Phage Therapy: A Model to Predict Its Efficacy against Pathogenic Bacteria

Photo (colorized) of scanning electron microscopy of a bacterium lyzed by the phages (© L. Debarbieux, Institut Pasteur; M. and C. Rohde, Helmholtz Centre for Infection Research).

Antibiotic resistance represents a major public health challenge, associated with a high mortality rate. While bacteriophages – viruses that kill bacteria – could be a solution for fighting antibiotic-resistant pathogens, various obstacles stand in the way of their clinical development. To overcome them, researchers from Inserm, Université Sorbonne Paris Nord and Université Paris-Cité at the IAME Laboratory, in close collaboration with their counterparts at Institut Pasteur and the Paris Public Hospitals Group (AP-HP), have developed a model to better predict the efficacy of phage therapy and possibly develop more robust clinical trials. Their findings have been published in Cell Reports.

The discovery of antibiotics had revolutionized the history of medicine in the 20th century, allowing us to effectively fight bacteria for the first time. However, antibiotic resistance – a phenomenon during which bacteria become resistant following mass, repeated use – has become a major public health issue in recent decades. Each year, these resistant bacteria are estimated to be responsible for 700,000 deaths worldwide. Yet the discovery of new antibacterial agents has been stagnating for several years.

In this context, phage therapy has recently generated renewed interest. This therapeutic approach involves the use of bacteriophages that target and destroy pathogenic bacteria whilst being unable to infect humans. While the concept has been in existence for a long time, its clinical development has been hampered by various limitations. Unlike “conventional” medicines, bacteriophages are complex biologics, whose action in the body, optimal dose, and most effective route of administration are difficult to study and anticipate.

In order to remove some of these obstacles, Jérémie Guedj’s research team at Inserm, in collaboration with Laurent Debarbieux’s team at Institut Pasteur, has developed a new mathematical model to better define the interactions between bacteriophages and pathogenic Escherichia coli bacteria in animals and to identify the key parameters that influence the efficacy of phage therapy.

Supporting clinical development

Various data from in vitro and in vivo experiments were used to construct this model. In particular, the researchers used the bacteriophages’ infection parameters determined in the laboratory (for example, the duration of the infectious cycle of the bacteria, the number of viruses released when a bacterium is destroyed…) and information collected during experiments using a mouse model of lung infection.

Some of the animals were infected with a bioluminescent strain of E. Coli (in order to best monitor it within the body). Among them, some were treated with bacteriophages at different doses and using different routes of administration. The quantities of bacteria and bacteriophages thus measured over time helped to feed the mathematical model and test which were the most important parameters for effective phage therapy. 

Using their model, the scientists show that the route of administration is an important parameter to consider when it comes to improving the animals’ survival: the more rapidly it brings the bacteriophages into contact with the bacteria, the more it is effective. In the animal model, the phage therapy administered intravenously was therefore less effective in comparison with the intratracheal route because fewer bacteriophages were reaching the lungs. On the other hand, when administered by intratracheal route, the model suggests that the dose of the medication given has little effect on the efficacy of the therapy.

Another important point is that this model incorporates data on the animals’ immune response in the context of phage therapy. The model confirms and extends the principle that bacteriophages act in synergy with the immune system of infected animals, enabling more effective elimination of pathogenic bacteria.

“In this study, we propose a new approach to streamline the clinical development of phage therapy, which otherwise continues to have its limitations. Our model could be reused to predict the efficacy of any bacteriophage against the bacteria it targets, once a limited number of in vitro and in vivo data are available on its action. Beyond phage therapy, the model could also be used to test anti-infective therapies based on the association between bacteriophages and antibiotics,” concludes Guedj.

Influenza: A New Avenue for Developing Innovative Treatments

Cellules épithéliales respiratoires humaines

Human respiratory epithelial cells (in red) infected with an influenza virus (in green). © A. Cezard, D. Diakite, A. Guillon, M. Si-Tahar, PST ASB-Microscopy Department.

Seasonal influenza is a major public health issue because it continues to remain associated with considerable mortality, particularly among people who are elderly, immunocompromised, or both. It also has a significant socioeconomic cost. With vaccination and current treatments still being of limited efficacy, research teams are trying to develop new therapeutic approaches. At the Research Center for Respiratory Diseases in Tours, scientists from Inserm, Université de Tours and Tours Regional University Hospital have shown that in a context of influenza infection, a metabolite[1] called succinate, which is naturally present in the body, has an antiviral and anti-inflammatory action. These findings open up new therapeutic prospects based on the use of succinate derivatives. The study has been published in EMBO Journal.

Often considered a mild disease, influenza continues to cause the deaths of 10,000 to 15,000 people each year in France. The socioeconomic cost of the disease is also significant because it is associated with high levels of absenteeism and a major burden on hospitals.

Seasonal influenza vaccination is a central pillar of the preventive strategies deployed to reduce the number of cases and fight the disease. However, its efficacy can vary from year to year, depending on the influenza viruses in circulation and the suitability of the vaccine to them. Drugs that directly target the influenza virus are available for severe cases, but the window of time for effective action with these treatments is very short. What is more, influenza viruses have become resistant to their action.

In this context, the development of innovative therapies is a priority. While current treatments work by targeting certain components of the virus, Inserm Research Director Mustapha Si-Tahar and his colleagues at the Research Center for Respiratory Diseases are trying to better understand the host’s cellular and molecular responses to viral infection, with the long-term aim of developing novel therapeutic strategies aimed at strengthening these responses.

The role of metabolites in immune response

While metabolism1 has long been considered to be a purely energetic mechanism essential for cell function, recent research has shown that some metabolites can also regulate the immune response.

Based on these data, Si-Tahar’s team wondered whether an influenza infection could cause the reprogramming of the metabolism of the target cells of the virus and whether specific metabolites play an especially active role in the immune response.

In mice infected with influenza, the researchers observed that a metabolite called succinate accumulates in the lungs. A phenomenon which was then confirmed in humans by comparing respiratory fluids from intensive care patients with and without influenza pneumonia. The presence of succinate was found to be significantly higher in the influenza patients.

They then exposed cells from the pulmonary epithelium to succinate, thereby demonstrating that the molecule has antiviral activity by blocking multiplication of the virus. Succinate also helps to reduce the strong inflammatory response that is triggered in the lungs following infection with influenza.

The researchers also found that mice exposed to the virus receiving intranasal succinate are better protected against infection and have a higher survival rate than those that do not receive it.

In search of molecular mechanisms

In order to better understand these different phenomena, the scientists sought to decipher the molecular mechanisms behind the antiviral action of succinate.

This involved analyzing the impact of succinate on the various stages of the viral replication cycle and demonstrating that, while there is no influence on the early stages of the cycle (entry, transcription, and translation), there is an influence on a later stage. The findings show that this metabolite prevents a major structural protein of the virus, the “nucleoprotein”, from exiting the nucleus of infected cells, thereby preventing the assembly of the final viral particle and interrupting the multiplication cycle of the virus.

These data all point to the key role of succinate in controlling influenza infection, as well as its therapeutic value.

“Our research has an interesting outlook in that it potentially paves the way for the development of new antiviral treatments derived from succinate,” underlines Si Tahar[2].

Additional studies are needed in order to test the therapeutic potential of succinate and identify other metabolites of interest.


[1] Metabolism refers to all of the chemical reactions that take place inside the body’s cells. A metabolite is an organic substance derived from metabolism.

[2] In keeping with this research, Si-Tahar has since early 2021 coordinated a French National Research Agency (ANR) program entitled “Development of succinate-based formulations and analogues against SARS-CoV-2-induced respiratory infections and influenza viruses.” His team is also the beneficiary of an “ERS-RESPIRE4 Marie Skłodowska-Curie fellowship” to develop a project entitled “Succinate-Producing Probiotics as an Innovative Therapy for Viral Respiratory Infections: a proof-of-concept study”.

HIV: The Antibodies of “Post-treatment Controllers”


© Adobe Stock

A very small percentage of people with HIV-1, known as “post-treatment controllers” (PTCs), are able to control their infection after interrupting all antiretroviral therapy. Understanding the fundamental mechanisms that govern their immune response is essential in order to develop HIV-1 vaccines, novel therapeutic strategies to achieve remission, or both. A recent study investigated the humoral immune response – also known as antibody-mediated immunity – in some PTCs in whom transient episodes of viral activity were observed. The researchers have shown their humoral immune response to be both effective and robust, which could help to control the infection in the absence of treatment. The findings of this study, carried out in collaboration with teams from Institut Pasteur, Inserm and Paris Public Hospitals Group (AP-HP) and supported by ANRS | Emerging Infectious Diseases and the National Institutes of Health (NIH), were published in Nature Communications on April 11, 2022.

A very small percentage of people with HIV-1 and who received early treatment maintained over several years have the capacity to control the virus over the long-term when their treatment is interrupted. However, the mechanisms of this control have not been fully elucidated.  

The team of researchers, led by Dr. Hugo Mouquet, director of the Laboratory of Humoral Immunology at Institut Pasteur (partner research organization of Université Paris Cité), conducted an exhaustive study in PTCs in order to characterize their humoral response (i.e. their production of B cells and specific antibodies), compared with non-controllers.

The scientists have shown that the humoral immune response profiles vary according to the activity of the virus observed in the subjects.

In PTCs who experience short episodes in which the virus resumes low-level activity after interruption of treatment, transient exposure to the viral antigens induces:

  • a strong anti-HIV-1 humoral response, involving more frequent intervention of HIV-1 envelope-specific memory B cells;
  • the production of antibodies with a cross-neutralizing action and which possess “effector” antiviral activities in which the innate immune cells recognize the infected cells bound to the antibodies, thereby inducing their elimination;
  • the increase in the blood of atypical memory B cells and subpopulations of activated helper T cells.

This specific, multifunctional, and robust humoral response could help to control their infection in the absence of treatment.

However, other PTCs in whom the virus continuously remains undetectable after treatment interruption do not develop a strong humoral response. The control mechanisms in these patients continue to be investigated in the VISCONTI study.

The discovery of these two types of humoral immune response, which depend on the profile of the PTCs, sheds new light on the phenomenon of HIV control. For Dr. Mouquet, researcher at Institut Pasteur and principal investigator of the study, “these findings show that early antiretroviral treatment can facilitate the optimal development of humoral immune responses, in some cases countering viral rebound after treatment interruption.” The example of the immune response of the PTCs having short episodes of “awakening” of the virus could even inspire novel therapeutic or vaccine strategies.

ANRS VISCONTI: to improve understanding of the HIV control mechanisms in “post-treatment controllers”

The “post-treatment controllers” whose samples were used for this research are part of the VISCONTI (Viro-Immunological Sustained COntrol after Treatment Interruption) study, coordinated by Dr. Asier Sáez-Cirión (Institut Pasteur) and Dr. Laurent Hocqueloux (Orleans Regional Hospital) and supported by ANRS for several years. This is the largest cohort of long-term “post-treatment controllers”.

It includes 30 patients who had received early treatment that was maintained for several years. Upon interruption of their antiretroviral therapy, they are able to control their viremia for a period exceeding 20 years in some cases. VISCONTI therefore provides the proof of concept of a possible and sustained state of remission for HIV-1-infected patients. It has paved the way for the development of novel therapies that target remission from the infection – if not its eradication. The objective is to enable people living with HIV-1 to stop their antiretroviral treatment on a lasting basis, while maintaining viremia at the lowest level and avoiding the risk of transmission of the virus.

Discovery of an immune escape mechanism promoting Listeria infection of the central nervous system

 vaisseau cérébral

Section of a cerebral vessel in an infected animal model containing infected monocytes adhering to endothelial cells. Listeria is marked in red, actin in white (including the actin tails propelling Listeria), nuclei in blue and macrophages in green. © Biology of Infection Unit – Institut Pasteur

Some “hypervirulent” strains of Listeria monocytogenes have a greater capacity to infect the central nervous system. Scientists from the Institut Pasteur, Université Paris Cité, Inserm and the Paris Public Hospital Network (AP-HP) have discovered a mechanism that enables cells infected with Listeria monocytogenes to escape immune responses. This mechanism provides infected cells circulating in the blood with a higher probability of adhering to and infecting cells of cerebral vessels, thereby enabling bacteria to cross the blood-brain barrier and infect the brain. The study will be published in Nature on March 16, 2022.

The central nervous system is separated from the bloodstream by a physiological barrier known as the blood-brain barrier, which is very tight. But some pathogens manage to cross it and are therefore able to infect the central nervous system, using mechanisms that are not yet well understood.

Listeria monocytogenes is the bacterium responsible for human listeriosis, a severe foodborne illness that can lead to a central nervous system infection known as neurolisteriosis. This central nervous system infection is particularly serious, proving fatal in 30% of cases.

Scientists from the Biology of Infection Unit at the Institut Pasteur (Université Paris Cité, Inserm) and the Listeria National Reference Center and WHO Collaborating Center led by Marc Lecuit (Université Paris Cité and Necker-Enfants Malades Hospital (AP-HP)) recently discovered the mechanism by which Listeria monocytogenes infects the central nervous system. They developed a clinically relevant experimental model that reproduces the different stages of human listeriosis, and involves virulent strains of Listeria[1] isolated from patients with neurolisteriosis.

The scientists first observed that inflammatory monocytes, a type of white blood cell, are infected by the bacteria. These infected monocytes circulate in the bloodstream and adhere to the cerebral vessels’ cells, allowing Listeria to infect the brain tissue.

The research team then demonstrated that InIB, a Listeria monocytogenes surface protein, enables the bacteria to evade the immune system and survive in the protective niche provided by the infected monocytes. The interaction between InlB and its cellular receptor c-Met blocks the cell death mediated by cytotoxic T lymphocytes, which specifically target Listeria-infected cells. InIB therefore enables infected cells to survive cytotoxic T lymphocytes.

This mechanism extends the life span of infected cells, raising the number of infected monocytes in the blood and facilitating bacterial spread to host tissues, including the brain. It also favors the persistence of Listeria in the gut tissue, its fecal excretion and transmission back to the environment.

“We discovered a specific, unexpected mechanism by which a pathogen increases the life span of the cells it infects by specifically blocking an immune system function that is crucial for controlling infection,” explains Marc Lecuit (Université Paris Cité and Necker-Enfants Malades Hospital (AP-HP)), head of the Biology of Infection Unit at the Institut Pasteur (Université Paris Cité, Inserm).

It is possible that other intracellular pathogens such as Toxoplasma gondii and Mycobacterium tuberculosis use similar mechanisms to infect the brain. Identifying and understanding the immune escape mechanisms of infected cells could give rise to new therapeutic strategies to prevent infection and also pave the way for new immunosuppressive approaches for organ transplantation.

This research was funded by the Institut Pasteur, Inserm and the European Research Council (ERC) and also received funding from the Le Roch-Les Mousquetaires Foundation.

[1] Uncovering Listeria monocytogenes hypervirulence by harnessing its biodiversity, Nature Genetics, February 1, 2016
Press release:

MICA: A New Immune Response Gene That Predicts Kidney Transplant Failure

Histological image of a kidney transplant rejection mediated by antibodies. Sophie Caillard/Jérome Olagne (Inserm U1109).

Although a kidney transplant is the only curative treatment for end-stage kidney disease, the risk of the patient’s body rejecting the graft means that success is not guaranteed. To reduce this risk, physicians are now able to look at a certain number of genetic and immunological parameters in order to evaluate the histocompatibility between donor and recipient – i.e. how compatible their organs and tissues are. Nevertheless, rejections continue to remain common, and many are unexplained. In a new study, researchers from Inserm, Université de Strasbourg and Strasbourg University Hospitals at Unit 1109 “Molecular Immunology and Rheumatology”, and their partners from the Laboratory of Excellence (LabEx) Transplantex, report that the MICA gene is a new histocompatibility gene, in that it helps to better explain and predict the success or failure of a kidney transplant. Their findings have been published in Nature Medicine.

Kidney transplant is currently the best way to treat patients with end-stage kidney disease. In France, an average of around 4,000 kidney transplants are performed each year (around 20,000 in the US). The kidneys mainly come from deceased donors, although the number of kidneys from living donors has been gradually increasing each year over the last two decades.

The possibility of rejection of the graft considered “foreign” by the recipient’s body is currently the main limitation of this procedure. While the use of immunosuppressant drugs[1] helps to reduce the risk, it does not eliminate it completely. “Chronic” rejection, which occurs over the years following the transplant, remains a major problem.

The discovery of the HLA system in the mid-20th century by French researcher Jean Dausset and his colleagues has enabled major advances. It is a set of proteins coded by the HLA genes – proteins which are present on the surface of our cells, particularly white blood cells.

Highly diverse and specific to each individual, this system makes it possible to assess the histocompatibility between donors and recipients – i.e. how compatible their organs and tissues are. The closer the HLA genes between donors and recipients, the lower the risk of rejection.

However, even when donor and recipient HLA genes are compatible, unexplained transplant rejections still occur. This phenomenon suggests that other as yet unidentified histocompatibility genes may play a role.

A role for the MICA gene

Researchers from Inserm, Université de Strasbourg and Strasbourg University Hospitals and their partners from LabEx Transplantex were therefore interested in a gene discovered almost thirty years ago by Seiamak Bahram[2] who coordinated this new research.

This gene, called MICA, codes for a protein expressed on several cell types. Previous studies had already suggested that this gene was important in predicting the outcome of a transplant, but the numbers of patients studied were insufficient (among other methodological limitations) in asserting that it was a histocompatibility gene. Furthermore, these studies did not focus on the entire MICA system, that is to say on both genetics (histocompatibility) and the serological aspects (presence of anti-MICA antibodies in the recipient’s blood).

In this latest study, the team studied MICA in over 1,500 kidney transplant recipients and their donors. Analyses of the MICA gene sequences show that when recipients and donors have a different version of the gene, the survival of the graft is reduced.

Furthermore, the researchers show that these MICA gene incompatibilities are responsible for the synthesis of antibodies directed against the donor’s MICA proteins, which are involved in transplant rejection. These antibodies are produced when the donor’s MICA proteins differ excessively from those of the recipient.

These findings suggest that MICA is a relevant histocompatibility gene to consider when envisaging a transplant, and that testing for anti-MICA antibodies may also be useful in predicting the success or failure of the graft. They must now be validated in large-scale prospective studies in which MICA will be considered in the same way as classic HLA genes.

Following this research, we can now consider the inclusion in routine clinical practice of MICA gene sequencing and the identification of anti-MICA antibodies in patients prior to transplantation to assess histocompatibility with the donor and post-transplant to improve the prevention of rejection. Finally, we also envisage studying the role of MICA in the transplantation of other solid organs, such as the heart, lung and liver,” emphasizes Seiamak Bahram.


[1] Treatments that limit the action of the immune system used in autoimmune diseases and transplants.

[2] University Professor-Hospital Practitioner, Director of Inserm Unit 1109 and LabEx Transplantex, and Head of the Department of Clinical Immunology Laboratory at Strasbourg University Hospitals.

Discovery of an innate immunological memory in the intestine

ILC3 intestinales

Intestinal ILC3s. Immunofluorescence staining of ILC3s (green) in the intestine (nuclei in blue and actin in red). © Nicolas Serafini – Institut Pasteur / Inserm

The innate immune system plays a crucial role in regulating host-microbe interactions, and especially in providing protection against pathogens that invade the mucosa. Using an intestinal infection model, scientists from the Institut Pasteur and Inserm discovered that innate effector cells – group 3 innate lymphoid cells – act not only during the early stages of infection but can also be trained to develop an innate form of immunological memory that can protect the host during reinfection. The study was published in the journal Science on February 25, 2022.

Combating Escherichia coli infections, which are responsible for intestinal diseases or gastrointestinal bleeding, is a major public health challenge. These bacteria, which are present in drinking water or food, can cause persistent diarrhea associated with acute intestinal inflammation. Consequently, enteropathogenic and enterohemorrhagic Escherichia coli are responsible for nearly 9% of child deaths worldwide.

The gut mucosa harbors a complex defense system that allows it to combat pathogen infection while maintaining tolerance to commensal microbiota, which are essential for the normal bodily function. This constant surveillance is performed by the innate immune system, which provides early defense in the initial hours after infection.

The adaptive immune system then develops a memory for the pathogens that it encounters by activating specific receptors expressed at the surface of B and T lymphocytes, thereby enabling the production of protective antibodies and inflammatory cytokines. Unlike the clearly established function of the adaptive system in long-term tolerance and protection, the role of the innate system in immune memory remains to be determined.

In 2008,[1] the team led by Inserm scientist James Di Santo (Innate Immunity Unit, Institut Pasteur/Inserm) described group 3 innate lymphoid cells (ILC3s) as a novel family of lymphocytes that were distinct from adaptive T and B lymphocytes. ILC3s play an essential role in the innate immune response, especially in the gut mucosa, by producing pro-inflammatory cytokines, such as interleukin (IL)-22.

The cytokine release activates the production of antimicrobial peptides by epithelial cells, thereby reducing the bacterial load in order to maintain the integrity of the intestinal barrier.

In this study, scientists from the Innate Immunity Unit (Institut Pasteur/Inserm) used an innovative protocol to expose the immune system to a time-restricted enterobacterial challenge based on Citrobacter rodentium (a mouse model of E. coli infection). They observed that ILC3s persist for several months in an activated state after exposure to C. rodentium.

During a second infection, the “trained” ILC3s have a superior capacity to control infection through an enhanced proliferation and massive production of IL-22.

Our research demonstrates that intestinal ILC3s acquire a memory to strengthen gut mucosal defenses against repeated infections over time,” explains Nicolas Serafini, first author of the study and an Inserm scientist in the Innate Immunity Unit (Institut Pasteur/Inserm).

The ability to “train” the innate immune system in the mucosa paves the way for improvements to the body’s defenses against a variety of pathogens that cause human diseases,” comments James Di Santo, last author of the study and Head of the Innate Immunity Unit (Institut Pasteur/Inserm).

This discovery demonstrates a new antibacterial immune defense mechanism and could lead, in the long term, to novel therapeutic approaches to treat intestinal diseases (IBD or cancer).


[1] Satoh-Takayama N. et al. Immunity 2008

A Novel Immunotherapy Approach Redirects Epstein-Barr Antibodies toward Disease-Causing Cells

Microscopic visualization of a cancerous cell (nucleus in blue) treated with bi-modular fusion proteins (BMFPs) to which EBV antibodies (green) bind. © Jean-Philippe Semblat and Arnaud Chêne – JRU1134 (Inserm/Université de Paris)


Monoclonal antibody therapy can be very effective in treating numerous illnesses, such as cancers, chronic inflammatory conditions, and infectious diseases. However, it is costly and uses molecules that are complicated to produce. Therefore, it is essential to identify new therapeutic alternatives so that as many patients as possible get the treatments they need. That is why researchers from Inserm, Université de Paris, Sorbonne Université and CNRS1 have designed and tested a new immunotherapy approach that uses pre-existing antibodies directed against the Epstein-Barr virus – part of the herpes family of viruses and present in over 95% of the world’s population – in order to target and destroy pathogenic (disease-causing) cells. Their findings have recently been published in a study in Science Advances.

The principle is to redirect a pre-existing immune response against the Epstein-Barr virus (EBV) to target cells that we wish to destroy. The Epstein-Barr virus – which belongs to the family of herpes viruses – is transmitted predominantly through saliva, and over 95% of the world’s population is infected with it.

The vast majority of people have no symptoms, and the virus has the ability to persist chronically in infected individuals under the effective control of the immune system. As a result, EBV antibodies circulate in these people throughout their lives.

Developing a therapeutic tool based on the recruitment of these pre-existing EBV antibodies is of major interest in redirecting this immune response against target cells that are predefined according to the disease in question. This immunotherapy may be applicable in a very large number of patients due to the presence of EBV antibodies in almost everyone.

A promising new system

The researchers have developed specific proteins called bi-modular fusion proteins (BMFPs). These possess a domain that will bind specifically to an antigen expressed on the surface of the target cell to be destroyed. This domain is also fused to the Epstein-Barr virus EBV-P18 antigen against which IgG2 antibodies are already present in the patient. The recruitment of these antibodies on the surface of the target cells treated with BMFPs will then activate the body’s immune defenses, leading to the destruction of the target cells.

The researchers first tested this system in vitro using several target cells and showed that it effectively triggers different immune system mechanisms capable of eliminating target cells.

The BMFPs were then engineered to target an antigen expressed on the surface of tumor cells and were tested in an animal model of cancer. The results are promising because the treatment led to a significant increase in survival as well as the complete remission of cancer in some animals.

“These results position BMFPs as novel therapeutic molecules that may be useful in the treatment of multiple diseases. It is a highly versatile system, since it is easy to change the binding module and as such the antigen targeted in order to adapt the treatment to many diseases, in oncology, infectious diseases, and also autoimmune conditions,” explains Arnaud Chêne, Inserm Research Officer and last author of the study.

“BMFPs are much easier and faster to produce than whole monoclonal antibodies and do not require the use of sophisticated engineering to optimize their functions, thereby reducing costs and opening up access to a broader spectrum of patients,” adds Jean-Luc Teillaud, Emeritus Research Director at Inserm.

“Pending clinical trials in a variety of diseases ranging from cancer to malaria, the technology has already led to the filing of two patents.” explains Benoît Gamain, Research Director at CNRS.


1 Two laboratories took part in this research: Integrated Red Blood Cell Biology (U1134 Inserm/Université de Paris) and Center for Immunology and Microbial Infection (U1135 Inserm/Sorbonne Université/CNRS).

2 IgGs represent the main type of antibody found in the blood and are involved in the secondary immune response

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. 

The Utility of a Two-Dose Ebola Vaccine Regimen Confirmed

vacnni anti Ebola

© Adobe Stock


In response to the 2014-2016 Ebola epidemic, the clinical development of a two-dose regimen of vaccines Ad26.ZEBOV and MVA-BN-Filo was accelerated. Approved in 2020 by the European Commission for use in epidemic emergencies, this regimen continues to demonstrate its relevance. An Inserm study led by Rodolphe Thiébaut (Inserm, INRIA, Université de Bordeaux, Vaccine Research Institute) has played a role in evaluating its safety and immunogenicity in healthy adults and in those with HIV and compared different time intervals between the two doses. It has confirmed that this regimen is well tolerated, that the antibodies acquired persist for at least one year, and that they can be easily reactivated by a booster shot. The findings of this trial have been published in Plos Medicine.

Since its discovery in 1976, Ebola has been found in several countries in Equatorial Africa with increasingly frequent epidemics (more than 30 to date). Infection with the virus begins in the form of flu-like illness but is often complicated by life-threatening organ failure and hemorrhage. During the largest epidemic in West Africa between 2014 and 2016, a total of 28,616 cases were identified leading to 11,310 deaths. During this epidemic, an initial single-dose vaccine was approved and used in the field (Ervebo). At the same time, pharma company Janssen launched the accelerated development of a different vaccine regimen1. This involves the administration of two different vaccines: the first being Janssen’s Ad26.ZEBOV, composed of an adenoviral vector containing the envelope protein of the Ebola Zaire virus that triggers antibody production, and the second being Bavarian Nordic’s MVA-BN-Filo, which uses a different viral vector and contains four different antigens of the Ebola virus family, including the Ebola Zaire virus glycoprotein.

Using the viral vector makes it possible for the Ebola virus antigen (the glycoprotein) to penetrate the immune cells in the manner of a Trojan horse, triggering the immune response. With this dual-administration strategy, we assumed that the immune response would last longer than with a single-dose vaccine,” explains Rodolphe Thiébaut, Inserm team leader and Professor of Public Health at Université de Bordeaux, which is participating in this EBOVAC accelerated development program.

This hypothesis has recently been validated by the publication of the findings of a Phase II clinical trial (EBOVAC 2) intended to assess the safety and immunogenicity of this regimen in healthy people and in those with HIV living in Africa. In the meantime, it was approved in July 2020 by the European Medicines Agency in adults and children over one year of age, based on data already available.

Nevertheless, this regimen continues to be developed in different populations (adults, children, pregnant women, caregivers), in different parts of the world (to confirm the robust immune response and tolerability profile) and with different follow-up durations, to confirm the preliminary data and evaluate its utility in prevention in populations potentially exposed to the virus – particularly rural populations in Equatorial African countries. The aim being to prevent the occurrence of a new epidemic. “While the epidemics are generated by the virus passing from bats to humans, their progression is facilitated by mobility that is increasing thanks to the advances in infrastructure,” warns Rodolphe Thiébaut, and “having vaccines tested in Africa with the collaboration of research teams from African countries to protect populations is a major development challenge for our countries with their limited means and limited hospital resources,” adds Houreratou Barry, investigator responsible for the trial at the Muraz Center in Bobo-Dioulasso, Burkina Faso.

This Phase II trial is moving in that direction. It enrolled 668 healthy adults between the ages of 18 and 70 and 142 adults between the ages of 18 and 50 with HIV (a common condition in African populations liable to influence immune response to the vaccine) whose viral load was controlled by antiviral therapy. Participants were recruited in Kenya, Burkina Faso, Côte d’Ivoire, and Uganda. They received the vaccine or a placebo solution according to the following regimen: one dose of Ad26.ZEBOV or placebo, followed 28, 56, or 84 days later by MVA-BN-Filo or placebo. In the group of healthy subjects, 90 people also received an additional booster dose of Ad26.ZEBOV one year later.

The researchers analyzed adverse event reports over the follow-up year as well as changes in the levels of antibodies to the Ebola virus glycoprotein. No vaccine-related serious adverse events were observed, only mild to moderate events common with vaccination, such as pain at the injection site, fatigue, headache, and muscle pain.

The increase in the interval between the vaccinations from 28 to 56 days improved the immune response and the antibodies persisted for at least one year in both the healthy subjects and in those with HIV. These antibodies were found in 78 to 88% of the participants. Extending the interval to 84 days provided no additional benefit (and would only extend the vaccination schedule unnecessarily), which confirmed the 56-day interval as optimal for this vaccine regimen.

In addition, the booster one year later sufficiently stimulated the production of antibodies with levels multiplied by 55, indicating that the first vaccination triggered an easily reactivable memory immune response, “which is very important in the context of the recurring epidemics observed in Africa,” concludes Thiébaut.


1 Supported by the IMI EBOLA+ program (a joint initiative of the European Commission and the European Federation of Pharmaceutical Industries and Associations [EFPIA]) within the framework of a consortium with the academic teams from Inserm, the London School of Hygiene and Tropical Medicine, the University of Oxford, and the Muraz Center in Burkina Faso.  This project was funded by the joint Innovative Medicines Initiative 2 ( under EBOVAC2 grant agreement no. 115861. This joint initiative is supported by the European Union and EFPIA’s Horizon 2020 research and innovation program.

Towards the elimination of cholera in Haiti

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Favored by poor access to clean water, sanitation, and hygiene, disease transmission has persisted in epidemic waves © Unsplash

In 2013, a medical team from the AP-HP, Sorbonne University, Inserm, the European Hospital of Marseille, the IRD, Aix-Marseille University (SESSTIM) and the AP- HM proposed to the Haitian government and to Unicef ​​a coordinated strategy to fight against cholera, aimed at breaking the chains of transmission. 

This strategy and its results, which show the apparent cessation of cholera transmission in Haiti since 2019, have just been the subject of a publication in the journal Emerging Infectious Diseases.

Unfortunately imported into Haiti in 2010 during a movement of troops from Asia, cholera caused in this Caribbean country one of the most violent epidemics of recent decades. Favored by poor access to safe drinking water, sanitation and hygiene, the transmission of the disease has persisted in epidemic waves to such an extent that the elimination of cholera in the country has been considered impossible by many. .

In 2013, a medical team from the AP-HP, Sorbonne University, Inserm, the European Hospital of Marseille, the IRD, Aix-Marseille University (SESSTIM) and the AP- HM proposed to the Haitian government and to Unicef ​​a coordinated strategy to fight against cholera, aimed at breaking the chains of transmission.

Mobile rapid response teams have thus carried out more than 50,000 interventions throughout the country in order to raise awareness, distribute water and hygiene treatment kits, and often “minute” antibiotic prophylaxis to contact subjects of patients received in the hospital. health centers.

In collaboration with the Haitian Ministry of Health, this medical team has just shown, in an article entitled ”  Towards cholera elimination in Haiti  ” that there is no longer the slightest sign of activity of the epidemic since February 2019 despite intense microbiological research.

These dramatic results suggest that case area targeted interventions led by rapid response teams have played a key role. They also question the theory that the bacteria responsible for the disease would persist in the country’s aquatic environments, preventing its elimination.