Omicron BA.1 virus infection in vaccinated patients remodels immune memory


Cells infected with SARS-CoV-2 © Alberto Domingo Lopez-Munoz, Laboratory of Viral Diseases, NIAID/NIH

Teams from the internal medicine department of the Henri-Mondor AP-HP hospital, the Institut Necker – Enfants Malades, the Mondor Institute for Biomedical Research, the Institut Pasteur, Inserm, and the Paris-Est Créteil University studied immune memory after infection with the Omicron BA.1 variant in patients vaccinated with three doses of the messenger RNA COVID-19 vaccine. The results of this study ( MEMO-VOC) , coordinated by Dr Pascal Chappert and Pr Matthieu Mahévas, in collaboration with Dr Pierre Bruhns and Dr Félix Rey were published on August 4, 2023 in the Immunity review .

The Spike protein of SARS-CoV-2 1 Omicron BA.1 carries 32 mutations compared to the ancestral strain (Hu-1) originally identified. These mutations significantly alter neutralizing antibodies induced by natural SARS-CoV-2 infection and/or vaccination with an encoding mRNA vaccine.

Immune memory is a mechanism that protects individuals against reinfection. This defense strategy of the body, which is the basis of the success of vaccines, includes the production of protective antibodies in the blood (detected by serology) as well as the formation of memory cells (memory B lymphocytes 2 ), capable of quickly reactivate into antibody-producing cells upon re-infection.

The scientific literature has already shown 3,4 that the repertoire of memory B cells generated by two or three doses of mRNA vaccines contains neutralizing clones against all variants of SARS-CoV-2 up to Omicron BA.1.

The research team studied memory B cells after infection with SARS-CoV-2 Omicron BA.1 in 15 individuals previously vaccinated with three doses of the mRNA COVID-19 vaccine encoding the initial Spike protein of the virus. She followed them up to 6 months after infection with Omicron BA.1 to characterize the response of B lymphocytes, from the early immune reaction to the late onset of long-term memory.

This study reveals that infection with the Omicron BA.1 variant mainly mobilizes memory B cells recognizing common proteins between the initial Spike protein and Omicron BA.1 already present in the repertoire formed after vaccination, but few cells directed against specific BA.1 mutations.

Nevertheless, infection with Omicron BA.1 still induces a reorganization in the memory B cell repertoire without altering its diversity, and an improvement in the overall affinity of the memory B repertoire against the common structures of the Spike encoded in the original vaccine (Spike Hu-1) and that of the Omicron BA.1 variant. This reorganization of the memory repertoire is associated with a significant improvement in the ability to neutralize Omicron BA.1.

These results suggest that Omicron BA.1 virus infection in vaccinated patients remodels the memory B cell repertoire and enhances the ability of memory cells to recognize conserved SARS-CoV-2 epitopes and neutralize the virus.

Future vaccine strategies will nevertheless be needed to extend the immune response beyond conserved epitopes to deal with future antigenic variations of SARS-CoV-2.

This study has been labeled a National Research Priority by the ad-hoc national steering committee for therapeutic trials and other research on COVID-19 (CAPNET). The authors thank the ANRS | Emerging Infectious Diseases for its scientific support, the Ministry of Health and Prevention and the Ministry of Higher Education, Research and Innovation for their funding and support.

[1] SARS-CoV-2 protein that allows the coronavirus to enter human cells.
[2] Immune cells produced mainly in the lymph nodes and spleen following an infection. They persist for a long time in these regions and retain the memory of the infectious agent. If the body is confronted with them again, these cells are immediately mobilized and quickly reactivate the immune system for effective protection of the individual.
[3] Sokal, A., Broketa, M., Barba-Spaeth, G., Meola, A., Ferna´ ndez, I., Fourati, S., Azzaoui, I., de La Selle, A., Vandenberghe, A., Roeser, A., et al. (2022). Analysis of mRNA vaccination-elicited RBD-specific memory B cells re- veals strong but incomplete immune escape of the SARS-CoV-2 Omicron variant. Immunity 55, 1096–1104.e4. immuni.2022.04.002.
[4] Goel, R.R., Painter, M.M., Lundgreen, K.A., Apostolidis, S.A., Baxter, A.E., Giles, J.R., Mathew, D., Pattekar, A., Reynaldi, A., Khoury, D.S., et al. (2022). Efficient recall of Omicron-reactive B cell memory after a third dose of SARS-CoV-2 mRNA vaccine. Cell 185, 1875–1887.e8. https://
[5] Part of a molecule capable of stimulating the production of an antibody.

Long COVID: The Persistence of SARS-CoV-2 in the Mucous Membranes May Be A Factor


This transmission electron microscope image shows SARS-CoV-2, isolated from a patient in the U.S., emerging from the surface of cells cultivated in a laboratory. © National Institute of Allergy and Infectious Diseases-Rocky Mountain Laboratories, NIH. Public domain.

Several months after infection with SARS-CoV-2, some patients still have symptoms: a phenomenon commonly referred to as “long COVID”. In new research, teams from Inserm and Université Paris Cité[1], in collaboration with the University of Minho in Braga (Portugal), have shown that this could be explained biologically by abnormalities of the immune system associated with the persistence of the virus in the mucous membranes. These findings, published in Nature Communication, could in the longer term pave the way for a diagnostic tool for long COVID.

Despite the fact that various studies consider long COVID to affect between 10 and 30% of people infected with SARS-CoV-2, its diagnosis and treatment remain difficult. The team of Inserm researcher Jérôme Estaquier, in collaboration with that of Ricardo Silvestre at University of Minho in Portugal, is conducting research to explain this phenomenon from the biological point of view.

At the present time, few biological criteria, apart from the persistence of symptoms beyond three months after the acute infection, enable its diagnosis. Once a patient is not fully recovered after this period, they are considered to have long COVID. Without a more reliable means of diagnosis, it is difficult to offer the appropriate care.

In order to better understand long COVID and find diagnostic markers, the researchers studied the immune systems of 164 people six months after they were infected.  They analysed the blood samples of 127 people, half of whom with long COVID (fatigue, shortness of breath, cough, muscle or chest pain, anxiety, etc.) and those of 37 controls who had not been infected.

The researchers focused on certain immune cells, namely the T cells (including CD8 cells) involved in eliminating the virus, and the SARS-CoV-2 antibodies. In addition, they had blood samples that were taken during the acute phase of the disease for 72 of these patients, enabling them to retrospectively compare the level of inflammation at the early stage in those who went on to develop long COVID or not.


Several immune markers identified

The researchers identified a number of blood markers present six months after infection in 70-80% of the subjects with long COVID, while those same markers were rare in the subjects who had not developed it.

In particular, the teams showed that a CD8 cell subtype expressing the inflammatory protein granzyme A is present in excess, whereas another CD8 subtype, this time expressing integrin b7, is present in small quantities. Yet it is the latter subpopulation that is essential for controlling viruses in the mucous membranes. In addition, virus-specific IgA antibodies are also present in excess whereas they should be rapidly eliminated if the virus is absent. These observations suggest the persistence of the virus in the body and especially in the mucous membranes.

The researchers hypothesise that SARS-CoV-2 could make itself at home in the intestinal mucosa as it is more “permissive” in immune terms than the rest of the body, insofar as the virus has to tolerate the bacterial flora. Other viruses, such as HIV, also use this escape strategy. Initially present in the lung mucosa, SARS-Cov-2 could therefore descend to the intestine and persist there without the immune system being able to eliminate it completely.

In the final stage of the study, when evaluating the initial level of inflammation during the acute phase, the scientists observed an association between an inflammatory response characterized particularly by very high levels of interferon IP-10 or interleukin IL-6 and the risk of going on to develop long COVID.

“This confirms clinical observations that the initial severity of COVID is associated with a higher risk of developing long COVID,” specify the researchers. “One hypothesis is that people with more exacerbated early immunodeficiency develop more severe initial forms of COVID-19 and fail to effectively eliminate the virus that passes into the intestinal mucosa, where it settles for a long time. The immune system kind of ends up tolerating it at the cost of persistent symptoms of varying intensity and nature,” explains Estaquier.

The objective is now to validate these findings in new cohorts to determine whether some of these markers could be used as a diagnostic tool.

“If measuring IgA some time after the acute phase and potentially CD8 b7 cells was able to diagnose long COVID, doctors could make an objective diagnosis. Then we could think about therapeutic targets based on this research,” concludes Estaquier.


[1]This research in France was supported by the Fondation pour la Recherche Médicale, the French National Research Agency (ANR), and ANRS | Emerging Infectious Diseases.

COVID-19: Infection-Vaccination is the Most Protective Combination Against Reinfection


Electron microscopy visualization of a cell infected with SARS-CoV-2. © Philippe Roingeard, Anne Bull-Maurer, Sonia Georgeault/Inserm.licence CC-BY-NC 4.0 international

A large part of the population has developed immunity against SARS-CoV-2 following infection, vaccination – or both. In addition, some infected patients enjoy “hybrid” immunity when they are vaccinated following their infectious episode. Scientists from Inserm, CNRS, Université Claude-Bernard Lyon 1 and ENS de Lyon at the International Center for Research on Infectious Diseases (CIRI) seek to characterize the imprint left by SARS-CoV-2 exposure through vaccination or the combination of the two events on immune memory. The objective? Deepen their understanding of the mechanisms of immune response to the virus in order to improve patient care and optimize vaccine strategies. In a new study, the scientists compared the immune memory of convalescent individuals, whether or not vaccinated against SARS-CoV-2, with that induced by vaccination in individuals having never been infected with the virus. Their findings show that those who are vaccinated following an infection are the best protected from SARS-CoV-2 reinfection. The full article has been published in Science Translational Medicine.

Our body keeps a memory of the infections it has already fought in order to protect us against possible reinfection. The efficacy of vaccination is based on a strategy of simulating an infection to induce protective immunity, i.e. the production of memory cells “trained” in recognizing the pathogen, which can protect the body in the event of infection.

In the case of COVID-19, immunity is conferred either by infection (natural immunity) or by vaccination (vaccine immunity). Some people also benefit from “hybrid” immunity since they have been vaccinated following an infectious episode.

In order to better understand the precise mechanisms of the immune response to SARS-CoV-2, researchers from Inserm, CNRS, Université Claude-Bernard Lyon 1 and ENS de Lyon compared different immune memory parameters from blood samples collected from individuals with natural immunity, vaccine immunity, or hybrid immunity to SARS-CoV-2.

They focused on the adaptive immune response and more specifically on the so-called “humoral” response (see box below).

More About Adaptive Immune Response

The adaptive immune response is established a few days after contact with the pathogen, unlike the innate immune response, which is immediate.

There are two main categories of adaptive immune response.

Cell responses, which are based on the recognition and destruction of the infected cells by the cytotoxic (killer) T cells.

Humoral responses, which are based on the production of antibodies by the B cells. These antibodies recognize the pathogen and neutralize it to prevent it from infecting the target cells.

Humoral immune memory has two compartments:

– serological memory, estimated by the levels of circulating antibodies produced by the memory plasma cells. These antibodies create a barrier that can prevent reinfection.

– cell memory, consisting of memory B cells that do not secrete antibodies but which can differentiate rapidly and massively into plasma cells to generate a new amplified antibody production. These memory B cells are called upon when the barrier of antibodies produced by the memory plasma cells is deficient or insufficient.

The findings show that six months after the last vaccine injection or after infection, people with hybrid immunity are those with the highest levels of neutralizing antibodies in the blood.

In addition to this quantitative variation in serological memory, the authors also show that hybrid immunity induces a qualitative change in the cell memory constituted by the B cells. This results in a multiplication of the number of certain memory B cells carrying receptors enabling their relocation in the respiratory and intestinal mucosa. This last point suggests that hybrid immunity could provide better protection to the SARS-CoV-2 penetration sites.

“As a whole, the findings of this study demonstrate the superiority of hybrid immunity over all other forms of immunity. They emphasize the importance of including previously infected individuals in vaccination campaigns,” explains Thierry Defrance, Inserm researcher and last author of the study.

“Finally, this study serves as a reminder that while serum antibody levels are certainly an important marker of immunity, they are not the sole determinant of protective immunity. Other components of immune memory, T cells and also memory B cells, may induce a rebound in antibody secretion when stimulated by the virus,” adds the scientist.

Using Modeling to Limit Infectious Disease Transmission at Airports and Train Stations

The model concerns London Heathrow airport. © Unsplash

In crowded places, such as airports and train stations, social distancing is difficult to maintain and the risk of infectious disease transmission is increased. In order to reduce this risk, it is essential that we improve our understanding of the dynamics of disease transmission within such places and the effective mitigation measures that can be implemented at low cost. This is the objective of a mathematical model developed by teams from Inserm and Sorbonne Université at the Pierre Louis Institute of Epidemiology and Public Health with the Spanish Institute CSIC-IFISC. Taking the example of London Heathrow airport and diseases such as H1N1 influenza and COVID-19, this model makes it possible to identify zones with the highest risk of transmission within crowded places. By targeting these hotspots with measures such as air filters or the use of Far-UVC lights[1], the scientists also show that it is possible to significantly reduce contamination. Their full findings have been published in Nature Communications.

Crowds and gatherings, with their prolonged contacts between individuals, are a crucial factor in the spread of infectious diseases. While it is possible to implement certain risk reduction measures such as the wearing of masks, the maintenance of social distancing cannot always be respected, especially in transportation hubs such as airports and train stations. After all, these locations are designed to optimize logistical efficiency rather than reduce crowding. They are characterized by a constant in and outflow of visitors, with a high risk of international disease transmission.

The study by the scientists from Inserm, Sorbonne Université and CSIC-IFISC describes a mathematical model that identifies, within these places, the hotspots for the transmission of infectious diseases. It is essential to know exactly where these hotspots are in order to implement appropriate “spatial immunization” strategies, i.e. specific prevention measures that target these zones and reduce contamination.

“In the hotspots that we have identified with our model, the development of dedicated approaches such as air filtration, systematic surface disinfection, and the use of Far-UVC lights can significantly reduce the risk of pathogen spread beyond the first cases arriving at an airport or train station without having been detected,” explains Mattia Mazzoli, Inserm researcher and first author of the study.


A Model Built From GPS Data

In this article, the scientists studied the example of Europe’s busiest airport: London Heathrow. Their model uses anonymized data concerning the movements of over 200 000 people within the airport, derived from the GPS tracking of cell phones between February and August 2017. Using this data, the researchers were able to visualize movements with a spatial resolution of 10 meters, reconstruct the contact networks between these different people, and thereby detect the zones where contacts were the most intense, with a higher risk of contamination.

In order to provide some practical examples, the scientists fed their mathematical model with data concerning the spread of diseases such as H1N1 influenza and COVID-19 in order to study their dissemination throughout the airport.


A Model That Can Be Applied to the Future

The results of this modeling show that the communal areas such as bars and restaurants are where the highest number of infections occur, as these are where travelers and airport staff are brought into contact for long periods of time.

“The danger of these contagion hotspots is driven by a balance between the number of people that use them and the time they spend there. While these are not always the busiest places in the airport, they do involve more sustained contacts for longer periods of time, enabling the spread of diseases,” emphasizes Mazzoli.

Although the model has only been tested with H1N1 influenza and COVID-19, it could still be used in the future to study any new and as yet uncharacterized pathogen. In addition, the method is immediately generalizable to other modes of transport such as trains, subways, bus stations or other crowded facilities where social distancing is impossible, such as malls and convention centers.

“Using spatial immunization measures reduces the number of infections among airport users and, to a lesser extent, among airport staff. When well-targeted and implemented in zones identified as presenting the highest risk, these measures are helpful in containing and/or delaying the spread of infectious agents to the rest of the world via airports or other crowded centers. Our model could be particularly useful in the early stages of a potential future epidemic, when the first cases imported into airports and train stations have not yet been detected,” concludes Mazzoli.

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.