Paris and Its Suburbs: Twice as Many Cardiac Arrests During Lockdown

© Jair Lázaro on Unsplash

Indirect consequences of the COVID-19 pandemic on the healthcare system and the management of other diseases are beginning to emerge. A study, sponsored by Inserm and conducted by Eloi Marijon at the Paris-Cardiovascular Research Center (Inserm/Université de Paris) in collaboration with Daniel Jost (Paris Fire Brigade), suggests that during lockdown the number of cardiac arrests in Paris and its suburbs had doubled compared with the same period in previous years. According to the authors, several hypotheses must be taken into consideration, such as healthcare system saturation and occasional disruptions in patient monitoring during lockdown. This study published in The Lancet Public Health is based on data from the Paris Sudden Death Expertise Center.

The impact of the COVID-19 pandemic on the organization of the healthcare system and the management of other diseases remains difficult to estimate, but initial data is beginning to emerge. Since March, significant efforts have been made to track, as precisely as possible the deaths directly linked to COVID-19, but other causes of death with more indirect links to lockdown and the reorganization of healthcare systems during the crisis have, until now, been less well documented.

A study by Eloi Marijon and Nicole Karam at the Paris-Cardiovascular Research Center (Inserm/Université de Paris) in collaboration with Daniel Jost (Paris Fire Brigade) published in The Lancet Public Health has evaluated the impact of the pandemic on the number and prognosis of cardiac arrests occurring in Paris and its suburbs.

The researchers show that over the previous nine years the number of cardiac arrests had remained stable in Paris and its suburbs, but experienced a marked increase during the first six weeks of lockdown (March 16 to April 26, 2020).

The data presented in the study suggests the number of arrests have even doubled in comparison with the same period in previous years. This research is based on data from the registry of the Paris-Sudden Death Expertise Center (Paris-SDEC), inaugurated in 2011 by Inserm, APHP, and the University of Paris. Its objective is to collect, based on a real-time surveillance system, information on all out-of-hospital cardiac arrests having occurred in Paris and its suburbs.

During the six weeks studied by the researchers, 521 out-of-hospital cardiac arrests were identified in Paris and its suburbs, or a rate of 26.6 arrests per one million inhabitants. Between 2012 and 2019 of the same period, this rate was 13.4 cardiac arrests per one million inhabitants.

A better understanding of the impacts of the crisis

Although there has been little change in the demographic profile of the patients, the study suggests that there had been drastic changes in the initial management and immediate prognosis of these cases during lockdown. Over 90% of the cardiac arrests occurred at home, with bystander less inclined to initiate cardiopulmonary resuscitation (CPR) and with longer intervention response times despite empty roads. This resulted in a lower survival rate of patients on arrival at hospital. During the lockdown period explored by the researchers, only 12.8% of the identified patients were alive on admission, versus 22.8% in the same period in previous years. “Over the previous nine years, we collectively worked to develop this database, which is updated more or less in real time, and upon which this new study is based. Out-of-hospital cardiac arrest is a particularly interesting multifactorial marker, which enables us to evaluate the extent to which the entire community has been impacted by this pandemic”, explains Marijon.

The authors were able to estimate that around 33% of the increased number of deaths observed is directly linked to COVID-19.

Other factors have probably had an impact: reduced monitoring and follow up of patients with heart conditions and/or presenting risk factors during the pandemic, the saturation of community doctors’ offices, pre-hospital and hospital services, the changes in the psychological behavior of some people during such an unprecedented time, and possibly the harmful effects of medicines used by patients to treat COVID-19.

In addition, previous studies conducted by the team have shown that those experiencing cardiac arrest are eight times more likely to survive when a bystander is able to perform rapidly real-time CPR. However, during to confinement, it appears that in some cases no CPR had been initiated or possible from bystanders.

“Amid the easing of lockdown, our findings help to understand the consequences of this crisis, and the lessons to learn, so that we can react better in the event of a second wave. Our findings reiterate that it is necessary, more than ever, to find a balance to ensure that both the epidemic is managed and other patients are monitored. This concerns us all”, concludes Karam.

Tests for everyone, really?

Deconfinement is now well under way. At the heart of the system is a promise: massive testing of the population to isolate people contaminated by Covid-19 and stop the epidemic. But these tests, what exactly are they? Are they reliable? Will everyone be entitled to them? And will they tell us if we’re immune once and for all? Canal Detox cuts off false information.

Hydroxychloroquine and azithromycin can have a deleterious impact on the cardiovascular system

©Hal Gatewood on Unsplash

Hydroxychloroquine and azithromycin can have a damaging impact on the cardiovascular system and are a life-threatening combination, according to large analysis from a World Health Organization (WHO) database of adverse drug reactions , published in Circulation.

The study is a retrospective and observational analysis of a WHO database including more than 21 million reports of adverse event cases, all classes of drugs, from more than 130 countries, between November 14 1967 and March 1, 2020, mainly before the COVID-19 pandemic.

The study compared reports of cardiovascular adverse reactions in patients who received hydroxychloroquine, azithromycin or a combination of the two drugs with reports of cardiovascular adverse reactions related to all other medicines in the database. data. The study period therefore mainly covers the period preceding the use of hydroxychloroquine and azithromycin, alone or in combination, to treat patients with COVID-19. Of the more than 21 million case reports of adverse drug reactions, the researchers extracted the case reports for hydroxychloroquine and azithromycin, alone or in combination:

– 76,822 cases have been reported with hydroxychloroquine alone, and in 21,808 (28.4%) of these cases, hydroxychloroquine was suspected of being associated with the adverse effect;

– 89,692 cases have been reported with azithromycin alone, and in 54,533 (60.8%) of these cases, azithromycin was suspected of being associated with the adverse effect;

– 607 cases have been reported in the combination of the two drugs.

Analysis has shown that:

1) There was a statistically significant increase in the number of reported cases of ventricular tachycardia (TV) and / or QT prolongation (LQT), including torsades de pointes (TdP / TV), for each drug taken individually in suspected cases, compared to all other drugs on the base.

2) hydroxychloroquine was also significantly associated with reports of the development of conduction disorders (mainly atrioventricular block and branch block) and heart failure.

3) Azithromycin alone was associated with a higher reported number of LQT and / or TdP / TV cases than hydroxychloroquine alone (0.8% versus 0.3% of the total number of cases reported with these molecules, respectively ).

4) The combination of hydroxychloroquine + azithromycin was associated with more reported cases of LQT and / or TdP / TV than either of the drugs taken alone (1.5% compared to 0.6% of the total number of cases reported with these therapeutic modalities, respectively).

5) No other cardiovascular adverse effects (including coronary syndrome and myocarditis) were significantly associated with these drugs.

6) The proportion of cases associated with death for TdP / TV cases was 8.4% (7/83) with hydroxychloroquine and 20.2% (52/257) with azithromycin, compared to 0 % (0/53) and 5.4% (12/223) for cases of LQT without TdP / VT with hydroxychloroquine and azithromycin, respectively. The increase in the frequency of these adverse events was statistically significant, although small in absolute numbers.

The researchers concluded that “potentially fatal acute cardiac proarrhythmic effects have been described primarily with azithromycin but also with hydroxychloroquine.” Their combination gave a stronger signal. Hydroxychloroquine has also been associated with life-threatening heart failure when exposure is prolonged for several months. Although the absolute number of cases is small, it is important to keep in mind these drug-related adverse cardiac effects in the context of patients with COVID-19 who may have additional risk factors for LQT / TdP, including inflammation with a high level of interleukin-6, hypokalemia, many drug combinations that can interact in a harmful way,

As outlined in the American Heart Association guideline of April 8, 2020 in, “Considerations for Drug Interactions on QTc in Exploratory COVID-19 (Coronavirus Disease 2019) Treatment”, both drugs are known to cause potentially serious complications for people with cardiovascular disease, including an increased risk of sudden death. The effect on the QT interval or the risk of arrhythmia of these two drugs combined has not been studied. “Taking hydroxychloroquine and azithromycin is associated with a risk of increased cardiovascular toxicity. They should not be administered outside of clinical trials and require close monitoring,” said Mariell Jessup of the American Heart Association .


The authors do not report any links of interest or external sources of funding for this study.

Inclusions in the hydroxychloroquine group of the Discovery trial are suspended.

Les inclusions dans le groupe hydroxychloroquine de l’essai Discovery sont suspendues depuis dimanche 24 mai, suite à la décision conjointe de Solidarity, essai conduit sous l’égide de l’OMS, et de Discovery, essai porté par l’Inserm qui lui est étroitement associé. Cette décision a été motivée par les publications scientifiques relatives à l’utilisation d’hydroxychloroquine dans des études observationnelles, notamment la récente étude parue dans The Lancet. Les inclusions dans les autres groupes de traitement de l’essai Discovery continuent. Pendant cette suspension les comités indépendants des 2 études vont examiner conjointement les données déjà collectées dans l’objectif de rendre définitive ou pas cette suspension.

La sécurité des patients étant, par définition, la priorité des investigateurs et du promoteur de l’étude, une surveillance cardiologique de tous les patients recevant de l’hydroxychloroquine a été mise en place dans le protocole de l’essai depuis le début de l’étude. Les investigateurs qui suivent les participants dans le cadre de l’essai répondront à toutes les questions que ces derniers pourraient se poser.

SARS-CoV-2: Will Summer Really Mean the End of It?

Our knowledge of SARS-Cov-2 remains for the moment too fragmentary to affirm with certainty its seasonality, but every publication insists on the importance of preventive measures. © chuttersnap sur Unsplash

Will SARS-CoV-2 die out with the arrival of summer? With the current lifting of lockdown restrictions, some are hoping that the warm weather will herald a decrease in the R0, as is the case with other viruses whose transmission is better documented, such as those of seasonal influenza.

The issue of viral seasonality has long been studied by scientists, but many questions remain. Some viruses are linked to epidemic peaks at certain specific periods of the year: not just influenza but also poliovirus which, in the absence of vaccination, leads to an increase in the number of cases of polio, particularly in summer and autumn. The rubella virus is associated with an increased number of infections during the months of April and May. Generally speaking – and as shown by a study published in The Lancet Infectious Diseases  in 2004 following the SARS epidemic in China – seasonality can be observed with most well-established respiratory viruses, appearing in the population in a cyclical manner. Given the lack of necessary data, this trend is a little less clear when it comes to emergent viruses such as SARS-CoV-2.

The seasonality of the coronaviruses

Research published on the other human coronaviruses nevertheless makes it possible to pinpoint useful avenues for understanding how the spread of SARS-CoV-2 could evolve during the summer. A study published at the beginning of April in The Journal of Infectious Diseases looked at four of the seven types of coronavirus that are known to infect humans and which are responsible for mild respiratory diseases. The authors identified 993 infections with these viruses in the USA between 2010 and 2018 – infections which had all been observed between December and May, with a peak in January and February.  This research echoes a study published in 2018 that looked at MERS-CoV infections in the Middle East between 2012 and 2017, showing that a certain seasonality of the virus can again be observed, with a peak between April and June.

It is therefore possible to imagine that the SARS-CoV-2 epidemic will also progress in a differentiated manner according to the seasons. A study published in Science is also suggestive of this. Based on data available on the seasonality of coronaviruses OC43 and HKU1, which are associated with common colds and in some cases pneumonia, the researchers modelled the possible spread of SARS-CoV-2.

The results suggest that this virus is capable of causing epidemics at any time of the year in the absence of social distancing measures or lasting immunity, but that the autumn and winter seasons are more conducive to a major resurgence in the number of cases.

Environmental and behavioral factors

What are the factors that explain the seasonality of certain viruses? This is a key question if we are to better understand the spread of infectious diseases and predict epidemic peaks over the course of the year. To learn more about the seasonality of SARS-CoV-2, it is necessary to examine various environmental and biological factors influencing the epidemic flows, climate, population behaviors, individual immune system fluctuations over time, and look at how these factors combine to promote transmission of the virus.

Several studies on the seasonality of viruses suggest that the climate and weather conditions could play a role. In temperate environments, a cold, dry winter climate is thought to be linked to the increased transmission of certain viruses.

A recent study on animal models published in PNAS suggests for example that a low level of ambient humidity promotes influenza virus infections. 

Concerning SARS-COV-2, a Chinese study published in Science of the Total Environment at the end of April, based on data collected in 166 countries suggests that temperature and humidity are factors to consider in the spread of the epidemic. A 1°C increase in temperature was associated with a 1.5% to 4.6% reduction in the number of daily new cases, and a 0.44% to 1.95% reduction in daily new deaths. Furthermore, a 1% increase in humidity was associated with a 0.51% to 1.19% reduction in the number of daily new cases.

According to the researchers, it must be noted that relying on the weather to improve the health situation is untenable: taking steps to prevent and control the sources of infection remains essential.

These findings still need to be confirmed by other research, especially given that other studies (currently published as preprints) state that the evidence that weather variations could stop the epidemic remains limited. It must also be borne in mind that the virus has spread everywhere, particularly in hot and humid countries. In a certain number of these countries, the demographic and environmental factors that could affect the spread of the virus remain difficult to clarify and control – not helped by the still often incomplete and poor-quality epidemiological data produced.

Added to these environmental factors are behavioral factors. The epidemic peaks observed in autumn and winter in the temperate climates can also be linked to the fact that people tend to spend more time in groups in confined environments during this period, thereby promoting contacts and exposure to viruses.

Some studies have also focused on the role of the immune system and how it varies with the seasons, whether or not it promotes infections. A weakening of the immune system in winter has been reported. A study by the University of Surrey (UK) in collaboration with Columbia University (US) has recently been launched in order to explore immune system changes according to the time of day and the seasons. Its objective is to open up new avenues in understanding the seasonality of viruses – including SARS-CoV-2 – and to identify whether administering vaccines at certain times of the day is more conducive to increased efficacy.

Our knowledge of SARS-CoV-2 is still too piecemeal to express with certainty whether or not it is seasonal, but what we can take away from the various studies is the importance of prevention measures. In the absence of certitude concerning collective immunity and without an effective vaccine, barrier measures, testing, and measures to control the epidemic continue to remain necessary.

Text produced with the support of Cécile Souty, epidemiologist at the Pierre Louis Institute of Epidemiology and Public Health (Inserm/Sorbonne Université) and Laurent Lagrost, Inserm Research Director at the Lipids – Nutrition – Cancer laboratory (Inserm/Université de Bourgogne).

Milestone: Inserm’s commitment to the fight against the Covid-19 pandemic

Intracellular observation of reconstituted human respiratory epithelium MucilAir™ infected with SARS-Cov-2 © Manuel Rosa-Calatrava, Inserm ; Olivier Terrier, CNRS ; Andrés Pizzorno, Signia Therapeutics ; Elisabeth Errazuriz-Cerda  UCBL1 CIQLE. VirPath (Centre International de Recherche en Infectiologie U1111 Inserm – UMR 5308 CNRS – ENS Lyon – UCBL1). Colorized par Noa Rosa C.


1.   React rapidly to accelerate research and tackle the pandemic

First identified in the central Chinese city of Wuhan in December 2019, the novel SARS-CoV-2 coronavirus has rapidly spread across the world, leading to the most serious pandemic in recent history. Inserm, as a leading biomedical research stakeholder in France and internationally, has been mobilized from the very beginning of this global health crisis, thanks to the commitment of its many experts in subjects related to fundamental research, therapeutic research, and modelling. Participating also in the French solidarity effort, the Institute has distributed tens of thousands of masks, gloves, gowns, shoe covers and reagents to medical teams working in the nation’s hospitals.

By May 6, 2020, Inserm had already been involved in 167 scientific publications on COVID-19 (including 19 preprints), reflecting the unfailing energy and proactiveness of its researchers. This research primarily concerns potential therapeutic approaches, the search for a vaccine, epidemiology, the deployment of telemedicine, predicting the spread of the virus in various countries, and its transmission. A large part of the research published has received REACTing consortium seed funding.

A key player in fighting the COVID-19 pandemic, REACTing – which stands for REsearch and ACTion targeting emerging infectious diseases – launched and coordinated by Inserm since 2013 under the egis of Aviesan, has been tasked with preparing and coordinating French research into emerging infectious diseases in order to prevent and fight epidemics.

A number of task forces (New Therapeutic Approaches, COVID-19 Vaccines, Animal Models, Modelling, and Digital) have been created in order to reflect on the major research priorities and evaluate the projects submitted to the consortium by research teams from across France and internationally.

In addition, Inserm is involved in various World Health Organization (WHO) working groups, the Scientific Advisory Board consulted by the French government, and the Analysis, Research and Expertise Committee (CARE) set up by the French Ministry of Solidarity and Health.

Never has Inserm’s mission, Science for Health, been so necessary. Although many questions remain unanswered concerning the evolution of the pandemic, Inserm will continue its efforts to inform public decision-making with research of excellence that combines rigor and ethics.

2.   Treat patients

Within REACTing, the New Therapeutic Approaches Task Force meets weekly to evaluate the many projects submitted to it regarding research into treatment avenues. Experts in the various themes addressed are invited in order to enrich discussions, in addition to members of CARE, the French Health Directorate, MESRI, and the REACTing COVID-19 Scientific Advisory Board.

The antivirals approach: focus on the Discovery trial

Discovery is a European project whose French component has begun thanks to REACTing seed funding paid jointly by MESRI and the Ministry of Solidarity and Health. It is also funded by the Program for Clinical Research in Hospitals (PHRC) and has been incorporated in the WHO international Solidarity trial.

The trial evaluates the efficacy of various antiviral treatments in limiting the viral multiplication observed in certain hospitalized patients whose condition often deteriorates on around day seven of the disease.

It intends to recruit 3,200 European patients with moderate to severe COVID-19, at least 800 of whom in France, admitted to a medical department or directly to intensive care. Over 750 patients have been enrolled in Discovery so far, mainly in France.

  • The treatments

The objective of Discovery is to evaluate the efficacy and safety of various experimental therapeutic strategies which, according to current scientific knowledge, have been identified as potential therapeutic candidates for COVID-19. To recap, it involves testing and comparing the following five strategies:

  • optimal standard of care;
  • optimal standard of care plus remdesivir;
  • optimal standard of care plus lopinavir and ritonavir;
  • optimal standard of care plus lopinavir, ritonavir and interferon beta;
  • optimal standard of care plus hydroxychloroquine.

Therefore, none of the patients enrolled in the trial is left without treatment and none of the patients is receiving placebo.

  • Why an open-label randomized trial?

Discovery is a randomized trial, meaning that the treatment is not chosen by the doctor but assigned randomly. Each arm of the clinical trial is assigned an equal number of patients so that it is balanced, with sufficient data obtained for each treatment tested.

An open-label trial design was chosen in order to save valuable time during this pandemic. It must be remembered that the molecules tested are not all available in the same dosage forms. For a double-blind trial to be possible, it would take a long time to prepare placebos that resemble each of the treatments being tested, therefore delaying the start of the trial.

However, in order to limit bias, although the patients and doctors know which treatment is being administered, the researchers responsible for statistical analysis do not. This controlled, open-label trial design will therefore enable results to be obtained as rapidly as possible whilst respecting rigorous and high-quality methodology.

The immunomodulation approach: focus on Corimuno-19

Some hospitalized patients present a specific profile in which the deterioration in their condition seems to be due to their excessive immune response to the infection rather than to the multiplication of the virus. One avenue currently explored by Inserm researchers is to understand and evaluate the effect on COVID-19 patients of treatments that would modulate this response.

This is the challenge of the Corimuno-19 project, a cohort of open-label, randomized, controlled trials. The overall objective of this large-scale study is to test various treatments (especially immunomodulator treatments) and determine which present the most favorable risk/benefit ratio in adult patients hospitalized for COVID-19 pneumonia – diagnosed either at the moderate to severe stage and requiring no mechanical ventilation, or at the critical stage requiring mechanical ventilation.

The antibodies approach: focus on Coriplasm

Particularly mediatized is Coriplasm – one of the Corimuno-19 clinical trials, and which is sponsored by the Paris hospitals group (AP-HP). With the support of Inserm and REACTing, the French Blood Establishment (EFS) is deploying a process to enable the collection, qualification, preparation and provision to the clinical teams of plasma from convalescent patients. The idea is to evaluate whether their plasma is capable of immediately transferring this immunity to other patients, as had been the case when treating various infectious respiratory diseases such as SARS-CoV-1, MERS-CoV or H1N1 influenza. The objective is to determine whether this strategy reduces the frequency of severe forms of COVID-19 and their associated mortality.

Other therapeutic research initiatives

Other drug repurposing strategies

Therapeutic repurposing consists of finding new therapeutic indications for drugs that are well-known, safe, and already available in the pharmacopeia. Within the context of the COVID-19 pandemic, a number of teams are testing molecules used for other diseases on SARS-CoV-2, in order to evaluate their potential antiviral or immunomodulating effects. The team of Inserm Research Director Manuel Rosa-Calatrava at the International Center for Research in Infectious Diseases (Inserm/Université Claude-Bernard Lyon 1/CNRS/ENS Lyon) is working on the implementation of a strategy to repurpose drugs for new antiviral therapeutic indications. An approach that his group had already validated by repurposing an antihypertensive drug as an inhibitor of the influenza viruses (a phase 2 clinical trial has been ongoing over the past three winters). His team had already repurposed two other commercially available molecules in vitro against MERS-CoV. The researchers are now testing these molecules on cell lines and in their unique ex vivo model of reconstituted human respiratory epithelium infected with SARS-CoV-2.

The Corona accelerated R&D in Europe (CARE) program, funded by the Innovative Medicines Initiative, is led by the Vaccine Research Institute under the supervision of Inserm in partnership with 36 research teams from a number of European countries, China, and the US. It has two key objectives: urgently develop effective molecules for the current COVID outbreak and find treatments that could be useful in controlling future epidemics, should other coronaviruses emerge. The scientists have developed an ambitious research and development program in order to facilitate the identification of candidate drugs for therapeutic repurposing. The project will also include a component focused on developing new molecules. All relevant molecules will be tested in vitro and on laboratory animal models, following which the most promising candidates will undergo large-scale clinical trials.

For more information: covid-projects-boosts-funding-pot-eur-72-million

MacCOV: a project to combat acute respiratory distress

In Villejuif, the team of Jean-Luc Perfettini (Inserm/Université Paris-Saclay/Gustave Roussy) is working on a new COVID-19 therapeutic strategy that involves reprogramming certain immune system cells (macrophages) in order to reduce their ability to promote inflammation.

Data available on the disease indicate that one of its severe complications, acute respiratory syndrome, is due to lung tissue lesions caused by a massive influx of inflammatory molecules (cytokines), which the specialists are even referring to as a “cytokine storm”. However, given that these pro-inflammatory molecules are essentially produced by the macrophages, the researchers hope that reprogramming these immune cells will prevent cytokine storm.

Corona-Pep-Stop: a project to develop fusion inhibitory peptides

The aim of the Corona-Pep-Stop project, led by Inserm Research Director Branka Horvat at the International Center for Research in Infectious Diseases (Inserm/Université Claude Bernard Lyon 1/CNRS/ENS Lyon), is to transpose findings from the team’s previous research into the measles and Nipah viruses. Their strategy is to block the entry of the viruses into cells using specific peptides of the viral fusion protein.

This protein enables viruses with a membrane, such as SARS-CoV-2, to fuse their membrane with that of the host cells in order to transfer their genome. The researchers hope to identify a new class of antiretroviral drugs (fusion inhibitory peptides) that target this protein and are effective against several coronaviruses. These new molecules could then be used for the prevention and treatment of SARS-CoV-2, and also against other coronaviruses that may emerge in the future.

CoV2-E-TARGET: venom vs. virus

Led notably by Inserm researcher Michel De Waard at the Thorax Institute (Inserm/Université de Nantes/CNRS), the aim of this project is to identify a treatment that targets a protein of the viral envelope – protein E – which has an ion channel function (in that it enables the selective passage of certain ions through the cell membrane and facilitates the entry of the virus into the cells). The laboratory has at its disposal a collection of different types of venom that includes over 40,000 peptides, a large number of which target the ion channels in very specific ways. The idea is to identify potential peptides derived from animal venom that could block the passage of the ions and prevent the replication of the virus in the host cells.

3.   Find an effective vaccine

Although phase I clinical trials to test candidate vaccines have now been launched in the USA and China, many questions persist concerning immune response to the virus and a potential vaccine.

Throughout the world, over one hundred teams are working on the development of vaccines, including a number of French groups. Of the thirty or so teams working on the candidate vaccines in France, twelve are from Inserm. Although their development work remains in the early stages for the most part, it is still furthering knowledge of the virus and vaccine research as a whole.

In order to provide support and identify research priorities, REACTing has set up a dedicated COVID-19 Vaccines Task Force. Its role is to collect information on the progress of the various candidate vaccines, catalogue the research of the French teams, and discuss the most relevant measures to deploy in the national context.

This Task Force has defined criteria for assigning priority to the French teams’ COVID-19 candidate vaccine development initiatives, which include the speed of the vaccine production cycle, minimization of the risk of disease exacerbation caused by immune mechanisms, the potential for producing the vaccine on a very large scale, and the availability of preclinical test results suggestive of the induction of disease protection.

The search for a new vaccine

REACTing COVID-19 Vaccines Task Force member Frédéric Tangy (Institut Pasteur) leads a team that is working on a COVID-19 candidate vaccine at quite an advanced stage of development. It uses as a platform the attenuated measles vaccine that had already been used in the development of certain candidate vaccines, notably against Chikungunya. A phase I clinical trial is scheduled for September 2020.

The Vaccine Research Institute also has a role to play in vaccines research within the context of the COVID-19 pandemic. Its researchers are mobilized for the accelerated development of an SARS-CoV-2 coronavirus vaccine based on its expertise and technology developed for other infectious diseases, such as HIV. The novel approach of this Institute is based on the targeting of dendritic cells, key cells in immune response.

Thanks to the involvement of this institute in French Covid-19 – the national cohort of patients infected with SARS-CoV-2, coordinated by REACTing in line with 56 hospitals in France, the objective of the research is to characterize patient immune response. Understanding this aspect of the infection is an essential prerequisite for the development of any vaccine.

The BCG vaccine to protect medical staff?

Several studies suggest that some live vaccines, such as BCG or the oral polio vaccine, have non-specific beneficial effects on certain infections. Thereforeit is possible that BCG could reduce the intensity of SARS-CoV-2 infection by stimulating the memory of innate immunity, the first line of immunity in the face of infection, and thereby induce “trained innate immunity”. Furthermore, what few contraindications there are to the use of this vaccine are well known, and its very low cost is an advantage.

An Inserm team is preparing the implementation of a French double-blind trial to test the non-specific protective effects of the BCG vaccine, the idea being to evaluate whether it could offer medical staff a certain level of protection against COVID-19. Collaboration between this team and Spanish scientists who are also conducting research in the area would enable large-scale comparison of the benefits of BCG versus a placebo common to both countries. Should such a trial go ahead, the participants would need to be followed up for several months in order to obtain reliable data.

4.   Understand the disease better

French Covid-19

French Covid-19 is an observational french cohort launched at the end of January that has recruited over 2,000 patients hospitalized in France. It is coordinated by Yazdan Yazdanpanah, infectious diseases specialist at Bichat Hospital and Director of the Inserm Immunology, Inflammation, Infectiology and Microbiology Theme-Based Institute. Its objectives are to describe the clinical characteristics of the forms of COVID-19 that require hospitalization and to identify the factors predictive of severity (ICU admission or death). This involves studying the various clinical, biological, virologic, and imaging data available in the records of the patients who will be followed up for six months after their discharge from hospital. The findings of this research will be crucial in better equipping doctors to treat the disease.

Another study, CritiSARS2, aims to identify viral markers, inflammatory markers, and/or markers that reveal immunization in the critical forms of COVID-19. It is led by Karine Faure, head of the Department of Infectious and Tropical Diseases at Lille Teaching Hospital and researcher at the Center of Infection and Immunity of Lille (Inserm/CNRS/Université de Lille/Institut Pasteur de Lille).

Studying the risk of reinfection

Simon Fillatreau (unit 1151, Inserm/Institut Necker-Enfants malades) and his colleagues are working on a key question: are we protected from a second infection after having recovered from the first? If so, how long does this protection last and is it affected by age or any other individual parameters? A number of components carry the memory of the immune system and are likely to protect us from SARS-CoV-2 reinfection. The team is particularly interested in the memory B-cells and T Follicular Helper cells.

Following reinfection after having previously been exposed to a pathogen, these lymphocytes are responsible for an extremely rapid and substantial increase in the levels of protective antibodies. In the case of hepatitis B, for example, it is the memory cells that protect the individual in the absence of persistent antibody production.

The project, entitled MEMO-CoV2, therefore looks at the immune memory carried by the B-cells and T Follicular Helper cells specific to SARS-CoV-2, in order to estimate their persistence, longevity, and origin of their formation during the response to the initial infection.

The search for biomarkers

Harmonicov, a project led by an Inserm team in Rennes, is based on a cohort of one hundred adults under the age of 65. Based on this cohort, the researchers will analyze the immune responses of people with COVID-19, comparing those of patients who have recovered with those of critical patients requiring assisted ventilation. The objective is to identify markers of the favorable or unfavorable evolution of the disease, and also to study the memory cells that produce SARS-CoV-2 antibodies.

5.   Model and monitor the epidemic

The Mathematical Modelling of Infectious Risks Task Force was set up very quickly and its modelling concerns both the general population and more specific populations, such as medical staff.

Modelling the spread of the epidemic

Since January 2020, work by the team of Inserm researcher Vittoria Colizza at the Pierre Louis Institute of Epidemiology and Public Health (Inserm/Sorbonne Université) has made it possible to model the spread of the epidemic from China to Europe and Africa, with the objective being to better orient prevention policies and improve surveillance of the epidemic.

Their first publication, in the journal Eurosurveillance, concerned the risk of importing the virus into Europe. This was based on the scenario of all Chinese provinces declaring more than ten cases at the time as well as on data from January 2019 on air travel flows from these regions to Europe, produced by the OAG (a global leader in the collection of flight data). Another study published by the group mid-February in The Lancet evaluated the risk of importing the virus into Africa, with Egypt, Algeria and South Africa presented as the countries most at risk.

Another major research avenue explored by Colizza and her team in collaboration with telecommunications group Orange is the impact of lockdown on population mobility, by studying aggregated and anonymized cell phone network data. The researchers are particularly interested in spontaneous changes in mobility occurring before and during lockdown, and their impact on the evolution of the pandemic. The collected data will also be integrated into models of pandemic spread developed by the team. This is to improve predictions of how the virus will spread and identify regions at risk of becoming clusters and having their healthcare systems overwhelmed. In a report published at the start of May, the team shows that mobility had decreased by 65% across the national territory during lockdown.

The team is also modelling potential scenarios on which to base decisions concerning the lifting of lockdown. In a report published mid-April on the EPIcx laboratory website, the researchers stress the need to support all lockdown-lifting strategies with measures involving mass testing, the identification of those having been in contact with confirmed cases, and the isolation of detected cases. A report on the role of the school reopenings was also published at the start of May, showing that reopening the elementary and preschools from May 11, whether gradual or not, would probably not lead to saturation of the ICUs. It is considered that these structures would reach 65% capacity at the most.

Surveillance of the epidemic intensified with Covidnet

Established in 2012 by the Sentinelles network (Inserm/Sorbonne Université) and the French Public Health Agency, the study is a comprehensive information resource for epidemiologists wishing to monitor the evolution of seasonal influenza. Each year, the network collects epidemiological data on influenza directly from the population, online and anonymously. began its ninth season at the end of November 2019 and has over 7,200 participants so far, who each week declare the symptoms that they had or had not experienced since they last logged on. For better monitoring of the current epidemic, the study has become Based on questionnaires sent to the volunteers of the cohort, it is currently the only health surveillance system in France that makes it possible to study the symptoms presented by patients having not sought assistance from the healthcare system.

The NoCov project led by Inserm researcher Chiara Poletto at the Pierre Louis Institute of Epidemiology and Public Health (Inserm/Sorbonne Université) also uses data from the Sentinelles network to model the spread of the epidemic in the short term and identify the main factors of virus transmission (notably by looking at disease transmissibility and severity according to age).

Risk of hospital transmission

The research also includes studies that aim to model the risk of SARS-CoV-2 transmission in the hospital setting (nosocomial risk). One such study is being conducted by Didier Guillemot and Lulla Opatowski, researchers at the Biostatistics, Biomathematics, Pharmacoepidemiology and Infectious Diseases laboratory (Inserm/Institut Pasteur/Université de Versailles Saint-Quentin-en-Yvelines).

6.   Study lockdown and its impacts

The Sapris study and the social challenges of lockdown

A vast survey based on five large, national, general-population cohorts (Constances, Étude familiale E3N-E4N, Elfe / Epipage 2, NutriNet Santé) conducted in close coordination with the leaders of those cohorts, the Sapris project (health, practices, relationships and social inequalities) looks at the epidemiological and social challenges presented by the exceptional prevention measures deployed against COVID-19. Coordinated by Nathalie Bajos, Inserm Research Director and sociologist-demographer, and Fabrice Carrat, Professor of Public Health at Sorbonne Université in collaboration with the French Public Health Agency, the study involves a multidisciplinary group of researchers from Inserm, France’s National Institute for Demographic Studies (Ined), National Center for Scientific Research (CNRS), Université Paris-Saclay, Sorbonne Université, Sorbonne Paris Nord and Université Paris Dauphine-PSL, National Health Insurance Fund (CNAM), Institut Gustave Roussy and the National Research Institute for Agriculture, Food and Environment (INRAe), covering fields as varied as epidemiology, sociology, demographics and economics.

By means of a questionnaire sent out at the start of April (completed by 115,000 participants), and repeated several times during and after lockdown, participants are asked about the specific challenges of the epidemic and the lockdown measures. The main themes studied are the incidence of COVID-19 symptoms and other health problems, the use of treatment for other health conditions or failure to seek treatment, the perception of risk to oneself and in general, the effects of the prevention measures on daily life, social relationships, work,and the education of children. In addition, in collaboration with the Emerging Viruses Unit (Inserm/IRD) led by virologist Xavier de Lamballerie, the participants are offered serological tests that provide indications on prevalence at national level and enable study of the factors associated with SARS-CoV-2 seropositivity. These tests will be repeated in order to study the persistence of the immune response against SARS-CoV-2 and to establish correlates of protection.

In addition, the EpiCOV (Epidemiology and living conditions) project is a large-scale public health study whose objective is to provide global and representative mapping, at national and departmental level, of the immune status of the population and of its dynamic. It also aims to study living conditions in this particular context of restricted movement, taking into account the diversity of socioeconomic situations.

Under the scientific responsibility of Inserm researchers Josiane Warszawski and Nathalie Bajos, sociologist-demographer, EpiCOV is conducted in collaboration with France’s Directorate for Research, Studies, Assessment, and Statistics (DREES), National Institute of Statistics and Economic Studies (INSEE) and Public Health Agency. A sample of 200,000 people aged 15 years or over, representative of the general population, has been created by INSEE in order to provide data on a territorial level and study socioeconomic conditions – notably for those in a situation of economic precariousness. The participants are required to complete a questionnaire similar to that used in Sapris and perform a serological home test. With this project, which began in early May, it will be possible to obtain detailed information on the spatial, temporal, sociodemographic and familial aspects of the epidemic and the lockdown measures. The survey will be repeated several times in order to study the evolution and circulation of the virus and its impact on living conditions. The survey fully involves the local authorities in the initiative and the future results.

Sapris and EpiCOV both require participants to collect a drop of blood by pricking the end of their finger and pressing it four times onto the absorbent paper provided before mailing it back to the researchers in a prepaid envelope.

Evaluating the contacts of French people during lockdown

A population survey to collect and analyze data concerning the contacts between French people during lockdown has been launched by Institut Pasteur in collaboration with Inserm and several universities. Called SocialCov, this study is based on online questionnaires concerning people’s contacts before and during lockdown, with the aim of gaining deeper insight into the impact of lockdown on our social and professional lives. More specifically, the survey will make it possible to identify the number of contacts we have each day, their frequency, and distribute these results by age group.

Supporting mental health during lockdown

The measures of social distancing, and particularly the lockdown of the French population, will doubtlessly have an impact on mental health and wellbeing. Several studies have already examined this issue with, for example, a meta-analysis published in The Lancet suggesting that lockdown is associated with a harmful psychological impact, characterized by mood disorders, confusion, and in the most extreme cases by the manifestation of post-traumatic stress disorder.

For a deeper insight into these effects, Anne Giersch, Inserm researcher and head of the Cognitive Neuropsychology and Pathophysiology of Schizophrenia laboratory in Strasbourg, is conducting a study in healthy volunteers. Its objective is to explore the positive and negative effects of lockdown, particularly on mental health. The participants are asked to answer anonymous questionnaires on their general health, concern about infection risk, conditions of lockdown, social network before and during lockdown, and also on their mood, emotions and stress levels.

In order to help the general population deal with anxiety related to the pandemic, Inserm researchers have developed a COVID-19 extension of the StopBlues initiative. This initiative, based on a free website and application, was developed in 2018 by the Eceve-Inserm research team led by Karine Chevreul. Its users are assisted in order to identify the signs of their malaise, look for the possible causes and find concrete solutions for confronting it. Within the context of the pandemic, the COVID-19 extension of StopBlues includes the publication of short videos describing the emotions that can be felt in the face of fear of the disease, lockdown difficulties, social isolation and family conflicts.

Tempo Covid 19: impacts on mental health and addictive behaviors

Maria Melchior, Inserm researcher at the Pierre Louis Institute of Epidemiology and Public Health (Inserm/Sorbonne Université), and her colleagues have launched the Tempo Covid 19 project. Every week since March 24, the participants of a French cohort (Tempo) were asked questions about their health and psychological difficulties, social isolation, tobacco, alcohol and cannabis consumption, professional, financial and familial situations, and activities during the lockdown period. The aim is to evaluate the impact of the epidemic and lockdown on mental health and addictive behaviors, according to social situation. Between 400 and 500 people answered the 6 questionnaires sent to them. The researchers will survey the same participants when lockdown is lifted in order to have the most comprehensive follow-up possible.

Melchior is also working in partnership with the French Public Health Agency on Echo, a survey to evaluate knowledge of the virus and protective measures (barrier measures, lockdown) in people living in situations of exclusion and accommodated in medical-social association structures, the majority of whom are migrants. The researchers would like to survey 300 people by the end of May.

Epidemic: the emotional impacts

Coordinated by Michelle Kelly-Irving from the Epidemiology and Public Health Analysis: Risks, Chronic Diseases and Disability laboratory (Inserm/Université Toulouse III Paul-Sabatier), the Epidemic survey looks at the social and psychosocial factors of the epidemic and lockdown. It also aims to measure the psychological impact and the emotional, social and behavioral repercussions of the epidemic in order to prevent their consequences and develop appropriate support tools.

Lockdown, sleep, and dreams

The team of Perrine Ruby at the Lyon Neuroscience Research Center (Inserm/CNRS/Université Lyon 1/Université Jean Monnet Saint-Étienne) wishes to evaluate the impact of lockdown on our lifestyles, sleep, and dreams. The aim is to understand the impact on dream content and frequency during this particular period. The questionnaire is still accessible for all who wish to participate.

COVID Ethics

Led by Léo Coutellec from the Research in Ethics and Epistemology team at the Center for Research in Epidemiology and Population Health (Inserm/Université Paris-Saclay), this project involves analytical and critical commitment by the researchers to the COVID-19 epidemic in order to better understand and reinforce our framework of analysis of the ethical challenges in the anticipation and management of pandemic situations. This study will be conducted over 18 months and several seminars have been scheduled.

7.   Test the population and protect and support medical staff

Inserm provides use of its laboratories

Inserm is participating in the population testing effort. A Decree and an Order published on April 5 authorize French prefects to requisition public research laboratories for COVID-19 testing using RT-PCR – a technique based on genetic material. For the laboratories under their supervision, the CNRS and Inserm have prepared for this by making inventories of the equipment available and the number of such tests that could be performed each day under the conditions set by the government.

Inserm launches a project to recycle masks

In close collaboration with Tours Regional University Hospital, Inserm Research Directors Nathalie Heuzé-Vourc’h and Mustapha Si-Tahar are leading a proof-of-concept study on an effective decontamination process for surgical and FFP2 masks, to enable their reuse. In the current context in which masks can be in short supply, various decontamination processes are being compared. The team has already shown that when 70°C moist heat is applied for a period of one hour, there is no deterioration in the structure of the masks. The decontamination appears to be effective, destroying several viruses and bacteria tested in the proof-of-concept study. Also, the properties of the masks are similar to the untreated masks. These findings must now be consolidated by testing the process on masks contaminated with SARS-CoV-2.

A project to develop an antiviral coating for people and surfaces

Inserm teams from the Biomaterials and Bioengineering unit (Inserm/Université de Strasbourg) and the Institute for Research on Viral and Hepatic Diseases (Inserm/Université de Strasbourg) have joined forces to work on antiviral coatings. This project involves developing an antiviral protection system that could be applied to various surfaces of medical devices and to people notably in the hospital environment – and which would be capable of destroying SARS-CoV-2 and limiting the transmission of the epidemic. The researchers intend to screen a number of molecules for their capacity to inhibit the virus, selecting those that are the most effective and with the most beneficial antiviral properties. The coatings will then be developed based on these molecules and their efficacy will be tested.

Aphro-Cov: strengthen the diagnosis and management of COVID-19 patients in five Sub-Saharan African countries

As part of the support given by France in response to the coronavirus crisis, Rémy Rioux, Chief Executive of the French Development Agency (AFD) and Gilles Bloch, Chairman and Chief Executive Officer of Inserm announced in March the launch of a joint initiative to improve the health surveillance and management of suspected cases of COVID-19 in five African countries (Burkina Faso, Gabon, Ivory Coast, Mali, Senegal). Called Aphro-Cov, this program steered by REACTing is focused on the laboratories, early warning system, clinical departments, and – by means of raised awareness and reinforced communication – the population as a whole.

Because research is needed more than ever to protect the health of everyone and to address the challenges posed by this new pandemic, Inserm has set up a platform for donations and is calling on public generosity. The funds collected will be used to sustain and complete these different research projects.

To make a donation and support the work of COVID-19 researchers:


Inserm in the fight against fake news

Fighting false information and publishing clear and high-quality scientific information are key concerns for Inserm. This is particularly the case with the COVID-19 pandemic, given the various rumors and scientifically unfounded information circulating on social media and other platforms. To counteract this and give the public the most accurate information, Inserm has, since January 2020:

  • Posted an episode on its Canal détox channel discussing the false information most often encountered.
  • Each week, the REACTing consortium prepares a thorough review of the scientific literature concerning SARS-CoV-2 and COVID-19. The group provides the public with a summary of high-quality scientific publications for those wishing to follow the scientific research more closely.

Blood Stem Cell Immune Memory: A New Research Avenue in COVID-19

Immune cells seen by fluorescence microscopy. Blood immune cells store information from past infections and then produce more immune cells like the macrophages captured in this image.© Sieweke lab/CIML.

Blood stem cells have a surprising ability. In addition to ensuring the continuous renewal of blood cells, they keep track of past infections so that faster and more effective immune responses can be triggered in the future. This is according to a new study co-led by Inserm researcher Sandrine Sarrazin and CNRS researcher Michael Sieweke at the Center of Immunology Marseille-Luminy (CNRS/Inserm/Aix-Marseille Université, France) and the Center for Regenerative Therapies Dresden (Germany). This discovery could have a significant impact on future vaccination strategies, particularly those being explored for COVID-19, and also further research into new treatments that modulate the immune system. These findings have been published in Cell Stem Cell.

It has long been known that the adaptive immune system has a memory. Following exposure to an infectious pathogen, lymphocytes in the blood become specific to it, with some of them remaining in the body long-term. The principles of vaccination are based on the knowledge of these immune mechanisms.

More recent studies suggest that the innate immune system, which enables immediate defense of the body in response to an infection, also has a form of memory. For example, researchers have shown that the innate immune system continues to be more efficient in the event of reinfection despite the very short lifespan of the immune cells, such as monocytes or granulocytes. They went on to suspect that this innate immune system memory is in fact inscribed in the blood stem cells, which have a very long lifespan and are at the origin of various mature immune cells.

To verify this hypothesis, scientists at the Center of Immunology Marseille-Luminy (CNRS/Inserm/Aix-Marseille Université) and the Center for Regenerative Therapies Dresden (Germany) carried out research whose findings have been

published in Cell Stem Cell. The researchers began by exposing mice to a molecule found on the surface of the E. coli bacterium (lipopolysaccharide or LPS), a pathogen which is commonly used in laboratories to mimic infections.

They then transferred blood stem cells taken from these animals to non-infected mice whose immune systems had previously been destroyed. The aim was to fully reconstitute their immune systems based on these stem cells.

The researchers then infected mice from this group with a live bacterium of the species P. aeruginosa, observing a mortality rate of just 25%. However, in the control mice whose stem cells had never been exposed to a pathogen, this rate was 75%. 

“This research strongly demonstrates that the blood stem cells have a memory function that we did not know existed. Initial exposure to a pathogen makes them better equipped to face subsequent infections”, explains Sandrine Sarrazin.

This mechanism is not specific to pathogens because, in another experiment, an initial exposure of the blood stem cells to a viral antigen protected the mice from secondary exposure to P. aeruginosa. The scientists made the surprising discovery that the protection afforded by this immune system memory extends beyond the infectious agent used for the first infection.

The researchers then looked at how this memory is coded. When studying the genome of the blood stem cells of the infected mice, they observed lasting modifications in its spatial organization. Changes that are likely to modify the expression of some genes implicated in the innate immune response. “At the time of first contact with the pathogen, genes required for the immune response are in fact put forward long-term so as to rapidly activate the immune system in the event of a second infection”, explains Bérengère de Laval, lead author of the study. Finally, the team looked for molecules implicated in this change of genome structure and discovered that the protein C/EBP beta played a major role.

Research relevant in fighting COVID-19?

These results are particularly relevant during this period of SARS-Cov-2 coronavirus pandemic.

Recent findings suggest that the BCG vaccine – it too known for inducing innate immune memory – also acts at blood stem cell level and offers a certain degree of protection from respiratory infections. Studies are ongoing in order to test its utility against COVID-19.

The team’s discoveries could elucidate the molecular mechanisms at play in this protection and open up new avenues for vaccines – particularly against COVID-19.

“Our discoveries represent a major contribution to understanding immune system memory and blood stem cell functions. They also point towards new strategies for stimulating or limiting immune response in various disease states and could make it possible to refine current vaccination strategies for better protection from various pathogens, including SARS-CoV-2″, hopes Michael Sieweke.