocialCov. Through questions relating to lifestyle, this online survey has identified the number of daily social interactions and their frequency in over 40,000 people. “Analysis of the data shows that on average the number of contacts went from six to twelve per day according to age group to fewer than four during lockdown,” reports Opatowski. The second component of the survey, which is about to be launched, will evaluate how lifting lockdown has affected these interactions. “This health crisis has had an unprecedented effect on the social behaviours of the population.” These data could in fine be used to model the spread of the virus in the community and would constitute essential information, particularly in the event of a new epidemic.

Opatowski’s team is also looking at the transmission of SARS-CoV-2 in healthcare facilities. The MOD-COV project created within the framework of a working group under the aegis of the REACTing consortium is aimed at reducing the risk of spread of the virus in hospitals. “We have adapted our mathematical models of nosocomial infection spread to answer the questions of clinicians confronted with the COVID-19 epidemic, explains the researcher. For example, from what stage of the epidemic should all patients be tested on admission? Should a special COVID-19 unit be set up? When can the measures taken to contain the epidemic be relaxed?” To answer these questions, the model simulates the different hospital departments and takes into account a certain number of variables: the number of patients and medical staff, the transfer of patients, and the interactions between people depending on the departments. Hundreds or even thousands of scenarios in which these variables are developed were then compared in silico to determine which make it possible to reduce the risk of transmission of the virus. “The purpose of the results obtained is to help the healthcare facilities to take the appropriate measures to best control the epidemic, concludes Opatowski. This type of modelling could also be applied to other types of facility, such as nursing homes, or to other emergent viruses.”­This represents another tool for decision-makers to improve how they prepare for a potential second wave.

Research into this novel coronavirus is very dynamic in France in general and particularly at Inserm. Researchers are mobilised to find an effective treatment, develop safe vaccines, and prepare the country for a potential new wave. Because the virus continues to circulate in France and worldwide. The threat linked to SARS-CoV-2 has not gone away and many countries are experiencing a cataclysmic ­wave, as shown for example by the recent surge in COVID-19 cases in Brazil, India, and the USA. Right now, we do not have the necessary data to predict individual susceptibility to SARS-CoV-2 according to country, contacts, immune pro­file, or sociodemographic characteristics. Pending more effective weapons to fight this novel coronavirus and more sensitive predictive tools, we must continue to respect the barrier measures to protect the most vulnerable.

REACTing: the French response to emergent infectious diseases

Created in 2013 on the initiative of Inserm, the REACTing consortium has two primary missions: prepare for potential infectious emergences and coordinate research in the event of an epidemic. These involve bringing together teams and laboratories from all disciplines – from basic research to the human and social sciences. In the face of the COVID-19 health crisis, “we rapidly swung into action to identify the research priorities,” relates Éric D’Ortenzio, Scientific Coordinator of REACTing. As such, it was possible to get twenty projects off the ground starting from February thanks to a seed budget of one million euros. “This funding has helped implement a patient cohort, clinical trials of potential treatments, mathematical models of the epidemic, and also surveys on the social challenges of the pandemic,” clarifies Yazdan Yazdanpanah, Director of the Inserm Immunology, Inflammation, Infectiology and Microbiology (I3M) Theme-Based Institute, which supervises REACTing. Apart from its role of coordinator, the consortium also endeavours to play an informative role. Every week, with the help of Inserm’s Collective Expertise Centre, REACTing selects the most relevant scientific publications so that the pandemic response stakeholders have a general overview of COVID-19 research and can as such make the appropriate decisions.

Notes :

1: Unit 1137 Inserm/University of Paris

2: JRU 7257 CNRS/Aix-Marseille University, Architecture and Function of Biological Macromolecules (AFMB)

3: Unit 1137 Inserm/ University of Paris

4: Unit 1111 Inserm/ENS de Lyon/Lyon I University, VirPath

5: Unit 970 Inserm/University of Paris, Paris Cardiovascular Research Centre (PARCC)

6: Unit 1222 Inserm/Institut Pasteur, Humoral Immunology

7: Unit 1019 Inserm/CNRS/University of Lille/Lille Regional University Hospital/Institut Pasteur de Lille

8: Unit 955 Inserm/Paris Est Créteil Val de Marne University, Mondor Institute for Biomedical Research

9: Unit 1209 Inserm/Grenoble Alpes University

10: Unit 257 Inserm/French National Research Institute for Sustainable Development (IRD)/ University Hospital Institute Mediterrannée Infection/Aix-Marseille University, Vectors-Tropical and Mediterranean Infections team

11: Unit 1136 Inserm/Sorbonne University

12: Unit 1027 Inserm/Toulouse III - Paul-Sabatier University

13: Unit 1018 Inserm/Institut Pasteur/Versailles-Saint-Quentin-en-Yvelines University