Long COVID: A Dysregulated Immune Response Could Explain Symptoms Persistence

Covid-19: 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 (International Research Center in Infectiology U1111 Inserm – UMR 5308 CNRS – ENS Lyon – UCBL1). Colorized by Noa Rosa C.


Several months after SARS-CoV-2 infection, some patients continue to have symptoms. This phenomenon, known as “post-COVID condition” or, more commonly, “long COVID”, remains poorly documented. In order to address this and improve patient care, research teams are trying to improve their understanding of the underlying biological and immunological mechanisms. In a new study, scientists from Inserm and Université de Montpellier at the Montpellier Cancer Research Institute, in collaboration with Montpellier University Hospital[1], have highlighted the possible role of the dysregulation of a part of the innate immune defense. They suggest that the production of “extracellular neutrophil traps”, a first-line defense mechanism against pathogens, could play a role in the persistence of symptoms six months later in patients having developed a severe form of COVID-19. Their findings have been published in the Journal of Medical Virology.

Neutrophils are the most abundant class of white blood cells and the first line of defense against viruses and bacteria. When activated, they are capable of producing a specific defense mechanism known as “neutrophil extracellular traps” (NETs). Made up of DNA fibers, bactericidal enzymes and pro-inflammatory molecules, NETs contribute to fighting pathogens, but in some cases can also trigger excessive inflammation that is harmful to the body.

In previous studies, Inserm researcher Alain Thierry’s team at the Montpellier Cancer Research Institute had shown that part of the innate immune response is dysregulated in patients with severe forms of COVID-19. In these patients, the formation of NETs is amplified, resulting in multi-organ damage.

In their new study, the scientists wanted to go further in studying the biomarkers characteristic of COVID-19. To do this they analyzed the biological samples of over 155 patients. These were individuals with COVID-19 in the acute non-severe (hospitalized) or severe (intensive care) phases, or who had a post-acute infection assessment more than six months after their discharge from critical care. These samples were compared with those of 122 healthy individuals.

NETS and auto-antibodies persisting in the body

The analyses performed in this study confirm that NET production is higher in SARS-CoV-2 patients than in healthy individuals. In addition, the patients have higher levels of auto‑antibodies known as “anticardiolipin auto-antibodies”. Produced by the immune system, these auto‑antibodies are often associated with the abnormal formation of clots in the veins (phlebitis) and in the arteries (arterial thrombosis).

Furthermore, the data collected by the research team also suggest that this dysregulated immune response is maintained in people who present symptoms of long COVID, six months after being hospitalized for a serious form of the disease. The amplified and uncontrolled production of NETs six months after infection as well as the persistent presence of auto‑antibodies could partly explain the symptoms of long COVID, notably via the formation of microthromboses.

“Our findings could indicate the persistence of a sustained imbalance of the innate immune response, and potential prolonged pro-thrombotic activity that could explain the sequelae of post-acute infection or ‘long COVID’. It is necessary to continue the research in order to both confirm this and better understand the nature of this phenomenon, which could be serious and long-lasting, to improve patient care,” concludes Thierry.

Research is already underway in some laboratories around the world to consolidate this data and explore other avenues of interest, with the aim of gaining a better understanding of the long COVID phenomenon in all its complexity. Thierry’s team had also filed an international patent application in August 2022.


[1] The research was partially funded by SIRIC Montpellier Cancer.

Highly Effective Memory B Cells Localized in the Lungs

Researchers showed that memory B cells can be localized in the lungs. © Adobe Stock

How can we increase the efficacy of vaccines used to protect against viral respiratory diseases such as influenza and COVID-19?  Scientists from Inserm, CNRS and Aix-Marseille Université at the Center of Immunology Marseille-Luminy are opening up new prospects in the field, with the triggering of memory B cells directly in the lungs looking to be a promising avenue. At present, the vaccines are administered intramuscularly and do not trigger the appearance of these cell populations. This research, which enhances fundamental knowledge in the field of immunology, has been published in the journal Immunity.

Memory B cells are immune cells produced primarily in the lymph nodes and spleen following infection. They persist for a long time in these regions and retain the memory of the infectious agent. If the body is confronted with the same agent in the future, these cells are immediately mobilized and rapidly reactivate the immune system for effective protection of the individual.

Following extensive research into these memory B cells, researchers discovered three years ago that they could also be localized in the lungs. The team led by Inserm researcher Mauro Gaya and his colleagues from the Center of Immunology Marseille-Luminy (AMU/CNRS/Inserm) and the Center for Immunophenomics (AMU/CNRS/Inserm) went further in order to describe the nature and functioning of this specific immune cell population.

The aim was to better understand these cells and their involvement in the long-term immune response against respiratory infections. For this, the scientists worked with two mouse models of infection: the influenza and Sars-CoV-2 viruses.


“Bona fide” and “bystanders”

They used fluorescent markers to track the appearance of memory B cells after infection, following which they performed a single-cell transcriptome analysis[1]. “These techniques enabled us to precisely localize these cells in the lungs of our animal models and describe their gene expression profile cell by cell to study their function,” explains Gaya.

Approximately ten weeks after inoculation of the virus and after its elimination from the body, the team observed the formation of groups of memory B cells in the bronchial respiratory mucosa, in a strategic position allowing them to be directly in contact with any new virus entering the lungs.

Furthermore, this research suggests that there are two subpopulations of memory B cells expressing different genes, known as “bona fide” and “bystanders”, with the “bona fide” cells having a particular affinity for the virus that triggered their appearance. In the event of new encounters with this pathogen, they immediately differentiate into plasma cells[2] and secrete highly specific antibodies against the virus.

Conversely, the “bystanders” do not directly recognize the virus but bind thanks to a specific receptor to the immune complexes formed by the antibodies that are produced by the “bona fides”.

The “bystanders” can therefore enable cross-reactions by increasing the response of different “bona fide” populations against several types of viruses. “What we have is a two-tier system that enables a synergistic effect and increases the efficacy of the anti-viral memory response in the lungs,” explains Gaya.

In addition to advancing fundamental knowledge in immunology, the research team sees in these findings a longer-term way of improving the efficacy of influenza or COVID-19 vaccines.

These findings could in fact form the basis for new research into the way vaccines are administered. “The hypothesis is that by intranasal vaccination, we could mimic the natural entry pathway of the virus, mobilize these lung memory B cells to block the virus as soon as it reaches the respiratory tract in the event of an infection. In this way, we could combat severe forms and also better protect against infection,” concludes Gaya.


[1] Single-cell transcriptome analysis: a technique used to study the genes expressed in each cell of a sample

 [2] Plasma cells:B cells that have reached a stage of terminal differentiation during which they produce antibodies

Long COVID: When Symptoms Persist Months after the First Wave

During the first wave of COVID-19, participants from the Constances cohort completed two questionnaires to determine the presence of symptoms during the previous 15 days. Credits: Adobe Stock

Several months after infection with SARS-CoV-2, some patients are still having symptoms – a phenomenon known as “long COVID” or “post-COVID-19 condition”. Still poorly understood, scientists are now attentively studying long COVID in order to improve knowledge and offer patients the best possible treatment. Researchers from Inserm, Université Paris-Saclay and Sorbonne Université at the Pierre-Louis Institute of Epidemiology and Public Health, in collaboration with ANRS | Emerging Infectious Diseases, have used data from around 26,000 Constances cohort volunteers to identify the persistent symptoms most commonly reported by SARS-CoV-2 patients compared with the rest of the population. These are mainly loss of taste or smell, difficulty breathing and fatigue and are particularly seen in patients who experienced typical COVID symptoms at the time of infection. Their findings have been published in The Lancet Regional Health – Europe.

Many people report symptoms that persist for several months after infection with SARS-CoV-2. Still poorly understood, “long COVID” is currently the subject of rigorous research in order to better define its prevalence in the general population and decipher its underlying pathophysiological mechanisms.

The persistent symptoms most commonly described in the scientific literature include dyspnea (difficulty breathing), asthenia (fatigue), joint and muscle pain, cognitive complaints, digestive complaints, and anosmia/dysgeusia (loss of smell and taste).

Apart from anosmia/dysgeusia, these clinical manifestations are not specific to COVID-19 and may, for example, be related to other infections occurring during the same period or to more restricted access to health care during the pandemic.

In order to better understand and treat long COVID, it is therefore essential for scientists to determine which persistent symptoms are more specifically associated with SARS-CoV-2 infection than with other conditions.

A general population study

A new study published in The Lancet Regional Health has examined this issue. One of the aspects that makes this research original is that it was carried out in a general population cohort.

General population cohorts differ from cohorts constructed from samples of COVID patients (who, by definition, are all “symptomatic”, often with severe clinical forms or hospitalized), which are not representative of everyone with the infection.

General population cohorts therefore make it possible to understand public health problems through the creation of comparison groups, for example focusing on the severity of symptoms at the time of infection.

Another novel aspect is that the participants all underwent a serological test to screen for a history of SARS-CoV-2 infection. This differentiates this study from the majority of its counterparts, which focus on those having performed a PCR test and who have presented symptoms.

For example, this study compared the persistence of symptoms seven to eight months after the first wave of the pandemic in four groups of participants[1] distributed according to the symptoms they had during that first wave and their serological status (whether or not they had been infected with SARS-CoV-2). 

Long-term symptoms according to serological status

A total of 25,910 participants from the Constances cohort (see box) completed two questionnaires during the first wave of COVID-19 to determine the presence of symptoms during the fifteen days prior. They then underwent a serological test, between May and November 2020, to identify those who had been exposed to the virus.

Finally, between December 2020 and February 2021, they completed a third questionnaire, which looked at symptoms having persisted or persisting for at least two months. This questionnaire included the list of symptoms focused on during the first waves of questionnaires, as well as new symptoms presented by people with long COVID (problems with concentration and attention, chest pains, etc.).

The researchers compared the individuals having presented symptoms suggestive of acute respiratory infection based on the results of their serological test. They observed that symptomatic individuals seropositive for SARS-CoV-2 had more persistent anosmia/dysgeusia, dyspnea and fatigue than those who were seronegative. The frequency of the other symptoms was equivalent.

Links between symptoms at the time of infection and persistent symptoms

The researchers then explored the link between infection, acute symptoms, and persistent symptoms. The results of their statistical analyses show that SARS-CoV-2 mainly affects the persistence of symptoms if it induces certain symptoms during the acute phase of the infection.

“Our findings confirm the importance of the clinical expression of the initial infectious episode in the risk of developing persistent symptoms. They can help guide public policies by providing more accurate data on the type of persistent COVID-19 symptoms and encourage the development of strategies for more effective treatment. Promoting preventive therapies and approaches, such as vaccination, that reduce symptoms in the acute phase of the disease could also have a beneficial effect on long COVID,” the study authors noted.

These findings reflect the complexity of the mechanisms that can explain the persistent symptoms, emphasizing that these symptoms may be related to the virus, to the initial clinical presentation of the infection, and to other non-specific causes.

They also suggest the importance of conducting studies on post-infectious conditions, regardless of the micro-organism in question.

Further research is under way to understand the mechanisms behind long COVID and to quantify the extent to which these persistent symptoms can be attributed to SARS-CoV-2 infection

The Constances cohort

Constances is a large-scale French epidemiological cohort, composed of a representative sample of 220,000 adults aged 18 to 69 years at the time of their inclusion. Participants are asked to have a health check every four years and to complete an annual questionnaire. Each year, their data are matched with the French national health insurance databases. This large-scale cohort is supported by the National Health Insurance Fund and financed by the Investments for the Future Program.

The data collected, which concern health, socio-professional characteristics, use of health care services, and biological, physiological, physical and cognitive parameters, enable us to learn more about the determinants of many diseases.

Constances is one of three cohorts on which is based the SAPRIS-SERO project led by Inserm and ANRS | Emerging Infectious Diseases – a project which aims to quantify the incidence of SARS-CoV-2 in the French population on the basis of serological tests.

For more information:

[1] The members of the first group of participants all had a positive COVID-19 serological test and had reported symptoms during the first wave. Those of the second group had a positive test but no symptoms. Those of the third group had a negative test and symptoms, while those of the fourth group were asymptomatic during the first wave and with a negative test.

La tenue d’un colloque à l’IHU intitulé « Premier bilan des connaissances et des controverses scientifiques… » interpelle, les membres fondateurs se mobilisent


COVID-19: “Reactive” Vaccination, Effective in Case of High Viral Circulation?

Scientists are considering new strategies to continue to promote vaccination among the populations that remain hesitant © Mat Napo on Unsplash

Although the majority of its population is fully vaccinated, the virus continues to actively circulate in France. As health restrictions are being lifted, fears of a resurgence of the epidemic and of the emergence of new more contagious variants are leading scientists to consider new strategies to continue to promote vaccination among populations that remain hesitant. A new modeling study by researchers from Inserm and Sorbonne Université at the Pierre Louis Institute of Epidemiology and Public Health shows that a “reactive” vaccination strategy targeting homes, schools and workplaces where cases are detected could have beneficial effects, reducing the number of COVID-19 cases in certain epidemic situations. The findings of this research have been published in Nature Communications.

Mass COVID-19 vaccination campaigns in many countries have greatly reduced the pandemic. However, the vaccination rate is now stalling in Europe and the USA due to logistical constraints and the vaccine hesitancy of part of the population.

In March 2022, 79% of French people were fully vaccinated with a two-dose regimen and 53% had received the third (booster) dose. While these figures are high, efforts to counter the epidemic must be maintained: against a background of ever-intense viral circulation and the lifting of health restrictions, a resurgence of the epidemic remains possible – and with it the appearance of more contagious variants.

In such a context, and to improve efficacy, many scientists therefore believe that other vaccine strategies promoting accessibility and acceptability should be tested.

Researchers from Inserm and Sorbonne Université were therefore interested in a “reactive” vaccination strategy, which involves vaccinating homes, schools and workplaces where cases have been detected. This approach is already used in other epidemics, for example against outbreaks of meningitis. In COVID-19, it has occasionally been used on the ground in France, for example in Strasbourg at the Haute Ecole des Arts du Rhine (HEAR), following the discovery of a cluster of the delta variant.

What is “ring vaccination”?

In other epidemic contexts, for example during some Ebola epidemics, other innovative strategies have been deployed to reach as many people as possible. The most well-known is that of ring vaccination, which involves immunizing contacts of confirmed cases or contacts of those contacts.

The research team wished to evaluate the effects of this reactive approach on viral circulation and the number of cases of COVID-19 in different epidemic scenarios. In order to build their model, the scientists used National Institute of Statistics and Economic Studies (INSEE) data to model a typical population with the sociodemographic characteristics, social contacts, and professional situations of a population the size of an average French city.

Several parameters were also incorporated into the model, such as disease characteristics, vaccination coverage, vaccine efficacy, restrictions on contact in workplaces or in the community, travel, and the implementation of contact tracing strategies.

The scientists were then able to study the impact of a reactive vaccination strategy on several scenarios of epidemic dynamics. They show that in the majority of the scenarios, with the same number of vaccine doses, a reactive strategy is more effective than other vaccination strategies in reducing the number of COVID-19 cases.

For example, in a context where vaccination coverage is approximately 45% and viral circulation is high, the reduction in the number of cases over a two-month period increases from 10 to 16% when comparing a mass vaccination program with a program in which reactive vaccination is set up in parallel to mass vaccination.

The findings suggest that this strategy is especially effective when vaccination coverage is low and when combined with robust contact tracing measures.

When vaccination coverage is high, a reactive strategy is less useful, as most of those in contact with an infected person are already vaccinated. Nevertheless, such an approach would still have the benefit of reaching people who are not vaccinated and convincing them more easily of the utility of the vaccine. Indeed, exposure to the virus increases one’s perception of the risks and tends to make vaccination more acceptable.

“The model we built enables reactive vaccination to be considered as an effective strategy for increasing vaccination coverage and reducing the number of cases in some epidemic scenarios, especially when combined with other measures such as effective contact tracing. This is a tool that can also be reused and adapted in France should another variant emerge and where the efficacy of a reactive strategy needs to be tested in order to administer any boosters. This modeling may also be of interest to other countries with sociodemographic characteristics similar to France, but lower vaccination coverage,” explains Chiara Poletto, Inserm researcher and last author of the study.

Better Understanding the Role of a White Blood Cell Type in SARS-CoV-2 Immune Response

cellule basophile

Image of a basophil showing the granules (dark circles) characteristic of granulocytes. ©Inserm/Janine Breton-Gorius

Although the response of various immune cells to SARS-CoV-2 infection has been relatively well studied, that of basophils (a category of white blood cells) had not been characterized yet – mainly because of their rarity in that they represent around 0.5% of the body’s white blood cells. In a new study, researchers from Inserm, Sorbonne Université, Université de Paris, CNRS, Institut Pasteur and Efrei describe how basophils respond to SARS-CoV-2 infection. They show that exposure to the virus activates them, leading to the production of certain cytokines and helping to reduce inflammation and promote the secretion of antibodies. The findings of this study were published in Frontiers in Immunology on February 24, 2022.

Basophils are leukocytes (white blood cells) that play a key role in immune response. They are produced in the bone marrow and make up around 0.5% of all leukocytes. In addition to their role in protecting against parasitic infections, basophils are involved in the response to various allergic inflammatory diseases of the respiratory tract (allergic rhinitis, asthma), gastrointestinal tract (food allergies), and the skin (atopic dermatitis).

Previous studies have evaluated the role of immune system cells known as granulocytes

– neutrophils, eosinophils, and basophils – in the immune response to SARS-CoV-2 infection. These findings had revealed a smaller number of basophils during the acute and severe phases of COVID-19, followed by an increase in their number up to the disease recovery phase, four months after discharge from hospital. These same basophils were also “activated”: they produced cytokines, molecules enabling communication between immune cells and capable of adapting the immune response to the nature of the infectious agent.

Through in vitro studies of the reaction of healthy basophils exposed to SARS-CoV-2, a team of researchers from Inserm, Sorbonne Université and Université de Paris at the Cordeliers Research Center, from CNRS and Institut Pasteur at the Evolutionary genomics, modeling and health laboratory, and from Efrei wished to describe the cytokine response of basophils more precisely. It observed that the activation of basophils resulted in the production of specific cytokines, known as interleukins IL-4 and IL-13.

These interleukins allow basophils to interact with the other immune cells, especially the T and B cells, and to establish a link between innate and adaptive immunity (see box). For example, IL-4 directs B cells towards the production of antibodies.

Basophils such as neutrophils and eosinophils are innate immune cells, whereas B and T cells are adaptive immune cells.

Innate immunity is an immediate response that occurs in any individual in the absence of prior immunization. It is the first barrier of defense against various pathogens and mainly brings into play pre-formed (natural) antibodies and lymphocytes that do not present receptors specific to the antigen.

Adaptive immunity is established a few days after contact with the pathogen and is the body’s second line of defense. Unlike innate immunity, adaptive immunity is specific for a given antigen.

Furthermore, the scientists have also shown that when basophils are stimulated by interleukin IL-3, itself produced by the T cells, they produce more IL-4 and IL-13.

These data highlight the potentially beneficial role of IL-3 in COVID-19 patients. Other research findings had already shown that low IL-3 levels in the plasma of patients infected with SARS-CoV-2 were associated with greater severity of the disease.

“More generally, these findings deepen the little scientific knowledge we had until now on the key role played by basophils in immune response and in the context of viral infections. The mechanism by which SARS-CoV-2 induces basophil activation is now the subject of new research,” explains Camille Chauvin, Inserm researcher and co-author of the study.

Whereas other studies have shown the pathological role of innate cells such as neutrophils, monocytes and macrophages activated by SARS-CoV-2, we found potential beneficial effects of the activation of basophils by the virus. Being able to modulate basophil activation, via IL-3 for example, could potentially allow us to regulate the protective antibody response to a viral infection such as SARS-CoV-2,concludes Jagadeesh Bayry, Inserm Research Director and last author of the study.

COVID-19: A “Programmed Cell Death” Phenomenon in Hospitalized Patients

Coronavirus SARS-CoV-2

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

Almost 60% of patients hospitalized for COVID-19 have lymphopenia – a lower than normal number of lymphocytes[1] in the blood circulation. The mechanisms underlying this condition have long been poorly understood. In a new study, researchers from Inserm and Université de Paris[2] in collaboration with Canadian and Portuguese teams (Université Laval and Life and Health Sciences Research Institute [ICVS], respectively)[3] have revealed a phenomenon of programmed cell death known as “apoptosis”[4] that would explain the loss of lymphocytes in these patients. They have also shown in vitro that this process can be reversed by using caspase inhibitors – molecules that block the action of the enzymes responsible for apoptosis. These findings, published in the January 22, 2022 issue of Cell Death & Differentiation, make it possible to envisage new therapeutic avenues for patients with severe forms of COVID-19.

COVID-19 is a disease that varies broadly from one patient to another. While most infected people are asymptomatic or have mild symptoms, others develop severe forms of the disease.

Research on hospitalized patients had until now focused mainly on the inflammatory state that characterizes serious forms, and less so on other biomarkers. Yet among these patients, 60% have lymphopenia. The number of lymphocytes in their blood is lower than normal, especially the number of CD4 T cells.

lymphocytes apoptotiques

Detection of apoptotic lymphocytes with nuclear condensation and fragmentation visualizable by electron microscopy and not immunofluorescence. © Jérôme Estaquier

The team of Inserm researcher Jérôme Estaquier, at Unit 1124 (Inserm/Université de Paris) and Université Laval in Quebec, has studied this phenomenon. Thanks to their long history of researching AIDS – a disease for which a low blood CD4 level is a marker of poor prognosis – the scientists were able to apply their knowledge of these processes to COVID-19.

As part of their research, the scientists studied blood samples taken from patients hospitalized from April to June 2020 for COVID-19 (some of them in intensive care) and compared them with those of healthy donors. They showed that lymphopenia was correlated with the presence of several severity biomarkers, including the death ligand, FasL.

Programmed cell death  

They also showed that a process of programmed cell death – apoptosis – is responsible for the disappearance of CD4 T cells in hospitalized patients with COVID-19.

In an attempt to block this process, the researchers then drew on their previous HIV research in animal models, in which they had shown that administering molecules called caspase inhibitors can stop apoptosis, restore CD4 T cells, and prevent the onset of AIDS. Here they show that, with these molecules, the process of lymphocyte apoptosis is also reversible in the case of COVID-19.

These findings[5] open up new therapeutic avenues for the early treatment of hospitalized patients with lymphopenia. “The idea is now to set up phase 1 clinical trials to test the safety of caspase inhibitors in humans. CD4 cells are the cornerstone of the immune system. As such, these molecules could ultimately be useful for patients presenting with lymphopenia on admission to hospital, ” emphasizes Estaquier.


[1] Lymphocytes are white blood cells that play a key role in the immune system. They defend the body in the face of attacks.

[2] At Unit 1124 “Environmental Toxicity, Therapeutic Targets, Cellular Signaling and Biomarkers”

[3] The study was also conducted in collaboration with and the French National Center for Scientific Research (CNRS) (Institute of Human Genetics, IGH).

[4] Apoptosis is the programmed death of cells. This is a process by which cells trigger their self-destruction in response to a stress signal or death ligand.

[5] This study was funded by FRM and AbbVie. 

COVID-19: New Avenues to Explain Why Children Are at Less Risk of Severe Forms

This colorized electron microscope image shows SARS-CoV-2 isolated from a patient in the USA. Viral particles emerge from the surface of the laboratory-cultivated cells. © NIAID-RML Creative Commons.


Why are children less susceptible than adults to critical forms of COVID-19? This question has been studied by many scientists since the pandemic began. A number of interesting avenues are emerging, notably suggesting differences in immune response following SARS-CoV-2 infection. In a new study, researchers from Inserm, Université d’Angers and Angers University Hospital, members or partners of the Regional Center for Research in Cancerology and Immunology Nantes-Angers (CRCINA) have shown that the interferon response, which is part of the innate immune response, differs according to the age of the patient. Their findings have been published in Frontiers in Immunology in November 2021.

The symptoms of COVID-19 vary widely from one person to another. While some are asymptomatic following SARS-CoV-2 infection, others develop severe and possibly fatal forms of the disease. Since the start of the pandemic, age has been identified as a major risk factor for developing a severe form of COVID-19. Unlike adults, and especially the elderly who are very vulnerable to infection, children usually have no clinical signs of the disease (or only mild symptoms).

Numerous research teams are trying to identify the immune response parameters that could explain this difference in susceptibility between young and elderly people.

In this collaborative research, scientists from Inserm and Université d’Angers at the Regional Center for Research in Cancerology and Immunology Nantes-Angers, as well as the Virology and Immunology laboratories at Angers University Hospital, have hypothesized that children are protected due to a stronger local innate immune response, in the nasopharyngeal mucosa. So far, there has been less research into innate immunity to COVID-19 than into adaptive immune response[1].

A closer look at immune response

Innate immunity is the immediate response that occurs locally, at the point of entry of a pathogenic microorganism, in any individual – even in the absence of prior contact with that microorganism. It is the first barrier of defense against pathogens. In the event of a viral infection, it primarily deploys Natural Killer cells

that kill the cells infected with a virus. It also induces the production of interferons by the infected cells, and it is these interferons that protect the adjacent cells from infection.

Adaptive immunity is a response that takes 5 to 7 days to become protective when the pathogen is encountered for the first time (primo-infection), but is more rapidly effective once the pathogen has already been encountered (this is known as a memory response). In the event of a viral infection, it deploys two types of protective immune cells: antibody-producing B cells that bind to the virus and “neutralize” it, namely by preventing it from entering the cells and by promoting its elimination, and cytotoxic CD8+ T cells that kill the infected cells. The B and T cells recognize protein structures (of the virus) known as antigens.

Following infection with a virus or vaccination, the level of antibodies and lymphocytes recognizing the virus decreases over time. Nevertheless, the so-called “memory” B and T cells remain in the body and keep watch, acting faster and more efficiently if they encounter the same virus in the future.

Different interferon responses

In their research, the scientists analyzed nasopharyngeal samples from 226 people who had come for a PCR test at a drive-through screening center at Angers University Hospital between March 2020 and March 2021. Of these individuals, 147 were infected with SARS-CoV-2. “Our research was original in that we had not preselected the participants, so as not to bias the results, and also that we were interested in innate immunity – and more specifically the interferon response,” emphasizes Yves Delneste, an Inserm researcher who took part in this study.

When cells are infected with any given virus, they rapidly produce type I (IFN-α/β) and type III (IFN-l) interferons, which are powerful natural antiviral molecules. They are called interferons because they “interfere” with the replication of the virus and protect the adjacent cells from infection.

While these interferons all have antiviral activity, their modes of action are not redundant. Each induces an antiviral response of a different intensity and duration and has a different but complementary action on immune response[2].

An inadequate or inappropriate interferon response will not make it possible to contain the replication of the virus or it may promote a pathological immune response (for example, an exacerbation of the immune system as seen with severe forms of COVID-19).

Analysis of the samples studied by the research team revealed that in subjects infected with SARS-CoV-2, the expression profiles of type I (IFN-α/β) and type III (IFN-l) interferons differ with age. Thus, children under 15 years of age have an increased expression of type III interferons, locally-acting molecules with limited inflammatory properties, which control the virus locally at its entry point in the nasopharyngeal mucosa. Conversely, adults, especially elderly adults, preferentially express type I interferons, which are inflammatory and have a more systemic action (in the whole body).

“These findings help to explain why children are less susceptible to critical forms of COVID-19 than adults. Type III interferons, which primarily act by protecting the epithelium at local level, could control infection at the point of entry, without inducing excessive widespread inflammation, thereby preventing the slide towards the inflammatory storm with mass cell destruction that is seen in severe forms,” emphasize Pascale Jeannin (university professor and hospital practitioner) and Dominique Couez (university professor) in Angers, who led this research.

Based on these findings, the scientists will now conduct a prospective study to evaluate whether, in children with clinical signs of the disease, the characteristics of the interferon response associated with severe forms in adults are present and whether they can predict the course of infection.


1 see text box on innate and adaptive immunity

2 see text box

Covid-19 booster doses: start of inclusions in the COVIBOOST trial

Vaccin Anti Covid

French health authorities recommend that all adults over 18 years of age perform a booster injection with a MRNA to ensure maximum and prolonged vaccine protection.© AdobeStock


In a context of winter circulation of the virus, a constant increase in the number of confirmed cases and the appearance of new variants, the French health authorities recommend that all adults over 18 years of age perform a booster injection with a MRNA to ensure maximum and prolonged vaccine protection.

Administration of a 3 rd dose of a different vaccine could nevertheless have advantages in terms of efficacy and safety, but also in terms of cost and acceptability.

The COVIBOOST trial is designed to study the immune response of the two candidates based recombinant protein vaccine associated with an adjuvant developed by Sanofi Pasteur and GSK and that of a 3 rd dose of the Pfizer-Biontech vaccine.

This randomized double-blind trial, promoted by Assistance Publique – Hôpitaux de Paris, will be carried out in 11 hospitals in the COVIREIVAC network coordinated by Inserm. It starts on December 8.

300 participants who had previously received two doses of the Pfizer-BioNTech vaccine ( 2nd dose received within 5 to 7 months) and without a history of Covid-19 will be included, half of them aged 65 and over.

They will randomly receive a booster dose:

– the mRNA vaccine from Pfizer-BioNTech (Comirnaty®)

– the adjuvanted recombinant protein vaccine from Sanofi-Pasteur / GSK based on the original strain of the virus (Wuhan strain)

– the adjuvanted recombinant protein vaccine from Sanofi-Pasteur / GSK based on the beta variant (South African variant)

The data from the trial will make it possible to measure the immune response induced by the three vaccines studied as a booster, and its effectiveness on the different variants but also its persistence at 3 and 12 months, depending on age.

This is the eighth study launched by COVIREIVAC.

The booster vaccination as part of the trial will validate the health pass for the 3rd dose according to national requirements.

Today the booster dose with an mRNA vaccine has become essential. But we hope to broaden the range of possibilities with other vaccine technologies. » Explains Marie Lachâtre, infectious disease doctor (Hôpital Cochin and Hôtel Dieu / APHP) and member of COVIREIVAC. “The Sanofi-Pasteur / GSK vaccine candidates have for several months been the subject of phase 3 clinical trials as a primary vaccination or as a booster. Today we want to assess the immune response they induce by booster compared to that of the Pfizer-BioNTech vaccine ”.

This clinical study has been labeled a “national research priority” on Covid-19 by the Ministry of Health and Solidarity.

Launched in October 2020, the COVIREIVAC platform coordinated by Inserm and F CRIN in conjunction with 32 university hospitals and a network of 11 immunology laboratories aims to conduct and promote excellent clinical vaccine research in France. Since October 1, 2020, 50,000 volunteers have registered to participate in research efforts and improve knowledge about these new vaccines. This is an unprecedented initiative in our country. The platform is managed by Inserm, and the clinical operational component is coordinated by the Assistance Publique-Hôpitaux de Paris of the various CHUs. New research projects are regularly launched within the framework of COVIREIVAC.

Even if several vaccines against Covid-19 are available, it is imperative to continue research in order to deepen scientific knowledge, in particular the duration of protection and the quality of the immune response.

The objective of the clinical studies coordinated by COVIREIVAC is to provide answers to these research questions.  

Lancement du Groupement d’intérêt scientifique Obépine sur les eaux usées