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Menstrual Toxic Shock Syndrome: Encourage Proper Tampon Use to Limit Risks

Inserm’s new educational video on staphylococcal toxic shock. © Camille Henry/Inserm

Staphylococcal toxic shock syndrome is linked to the presence of Staphylococcus aureus bacteria in the vaginal microbiota of some women for whom the misuse of intravaginal protection (tampons, menstrual cups, etc.) could increase the likelihood of developing it. Toxic shock is characterized by multiple symptoms that include digestive disorders, high fever, and skin rashes. In the most severe cases, it can lead to multi-organ failure and death.

Although the incidence of toxic shock remains very rare, researchers from Inserm, CNRS, Hospices Civils de Lyon, Université Claude Bernard Lyon 1 and ENS Lyon within the International Center for Research in Infectious Diseases and the National Reference Centre for Staphylococci have identified the risk factors that may in some cases favor it. In a study published in March 2020 in the journal EClinical Medicine, Prof. Gérard Lina’s team suggests simple measures to put in place for better tampon use during menstruation.

 

All the advice can be found in Inserm’s new educational video aimed at raising awareness and reassuring tampon users. 

Do not hesitate to share this prevention tool on your platforms and distribute it widely.

COVID-19: Vaccine Research at Inserm

The mobilization of Inserm researchers has led to major advances in SARS-CoV-2 knowledge and vaccine research.

© Inserm/Depardieu, Michel

Developing an effective and safe vaccine is one of the priority objectives in the fight to contain the COVID-19 pandemic. Since the complete sequencing of the SARS-CoV-2 genome in January 2020, research teams in France and internationally have been working tirelessly to better understand the immune response following infection and to test candidate vaccines. At Inserm, a dozen teams are involved in vaccine research projects. In particular, three initiatives have recently been selected by France’s Ministry of Higher Education, Research and Innovation on the advice of the COVID-19 Analysis, Research and Expertise Committee (CARE) and Inserm’s REACTing consortium, in order to receive special support and thus accelerate research.

Currently, more than 200 teams around the world are engaged in research projects to develop a vaccine against COVID-19. These include some thirty French groups that are members of the AVIESAN alliance or the biotech/industry ecosystem. Researchers from Inserm are also not to be outdone, since a dozen of these projects involve its units.

While the degree of progress of this research varies, some of these teams are currently in the phase of identifying the antigenic sequences of the virus that induce the specific immune response against SARS-CoV-2 and minimize the possible production of facilitator antibodies (a type of antibody that facilitates the entry of the virus into cells). In addition, some of the proposed vaccine platforms have been used previously for other candidate vaccines, including against HIV, influenza and toxoplasma, or for oncology vaccines.

The various ongoing projects can be divided into three main categories. The first is that of subunit vaccines, which do not contain live components but rather antigenic fragments of the pathogen. The second is a group of live attenuated candidate vaccines, all of which are prophylactic. The third is vaccines based on DNA or RNA coding for SARS-CoV-2 antigens.

Innovative candidate vaccines

Within this dynamic ecosystem, three projects involving Inserm units have been identified as priorities by the Ministry of Higher Education, Research and Innovation.

The first is driven by the Vaccine Research Institute (VRI), under the supervision of Inserm. The team led by Pr. Yves Lévy is involved in French COVID-19, the national cohort of patients infected with SARS-CoV-2, coordinated by Inserm’s REACTing network, in conjunction with 56 hospitals in France. Initially, using data from these patients, the researchers’ objective was to characterize the immune response in COVID-19 positive patients. Indeed, this data is essential and a prerequisite for the development of any vaccine. Based on this work, but also on their expertise in vaccine research, they are now developing a candidate vaccine in which the SARS-CoV-2 antigens would be presented by monoclonal antibodies to certain key cells of the immune system (dendritic cells). VRI has already developed several candidate vaccines based on this strategy, including against HIV (for which clinical trials will start in 2020).

The second vaccine research project, carried out at the Lille Center for Infection and Immunity by Inserm researcher Camille Locht and his team, is based on the repurposing of vectors with known activity, by integrating SARS-CoV-2 antigenic sequences. In this particular case, the chosen vector is a whooping cough vaccine. The objective is to develop a safe candidate vaccine, whose action on the body is well documented and very specific to the novel coronavirus because it incorporates carefully selected antigens.

Led by Inserm researcher Patrice Marche at the Institute for Advanced Biosciences and researcher Fabrice Navarro, head of CEA-Leti’s Microfluidic Systems and Bioengineering Laboratory, the third project also proposes an original vaccine approach against SARS- CoV- 2. It is based on an innovative delivery system involving lipid nanoparticles developed by the researchers. These highly stable and well-tolerated nanoparticles were originally created to encapsulate and transport drugs to target cells. In the fight against SARS- CoV-2, the researchers hope to encapsulate antigens of the virus to elicit a strong immune response.

Having already used this technique in HIV vaccine research, the team should quickly be able to develop this new candidate vaccine on a large scale, which represents a major advantage in making research faster and more efficient.

Developing a safe and effective vaccine against COVID-19 is a long process. Nevertheless, the mobilization of the scientific community, and in particular Inserm researchers, is enabling major advances to be made in terms of understanding the virus and the immune response to it, and in terms of setting up numerous trials to test a wide variety of vaccine strategies in record time.

Cardiac arrest outside the hospital during the peak of the COVID-19 epidemic: studies highlight pulmonary embolism as the main determinant

Cardiac arrest outside the hospital during the peak of the Covid-19 pandemic could be partly due to massive pulmonary embolism© Adobe Stock

French investigators from the Paris Medico-Legal Institute, the radiology department of the Sainte-Anne hospital / GHU Paris, the anesthesia-resuscitation department of the AP-HP hospitals Saint-Louis and Lariboisière, the University of Paris, Inserm and CNRS have hypothesized that cardiac arrests outside the hospital during the peak of the COVID-19 pandemic could be partly due to massive pulmonary embolism. The details of this work were published on May 28, 2020 in the European Journal of Heart Failure .

The Forensic Institute of Paris and the radiology department of Sainte-Anne hospital use whole-body scanners for examinations requested by the justice authorities. These scanners were compared between the two-week period corresponding to the epidemic peak (March 23 to April 7, 2020) and all of 2019. The elements sought on the scanner were the presence of signs of pulmonary infection suggestive of COVID-19, phlebitis of the lower limbs and proximal pulmonary embolism, responsible for cardiac arrest.

This study shows that requests for forensic autopsies for unexplained sudden death were 14 times more frequent during the epidemic peak than in 2019.

The vast majority of unexplained sudden deaths during the epidemic peak had lung lesions suspected of Covid-19 infection.

The age of the deceased patients ranged from 27 to 99 years. Most people died at home, some had fever and / or cough, and the majority suddenly lost contact with family or emergency services 30 minutes to a few hours before the onset of cardiac arrest.

CT analysis shows a 3 times higher frequency of proximal pulmonary embolism and phlebitis during the epidemic peak compared to all of 2019.

These results suggest that a significant proportion of the victims of sudden death during the epidemic peak were probably linked to proximal pulmonary embolism which must be quickly referred to cardiogenic shock treatment centers. This study also confirms the vital role of intensive prevention of thrombosis in patients with COVID-19 infection.

Inflammatory Bowel Disease: Immune Cells Spearheading the Cure

This microscopic image of a section of mouse intestine shows significant lesions, inflammatory signs and dysfunctional healing of the intestinal mucosa. © Sonnenberg Lab

Inflammations of the intestine affect many patients, often with reduced therapeutic prospects. The role of iron in these inflammatory processes is increasingly well documented, opening up new avenues of treatment. A collaborative study between the team led by Inserm research director Carole Peyssonnaux at Institut Cochin (Inserm/CNRS/Université de Paris) and Greg Sonnenberg’s team in New York (Weill Cornell Medicine) shows that the hormone that regulates iron levels in the body is produced by immune cells during inflammation of the intestine, and that it helps repair damage to the intestinal mucosa. This research has been published in Science.

Infections, inflammatory bowel disease (IBD) such as Crohn’s disease, and colorectal cancer are associated with inflammation of the intestine. In patients, the intestinal mucosa may then be damaged, with bleeding and impaired distribution of iron in the body often being observed.

For several years, Inserm research director Carole Peyssonnaux and her team at Institut Cochin (Inserm/CNRS/Université de Paris) have been interested in the role of hepcidin in disease settings. This hormone regulates iron metabolism in the body and is mainly produced by the liver. However, the researchers had already shown that in the case of certain pathologies, hepcidin is also secreted in other tissues.

Their new study, carried out in collaboration with Gregory F. Sonnenberg’s team from Cornell University in the United States and published in April 2020 in the journal Science, shows that in a context of intestinal inflammation, hepcidin is also expressed by specific immune cells, the dendritic cells of the intestine.

New therapeutic avenues

The scientists first studied the intestinal healing process in several groups of mice, all with inflammation of the intestine. For one of these groups of mice, the gene coding for hepcidin was not expressed. Compared to the other groups of mice in which this gene functioned normally, this resulted in greater continuous weight loss, but also in less effective healing of the intestinal mucosa.

The researchers have confirmed that hepcidin plays an important role in the healing of intestinal lesions. However, they still wondered whether it was the hepcidin normally secreted by the liver that had this beneficial effect or whether, in this disease setting, this iron-regulating hormone was produced in other organs.

Using mouse models in which the gene coding for hepcidin was only deficient in the liver, the researchers were able to show, surprisingly, that the healing process was independent of hepatic hepcidin production. Following intestinal injury and in a context of inflammation, the local dendritic cells of the intestine were the dominant source of production of this hormone.

The research also emphasizes that hepcidin interacts with a key iron transporter called ferroportin, which is present on other immune cells in the intestine (macrophages), thereby promoting iron sequestration and preventing the proliferation of iron-dependent bacteria in intestinal lesions. This process helps to limit the severity of the inflammation.

To determine whether this phenomenon also occurs in humans, the researchers looked at samples taken from pediatric IBD patients. They confirmed that the dendritic cells in the human intestine also produce hepcidin in response to injury. This pathway may therefore be clinically important for people with IBD. “Our study suggests that hepcidin may have a protective role because if the gene that codes for this hormone is deleted, the severity of the disease is greater. The use of hepcidin mimetic treatments could therefore have a therapeutic role in promoting iron sequestration, reducing its availability to bacteria that proliferate in the intestine and promoting the healing of lesions,” concludes Peyssonnaux.

Covid-19: Publication of a prospective observational study in the journal BMJ in children with hyper-inflammatory syndrome related to Kawasaki disease

©Piron Guillaume on Unsplash

The team of the Department of General Pediatrics and Infectious Diseases of the Necker-Enfants Malades AP-HP Hospital, the Institut Pasteur, Inserm and the University of Paris, conducted a prospective observational study between April 27 and May 15, 2020 to describe the characteristics of children and adolescents hospitalized in a context of Kawasaki disease-like syndrome in a COVID-19 epidemic context, with a systemic hyper-inflammatory expression. The results of this study were published on June 3, 2020  in the journal BMJ.

This work included all children and adolescents hospitalized during the study period with signs of Kawasaki disease. Clinical and biological data, imaging and cardiac ultrasound data, treatments and clinical course were collected. A nasopharyngeal sample for SARS-CoV-2 by RT-PCR and a sample for IgG antibodies against the virus were systematically performed for all patients included.

During the study period, 21 patients were admitted to the general pediatrics and infectious diseases department with signs of Kawasaki disease. Their median age was 7.9 years (range, 3.7-16.6 years), and 12 patients (57%) had a parent or grandparent born in a sub-Saharan African country. Twelve patients (57%) developed shock syndrome related to Kawasaki disease and 16 patients (76%) developed myocarditis. Seventeen patients (81%) required intensive care or pediatric resuscitation. All of these children had noisy digestive symptoms at the onset of the disease and all had high inflammatory markers. Nineteen patients (90%) had markers of recent SARS-CoV-2 infection (RT-PCR positive for 8/21, and presence of IgG antibodies for 19/21 patients). All patients received intravenous immunoglobulins and ten (48%) also received corticosteroids. The clinical course was favorable in all cases. Coronary dilations were detected in five (24%) patients during hospitalization.

The abnormally high number of children and adolescents with Kawasaki disease recently observed in the Paris region could be linked to exposure to SARS-CoV-2. The study conducted cannot formally establish a causal link with infection with the SARS-CoV-2 virus despite very strong suspicion.

The characteristics of these patients differ from those observed during classic Kawasaki disease: these patients are older, more often of descent from a sub-Saharan African country, with more frequently digestive manifestations in the foreground, severe forms of myocarditis and hemodynamic instability.

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.

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.

EpiCOV: Population Immune Status Data to Guide Public Decision-Making

© Campaign Creators on Unsplash

Quantifying the proportion of French citizens who have developed SARS-CoV-2 antibodies and documenting the effects of the epidemic on their living conditions appear as key factors in preparing the most appropriate deconfinement and prevention strategies, in enabling the early detection of any resurgence of the epidemic and, over the longer term, in monitoring the efficacy of the measures taken.

Driven by Inserm and the Directorate for Research, Studies, Assessment and Statistics (DREES) of France’s Ministry of Solidarity and Health, in conjunction with their partners (National Institute of Statistics and Economic Studies [INSEE], Public Health Agency, National Center for Scientific Research [CNRS], National Institute for Demographic Studies [INED], Université Paris-Saclay), EpiCOV is a large-scale epidemiological study based on a major statistical survey. It is proposing global and scientifically reliable mapping of population immune status and dynamics across the French territory through the collection of biological samples paired with questionnaires.

The aims of EpiCOV are twofold: to provide precise mapping of the population’s immune status, health, living conditions and the social inequalities relating to these three parameters, and to monitor the dynamics of the epidemic over the short, medium, and long term. The exceptionally rapid deployment of a large-scale epidemic surveillance cohort that is statistically representative at local level will in particular provide data used in modelling the epidemic.

The project will be based on a major national survey of a representative sample selected at random by the National Institute of Statistics and Economic Studies (INSEE) of over 200,000 people aged 15 or over, resident throughout the territory (mainland France, Martinique, Guadeloupe and Reunion Island). They will be required to answer a 20 to 30-minute questionnaire (online or by telephone) with, in parallel, a consenting 100,000 of them mailing a small sample of their blood taken at home in order to determine whether they have come into contact with the virus. The responses will be treated in a confidential manner by the research teams, respecting current regulations (statistical confidentiality, French data protection authority [CNIL] regulations, and GDPR).

Results expected

With this project, it will be possible to elucidate the spatial, temporal, sociodemographic and familial aspects of the epidemic and of the confinement measures. It aims to describe the frequency of COVID-19 symptoms, supply data for models of population immunity evolution, provide estimations of the frequency of exposure to the virus, including the asymptomatic forms of transmission, and evaluate changes in the health, wellbeing and behaviors of people living in France. Intended to be both precise and representative of the entire French population, it includes geographically and sociodemographically defined subgroups. All French departments (including certain overseas departments and regions [DROM]) will be included in the survey.

Schedule

The first wave of data collection will take place from April 30 to May 24, with a second wave to come in June. This operation may be repeated regularly to monitor the dynamic of the epidemic and the evolution of the country’s health and social conditions, across all territories, age groups and major social groups.

Initial findings based on responses to the questionnaires should be available on a national scale at the end of May.

The first results of the biological samples will be provided as early as possible from the end of May, depending on the availability of qualified serological tests currently under development and the capacity of the test platforms.

Local authority participation

The local authorities will be fully involved in this initiative and mobilized to communicate its importance to their citizens, given that the validity of the study depends on their good participation. The local authorities will have access to the results that concern them directly.

A local authorities-researchers liaison committee will be established in order to present the study, discuss the initial findings and their consequences, and disseminate information concerning additional studies initiated on the territories.

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). Colorisé par Noa Rosa C.

 

1.   Accelerating research to tackle the pandemic

After appearing 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. From the very outset of this global health crisis, Inserm has played a leading role in the French and international research spheres, rallying its many experts working on subjects as varied as fundamental research, therapeutic research, and modelling. The Institue also participates in France’s solidarity effort, taking action to distribute tens of thousands of masks, gloves, gowns, shoe covers and reagents to medical teams working in the nation’s hospitals.

By April 13, 2020, Inserm had already participated in 44 scientific publications on COVID-19 (including preprints), reflecting the 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 been funded by the REACTing consortium.

A key player in fighting the COVID-19 pandemic, REACTing – which stands for REsearch and ACTion targeting emerging infectious diseases – was launched and coordinated by Inserm since 2013 under the Aviesan banner. A number of task forces (New Therapeutic Approaches, COVID-19 Vaccines, Animal Models, Modelling, and Digital) have been created in order to identify the main research priorities and evaluate the projects submitted to the consortium by research teams across France and in other countries.

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

Never has Inserm’s mission – Science for Health – been so important as it is right now. Although many questions remain unanswered regarding the evolution of the pandemic, Inserm will continue its efforts to inform public decision-making with research of excellence that combines rigor and ethics. The information contained in this press kit is likely to change as research progresses.

2.     Treating patients

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

The antivirals approach: focus on the Discovery trial

Of all the research projects linked to treatments, it is most certainly the Discovery trial coordinated by Inserm that is generating the most public interest and questions. Discovery is a European project, whose French component has started 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 some hospitalized patients whose immune response is too weak, and whose condition deteriorates often around the seventh day 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.

– 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. As a 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 in these times of 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 make it possible to obtain results as rapidly as possible whilst respecting a 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 does not seem to be due to the multiplication of the virus but to their excessive immune response to the infection. One avenue currently being 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 and 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

Coriplasm – one of the Corimuno-19 clinical trials has received a lot of media attention.  It 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 treatment repurposing initiatives

Therapeutic repurposing is about finding new therapeutic indications for treatments that are well-known, safe and already available. 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 effects. The team of Inserm researcher 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 development and validation of a strategy to repurpose drugs for new antiviral therapeutic indications. Having already repurposed in vitro two molecules available on the market for respiratory viruses, including MERS-CoV, the researchers are now testing them against SARS-CoV-2 on cell lines and on an ex vivo model using reconstituted human respiratory epithelium.

 

3.     Finding an effective vaccine

Although phase I clinical trials to test candidate vaccines have now been launched in the USA and China, many questions remain regarding the immune response to the virus and to 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, their efforts are important to improve our knowledge of the virus and vaccine research as a whole.

In order to support them 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, to catalogue the actions of the French teams, and to discuss the most relevant measures to deploy in the national context.

The group has defined a set of 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 Vaccination Task Force member Frédéric Tangy (Institut Pasteur) heads up 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 under the supervision of Inserm 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 the technology developed for other infectious diseases, such as HIV. The novel approach of the 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 (including Henri-Mondor Hospital in Créteil), the objective of the research conducted there 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. Therefore it 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 inducing “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 is 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 in 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.     Modelling and monitoring the epidemic

The Mathematical Modelling of Infectious Risks Task Force has been set up very quickly. 

Modelling the spread of the epidemic

Since January 2020, work by the team of Inserm researcher Vittoria Colizza has made it possible to model the spread of the epidemic from China to Europe and Africa, the objective being to better orient prevention policies and improve surveillance of the epidemic.

Their first publication, in the journal Eurosurveillance, looked at the risk of importing the virus into Europe. This was based data emerging from all Chinese provinces declaring more than ten cases at that 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 the 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 the lockdown, and their impact on the evolution of the pandemic. The 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 of having their healthcare systems overwhelmed.

The team is also working on the modelling of potential lockdown exit scenarios in order for quarantine to be lifted under the most favorable conditions. In a report published mid-April on the EPIcx laboratory website, the researchers stress the need to support all these strategies with measures involving mass testing, the identification of those having been in contact with confirmed cases, and the isolation of detected cases.

Surveillance of the epidemic intensified with Covidnet

Established in 2012 by the Sentinelles network (Inserm/Sorbonne Université) and the French Public Health Agency, the GrippeNet.fr 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, anonymously via online questionnaires. GrippeNet.fr 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 GrippeNet.fr study has now become Covidnet.fr. Based on questionnaires sent to the volunteers of the GrippeNet.fr/Covidnet.fr cohort, it is currently the only health surveillance system in France that makes it possible to study the symptoms presented by patients who have sought assistance from the healthcare system.

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).

5.     Study the lockdown and its impacts

The Sapris study and the social challenges associated with the lockdown

Sapris, 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, looks at the epidemiological and social challenges posed 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 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, which will be repeated several times during the lockdown and after it has ended, participants are asked about the specific challenges they are facing related to the epidemic and to these quarantine 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, the effects of the prevention measures on daily life, social relationships, work, and the education of children. In addition, once serological tests become available, the researchers would like to establish the prevalence of COVID-19 based on self-sampling offered to the study participants, which will provide information on prevalence on a national scale.

Evaluating the contacts of French people during lockdown

A population survey to collect and analyze data concerning the contacts between French people during the lockdown has been launched by Institut Pasteur in collaboration with Inserm and several universities. Called SocialCov, this study is based on online questionnaires focused on people’s contacts before and during the lockdown, with the aim of gaining deeper insight into its impact 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 to distribute these results by age group.

Supporting mental health during the lockdown

The measures of social distancing, and particularly the lockdown of the French population, will have an impact on mental health and wellbeing. Several studies have already examined this issue such as a literature review published in The Lancet suggesting that the 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 the lockdown, particularly when it comes to mental health. The participants are asked to answer anonymous questionnaires on their general health, their concerns about infection risk, their social network before and during the 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 also developed a COVID-19 extension of the StopBlues initiative. This initiative, which can count on a freely accessible website and app, was developed in 2018 by the Eceve-Inserm research team led by Karine Chevreul. Its users can be helped to identify whether they are suffering from mental health issues, to look for the possible causes and to find concrete solutions. Within the context of the pandemic, the COVID-19 extension of Stop-Blues includes the publication of short videos describing the emotions that can be felt during the pandemic and faced  with social isolation and family conflicts.

 

6.     Testing the population and protecting medical staff

Inserm allows the 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 conduct a requisition a public research laboratories for COVID-19 testing. 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 in their labs 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 are 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.

Aphro-Cov, a project to 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 our researchers: https://don.inserm.fr/donner

Inserm in the fight against fake news

Fighting fake news 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 possible, Inserm has, since January 2020:

  • Aired an episode on its Canal détox channel discussing the false information most often encountered.
  • Published information bulletins with the most important news regarding the Institute and international research, and which also takes a look at a number of fake news online.
  • Each week, the REACTing consortium prepares a thorough review of the scientific literature concerning SARS-CoV-2 and COVID-19. The group provides a summary of high-quality scientific publications for those wishing to follow the scientific research more closely.

COVID-19 and Confinement: A Large-Scale French Survey of Social Challenges and Health

©Helloquence on Unsplash

For a deeper insight into the social and epidemiological challenges posed by the exceptional prevention measures taken in response to the COVID-19 pandemic – particularly confinement – a multidisciplinary group of researchers has joined forces with Inserm and the Public Health Agency to launch a survey of around 200,000 participants from five major French cohorts.

In response to the COVID-19 pandemic that is currently raging across most of the world, exceptional prevention measures are being implemented – with possibly the most striking example being the confinement of a large part of the population. In the face of this measure, on such an unprecedented scale in our history, many questions are emerging in regard to health, quality of life, social relationships, and the education of children. In order to obtain answers to these questions, deepen our understanding of the short and long-term consequences of the measures, and better describe the frequency of COVID-19 symptoms in the general population, the role of the scientific community is of primary importance. These efforts complement the clinical studies being conducted in hospitals to identify the most effective treatments and understand the outcomes of hospitalized COVID-19 patients.

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, has been established in order to study the principal epidemiological and social challenges of this epidemic via a major national study conducted in the population. Approved by the French Data Protection Authority (CNIL), this study is part of an accelerated procedure implemented in order to tackle the challenges of this health crisis.

The SAPRIS study (“Santé, pratiques, relations et inégalités sociales en population générale pendant la crise COVID-19 – General population health, practices, relationships, and social inequalities during the COVID-19 crisis“) is coordinated by Nathalie Bajos, Inserm Research Director, sociologist and demographer, and Fabrice Carrat, Professor of Public Health at Sorbonne Université, in collaboration with the French Public Health Agency.

It is based on the five large national general population cohorts (Constances – Etude familiale E3N-E4N – Elfe / Epipage 2 – NutriNet Santé) and is being conducted in close coordination with their leaders. 

“The advantage of these cohorts is that they concern several tens of thousands of people who have been followed up for years already, whose pre-epidemic lifestyles, dietary habits, health, treatment consumption, work activities and biological data are finely detailed”, enabling the researchers to study the impact of confinement by documenting social and geographic inequalities of risk exposure and living conditions, and to characterize the factors relating to vulnerability to and severity of the infection, emphasize Bajos and Carrat.

Using a questionnaire filled in at the start of April, which will be repeated several times during confinement and once it has ended, the SAPRIS study will ask the participants about the specific challenges of the epidemic and the confinement measures. Particular attention will be paid to 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.

Once serological tests are available, it will be possible to establish the prevalence of COVID-19 based on self-sampling offered to the study participants, which will provide information on prevalence on a national scale.

Inserm and the African Countries: Partners in Fighting COVID-19

Image de microscopie du  Coronavirus SARS-CoV-2 responsables de la maladie COVID-19 accrochés aux cellules épithéliales respiratoires humaines

Coronavirus SARS-Cov-2 responsible for COVID-19 disease attached to human respiratory epithelial cells©M.Rosa-Calatraval/O.Terrier/A.Pizzorno/E.Errazuriz-cerda

Furthering scientific knowledge knows no frontiers. Therefore, Inserm would like to reaffirm that the countries of Africa are – more than ever – key scientific partners and that:

  • Inserm has long been committed to numerous research projects with African countries concerning a variety of diseases, including Ebola, malaria, and HIV.

 

 

 

 

  • Inserm, through the Reacting consortium, has an ethical charter for research conduct in emerging infectious disease epidemics.
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