The mechanism of an AIDS vaccine candidate filmed in vivo

Using innovative technology, scientists from the Institut Pasteur and Inserm have filmed in vivo the process by which an AIDS vaccine candidate, developed by the French Vaccine Research Institute and the ANRS, triggers the immune response. This previously unseen footage clearly shows how the vaccine recruits the immune cells needed to destroy infected cells. These results, published in the journal Nature Medicine on December 21, 2015, shed new light on the mode of action and potential of this vaccine.


The aim of the study conducted by scientists from the Dynamics of Immune Responses Unit (Institut Pasteur / Inserm / VRI), directed by Inserm research director Philippe Bousso, was to observe the effect of the HIV/AIDS vaccine candidate MVA-HIV – currently undergoing clinical trials by the French Vaccine Research Institute (VRI) and the ANRS – on the immune response.

The scientists administered the vaccine to healthy mice, then observed in real time how cells from the immune system were mobilized to the lymph node, the organ where the vaccine response is developed, in just a few hours.

For the first time, using a powerful, non-invasive microscopic imaging technique, the scientists were able to watch in vivo and in real time as the vaccine induced the formation of the inflammasome, a complex assembly of proteins with a highly specific structure which appears in macrophages, the first immune cells targeted by the vaccine.

The inflammasome promotes the maturation of the chemical messenger interleukin (IL)-1 but also induces macrophage death, thereby releasing this inflammatory messenger in the lymph node. This signal triggers a chain reaction which assembles several key players of the immune system in the lymph node, including killer cells, which are vital for the vaccine response.

These in vivo films have given the scientists a detailed picture of the main stages in the mechanistic action of this vaccine and highlighted an important pathway that orchestrates the effective mobilization of the immune response.

This is the first time that the formation of this original structure, the inflammasome, has been observed in vivo and in real time,” commented Philippe Bousso. “Our research demonstrates the potential of the vaccine candidate MVA-HIV to trigger a significant, diverse immune response.”

This research was supported by the French Vaccine Research Institute, the French Foundation for Medical Research and the European Research Council (ERC).

Image/ film: In green, the cells targeted by the MVA-HIV vaccine soon activate the inflammasome (circled green spots) and die. This signal triggers a mass mobilization of immune cells. © Initut Pasteur

Brand new intervertebral discs for back pain

Throughout life, extremely heavy demands are made on the spinal column. Spinal wear very soon affects the quality of life, and back pain is often described as the illness of the century. 40% of back pain may be due to irreversible deterioration of the intervertebral discs (which act as “cushions” between the vertebrae), which can no longer play their role as shock absorbers. Researchers from Inserm led by Jérôme Guicheux (Inserm Unit 791, “Laboratory of Osteoarticular and Dental Tissue Engineering,” Nantes) have successfully transformed adipose stem cells into cells that might be able to replace damaged discs. This work is published in the journal Stem cells.


Our spinal column is made up of a stack of vertebrae. Its articulation and flexibility are made possible by the presence of intervertebral discs that form “cushions” between the vertebrae. Degenerative diseases of the vertebral discs are related to the strong and repetitive demands made on the spinal column throughout life—carrying loads, sports, repetitive movements and twisting motions. With time, the discs become worn and deteriorate, and can no longer play their role as shock absorbers. Although these conditions appear slowly and progressively, they soon manifest as pain in the area where the discs are damaged. It is estimated that degeneration of the intervertebral discs is responsible for approximately 40% of lumbar pain. Current research is therefore aimed at developing treatments to slow or prevent the degeneration of the discs and the cells that constitute them.

From a physiological standpoint, the nucleus pulposus, the central part of the intervertebral disc, is the first to be affected. It is largely made up of water, which gives it its shock-absorbing properties. With age, the cells of the nucleus pulposus gradually become less proliferative, and are then subject to apoptosis and unable to produce this famous highly hydrated extracellular matrix.

How then can they be replaced with functional cells? The researchers focused on the adipose tissue, which constitutes a large reservoir of stem cells that can differentiate into a vast array of cell types. It was also necessary to find the right protocol to successfully enable stem cells from the adipose tissue to become transformed into nucleus pulposus cells.


A finely tuned recipe

The development of this protocol can be compared to a food recipe. The researchers were able to find the right ingredients and correct proportions for it to succeed. The winning strategy involved adding a combination of two growth factors, TGFβ and GDF5, to the cell medium. In 28 days the researchers obtained in vitro, from adipose tissue taken from nine patients, functional nucleus pulposus cells resembling those that exist naturally in the intervertebral discs.

“The protocol proved successful independent of patient age and weight,” says Jérôme Guicheux.

However, we had to go further, since these cells had no chance of survival if they were merely reimplanted into a damaged intervertebral disc, without all the nutrient substrate they need.”

The second trick was therefore to couple these cells to a synthetic biomaterial to recreate a favourable environment for their multiplication once they had been injected into the intervertebral disc. The researchers assessed the biological activity of these cells in vivo after transplanting them into mice. “This system most closely resembles intradiscal transplantation in humans. We have demonstrated that the protocol we apply to these cells was sufficient for them to retain their specific secretory activity and their specialised phenotype when reinjected in vivo.”

This work in regenerative medicine now allows the researchers to contemplate the next step before moving to the clinical setting: testing the therapeutic efficacy of these brand-new cells in a relevant animal model of degenerative vertebral disc disease.

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(c) S Renaudin/le Design de Solène for Inserm

Seasonal epidemic diseases: surveillance continues

The Sentinelles network, developed by Inserm and Pierre and Marie Curie University (UPMC), is a national surveillance system made up of 1,300 general practitioners and about a hundred private paediatricians, which allows the creation of large databases for several diseases, for purposes of health monitoring and research.

The Sentinelles physicians collect information from their patients on 8 health indicators, and submit it via the Internet. Analysis of these data allows estimation of the weekly incidence rate for each indicator, so that changes in these indicators can be monitored on the territory in real time.


According to the Sentinelles network’s weekly bulletin of 16 December, cases of gastroenteritis are up slightly in metropolitan France. 110,500 new cases were seen during visits to general practitioners last week. The incidence rate, estimated at 171 cases per 100,000 inhabitants, is, however, below the epidemic threshold. At regional level, Limousin, Aquitaine and Auvergne observed the highest incidence rates.

Spread of chickenpox remains moderate on the territory, with 22 cases per 100,000 inhabitants, with the most severely affected foci to be found in Picardy, Upper Normandy and Poitou-Charentes. For influenza, the incidence rate is well below the epidemic threshold.


Inserm recruiting about 300 volunteers to test vaccine against the Ebola virus

Although the acute stage of the Ebola epidemic in West Africa is behind us, the need for research to find preventative measures remains urgent. The global community shares the same goal: to prevent future epidemics as catastrophic as the one we have witnessed over the past two years.

To this end, Inserm is coordinating the Ebovac2 project, a collaborative effort, funded under a grant from the Innovative Medicines Initiative Ebola+ programme. The project was launched in response to the Ebola virus disease outbreak, to assess the safety and immunogenicity of a novel ‘prime-boost’ preventative vaccine regimen against Ebola Virus Disease (EVD). In France, clinical research centres specialised in vaccination are now recruiting approximately 300 healthy volunteers from 18 to 65 years old. The project is coordinated by Inserm under the scientific responsibility of Professor Rodolphe Thiébaut (Inserm Unit U897).

People interested in volunteering for the clinical trial can find out more information at

The objectives of the Ebovac2 studies are to further determine the vaccine regimen’s safety profile and how well it stimulates the immune system to protect against Ebola infection.

Two vaccines[1] will be given a few weeks apart. The first dose is intended to stimulate, or ‘prime’, an initial immune response. The second dose then is designed to ‘boost’ the level of the body’s immune response further.

Researchers also want to work out the best timing for each of the vaccine doses. Volunteers will be put on different schedules, where the gap between ‘prime’ and ‘boost’ dose will be 28, 56 or 84 days. This strategy offers the advantage of potentially leading to improved and, especially, longer lasting immunity.

“The volunteers are divided into three groups. Participants in this trial cannot become infected with the Ebola virus. Only synthetic proteins or parts of proteins are used in the various vaccines being tested. They cannot in any way cause infection. This is based on the same principle as many existing vaccines for infectious diseases,” explains Professor Rodolphe Thiébaut, coordinator of the Ebovac2 Project.

How is the vaccine trial for the Ebovac2 project organized?

Commencement of the Ebovac2 Phase 2 trials has been subject to the preliminary results from several ongoing phase 1 trials being carried out in Africa, the United Kingdom, and the United States, which show that the vaccine regimen is well-tolerated.

As part of the Ebovac2 Phase 2 studies, one trial (EBL2001) will be carried out in France and the United Kingdom (Oxford University) with a total of 630 volunteers, about 300 of whom will be in France. A second trial (EBL2002) will be conducted in several countries in Africa with a total of 1188 volunteers expected to be recruited.

Volunteers are expected to participate in the trial for 1 year. Each volunteer will be rigorously monitored, and will be personally followed up by a doctor involved in conducting the study. Volunteers will be visited between 9 and 15 times, and will receive either the vaccine or a placebo. They are entirely free to interrupt their participation at any time and will be reimbursed for their time.

The vaccine trial has received all necessary authorisations guaranteeing the safety of volunteers (approval from the Comité de Protection des Personnes de Ile de France III, an institutional review board, as well as approval from the Agence Nationale de Sécurité du Médicament et des Produits de Santé, or French Agency for the Safety of Health Products).

What criteria must volunteers meet?

  • Be between the ages of 18 and 65
  • Live near one of the centres taking part in the trial: Paris (target enrollment: 75 people), Créteil (94), Lyon (69), Marseille (13), Rennes (35), Saint Etienne (42), or Strasbourg (67)
  • Be in good health
  • Be affiliated with, or be a beneficiary of the French social security system
  • For women, not be pregnant or breast feeding, and to use an effective contraceptive
  • Not participate at the same time in any other biomedical research programme, and not to give blood during the trial period

Setting up a recruitment campaign

In order to optimise chances for success of this clinical trial and recruit the requisite number of volunteers, Inserm uses various communication methods to provide all the necessary information and answer the questions of volunteers.

A website:

A poster campaign

A toll-free number – 0800 156 156 – is operational as of now, and until February 2016. Trained staff welcome volunteers, answer their questions, and orient them towards centres close to where they live.

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The organisers of the clinical trials

As coordinators of the project, Inserm works in conjunction with Crucell Holland, B.V., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, the London School of Hygiene & Tropical Medicine (LSHTM), Oxford University, the Muraz Centre in Burkina Faso, and Inserm Transfert. In December 2014, the Ebovac2 project was funded under a grant from the Innovative Medicines Initiative’s Ebola+ programme which was launched in response to the Ebola virus disease outbreak.  This project has received funding from Innovative Medicines Initiative 2 by the Agreement No. 115861, as well as support from Horizon 2020 research and innovation program of the EU and the European Federation of Pharmaceutical Industries and Associations (EFPIA);

More information is available at

Inserm has been committed to fighting the Ebola virus from the beginning

“Inserm has been focusing on the Ebola virus ever since the alarm was raised by WHO in late 2013”, reaffirms Yves Lévy, Chairman and Chief Executive Officer of Inserm. “Since early 2014, researchers at Inserm (P4 Laboratory in Lyon) and the Institut Pasteur characterised the virus discovered in Guinea and its circulation area in the first months of the epidemic. Inserm has promoted JIKI, the only therapeutic trial evaluating the treatment of people infected with the Ebola virus in Guinea. This began in late 2014, and the results have been encouraging. Inserm is the co-promoter, with the U.S. National Institutes of Health, of this clinical trial (JIKIMAP), which began in Guinea in early July 2015.”

[1]Ad26.ZEBOV developed by Crucell Holland B.V., one of the Janssen Pharmaceutical Companies of Johnson & Johnson and MVA-BN® Filo developed by Bavarian Nordic.

Individual susceptibility to liver toxicity of alcohol depends on the intestinal microbiota

Despite excessive alcohol consumption, some individuals remain in good health while others develop liver disease. This inequality regarding the toxicity of alcohol for the liver depends on the intestinal microbiota. This has just been demonstrated by scientists and physicians from Paris-Sud University, Inserm, AP-HP (Antoine-Béclère Hospital), INRA (French National Institute for Agricultural Research), AgroParitech and Aix-Marseille University. These results are published online in the journal Gut.

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(c) Fotolia

Alcoholic liver disease is a major public health problem. The liver is affected to a variable degree, from a simple accumulation of fat to acute alcoholic hepatitis and cirrhosis. Nonetheless, people do not all react in the same way to the toxic effects of alcohol on the liver. For an equivalent intake of alcohol in terms of quantity and duration, only some excessive drinkers will develop liver disease. This unequal risk from the effects of alcohol toxicity indicates that other factors influence the initiation and progression of liver lesions. The intestinal microbiota is the complement of bacteria present in our digestive system. These bacteria perform many metabolic functions. Scientists and physicians from Paris-Sud University, Inserm, AP-HP (Antoine-Béclère Hospital, one of the Paris Public Hospitals), INRA, AgroParitech and Aix-Marseille University have studied the potential role played by the intestinal microbiota in the unequal toxicity of alcohol for the liver.

The scientists found an imbalance in the intestinal microbiota (dysbiosis) of patients with acute alcoholic hepatitis, which was not found in patients who consumed alcohol but did not have serious liver disease.

In order to ascertain whether this dysbiosis plays a causal role in the occurrence of lesions on the liver, the scientists humanised germ-free mice by transferring the microbiota of alcoholic patients to them. One group of mice received the microbiota of alcoholic patients suffering from acute alcoholic hepatitis, and another group of mice received the microbiota of alcoholic patients without serious liver disease. The mice were then fed alcohol. It was observed that the mice from the first group developed inflammation of the liver and adipose tissue, and a greater increase in intestinal permeability than those from the other group. Moreover, some harmful species of bacteria were specifically associated with sensitivity or insensitivity to alcohol. A study of metabolites showed that ursodeoxycholic acid levels were higher in alcohol-resistant mice.

When this type of experiment was repeated with conventional mice, which have the advantage of more closely mimicking the human disease, the work showed that it was possible to reduce the liver lesions in diseased mice by transferring the microbiota from alcoholic patients without liver lesions to them.

This work thus proves that individual susceptibility to alcoholic liver toxicity depends, at least to a substantial extent, on the intestinal microbiota. Moreover, the composition of the intestinal microbiota can be modified by diet, prebiotics, probiotics or by transfer of faecal microbiota. Furthermore, this type of experiment shows that it is possible to transfer alcohol susceptibility from human to mouse via the intestinal microbiota, and makes it possible to anticipate the development of treatments of this nature.

These results thus open up new possibilities, not only for identifying individuals likely to be sensitive to alcohol toxicity, but also for improving the treatment of alcohol-induced liver lesions by modulating the intestinal microbiota

Innate lymphoid cells: a backup system for fighting intestinal infections

Éric Vivier’s team at Marseille-Luminy Immunology Center (CIML), a CNRS, Inserm and Aix-Marseille University research centre, in collaboration with Gabrielle Belz’s team at Walter and Elisa Hall Institute (WEHI), Melbourne, sheds new light on the dynamics of the immune networks that protect our intestine. During episodes of bacterial diarrhoea, innate lymphoid cells (ILCs) “share the work” with memory T lymphocytes, but can also compensate for them in the event of failure.
The authors also show that ILCs protect the appendix from potential damage caused by infection, a finding that may confer a new status on this organ. These discoveries are presented this Monday, 30 November, in the scientific journal Nature Immunology.


The intestinal immune system includes different populations of cells from the innate and adaptive immune system that protect us from infection. Once the pathogen is detected, cells from the innate immune system launch the initial attack, and call for reinforcements from the B and T lymphocytes of the adaptive immune system in order to “finish the work” and memorise the intruder’s profile. Although the sequence of events is known, cooperation between the different components is still poorly understood. The researchers are thus trying to uncover the relationships that form within the intestine between the T lymphocytes and the innate lymphoid cells (ILCs). Discovered simultaneously in 2008 by 12 laboratories, including that of Éric Vivier, ILCs represent a new type of lymphocyte that had been completely unknown until then. These cells can be likened to a “rapid version” of T lymphocytes. Divided into different groups, they have the morphology of a lymphoid cell, and produce the same cocktails of cytokines as the T lymphocytes, but they uniformly lack antigen-specific receptors.

The authors are now revealing another aspect of their biology: their choreography with the T lymphocytes. Using the bacterial species Citrobacter rodentium in the mouse as a model of human diarrhoea caused by enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC), they have thus demonstrated that the protective action of T lymphocytes and of an ILC subtype (ILC3 NCR+) is not only redundant, but that the latter can even “take over the work” where the T lymphocytes fail.

“This is the first time that redundancy between these 2 cell populations has been formally demonstrated,” says Éric Vivier. “All the evidence suggests that these two defence systems were co-selected during evolution to ensure optimal protection against infection.”

Ultimately, this discovery could thus lead to new therapeutic approaches to intestinal diarrhoea, a public health challenge of planetary proportions, since every year nearly 4 billion people are affected by these diseases, which represent nearly 4% of deaths worldwide.
Furthermore, this study includes another unexpected discovery: during infection, these same ILCs protect the caecum/appendix pair from inflammation and potential injury.

“The caecum and appendix have long been considered vestigial organs in terms of immunity. Our work is part of a quite different hypothesis, which proposes a role for this part of the intestine as a refuge for commensal bacteria during infection. Thus the ILCs would help to nurture the “good” bacteria that help to maintain the balance of the intestinal microbiota and hence fight infections more effectively,” concludes Professor Éric Vivier.

Benzodiazepine use is associated with a risk of developing dementia

A link between benzodiazepine use and the occurrence of dementia has been observed in a study, the results of which are published in the journal Alzheimer’s and Dementia, conducted by a team of Inserm researchers directed by Christophe Tzourio (Inserm Unit 897, “Epidemiology and Biostatistics Center,” Univ ersity of Bordeaux). More precisely, it is mainly the long half-life benzodiazepines (which disappear from the body in over 20 hours) that are associated with the risk of dementia. In this study, people taking long half-life benzodiazepines have a 60% increased risk of dementia.

Healthy Brain Pills

(c) Fotolia

Benzodiazepines and psychotropic drugs are the mostly widely used drugs in France. It is estimated that 30% of people aged 65 and over are users. They are prescribed for a wide spectrum of illnesses, from sleep disorders through to anxiety and depressive symptoms. Since they are widely used, the researchers are looking at their potential side-effects in relation to their interactions with neurotransmitters in the brain. Although previous studies had already suggested an increased risk of dementia following use of psychotropic drugs, many questions remained unresolved. One such question concerned the difference in the potential effects of short half-life benzodiazepines (which disappear from the body within 20 hours) versus those of long half-life benzodiazepines.

To try to find out more, the Inserm researchers focused on data from The Three City Study (3C Study; Bordeaux, Dijon and Montpellier), i.e. 8,240 people aged over 65 years and monitored for over 8 years. 830 new cases of dementia were diagnosed during this period of monitoring. A procedure for screening and diagnosing each case of dementia was established by an expert committee. It was also possible to systematically record all drugs used by the participants at home, by referring to prescriptions.

“There is a clear difference in effect between long- and short-lived benzodiazepines. Moreover, the former have already been identified as dangerous for older people, particularly because of the risk of falls, and we were surprised to see that they were still in frequent use,” says Christophe Tzourio, neurologist, Director of Inserm Research Centre U897 and Professor of Epidemiology at the University of Bordeaux.

Older people taking long half-life benzodiazepines have a 60% increased risk of developing a dementia (mainly of Alzheimer’s disease type) that cannot be explained by other factors. The authors performed in-depth statistical analyses that allowed the elimination of some bias, including the fact that taking benzodiazepines may have been due to early symptoms of dementia.

It is, however, an observational study, which does not allow analysis of the mechanisms of this association. These should become the subject of physiopathological studies, studies using imaging, animal models, etc.

Despite the absence of certainty about the mechanism, “The suspicion is strong enough to encourage physicians and patients to find alternative treatments for sleep disorders in older patients, which are the main reason for prescribing these drugs: advice on lifestyle changes, non-drug products, and, at most, less dangerous drugs such as the short half-life benzodiazepines.”

“Our results suggest, at a minimum, that there should be greater vigilance by all, especially physicians and health authorities, to avoid this use of long half-life benzodiazepines in older people,” says Christophe Tzourio.

The effect for psychotropic drugs overall, including anti-depressants, needs to be confirmed by further studies, but it also gives rise to some concerns over these products as a whole, and not only benzodiazepines.

Inserm rallies around COP21

The 21st International Session of the Conference of the Parties to the United Nations Framework Convention on Climate Change (COP21/CMP11) opened on Monday 30 November, underlining the willingness of participating governments to fight climate change and its consequences.

In this context, Inserm wishes to raise awareness among professionals and the general public about the impacts of climate change on health, and from now until 11 December, is offering scientific conferences, public lectures and an educational exhibition.

See the press release “Inserm at COP21” with the events programme.

At Inserm, there is an active research effort to understand the health effects associated with climate change.

Here are our latest news items on the theme:

In 40 years the French have adapted their behaviour to climate change

Climate change and health: what are the implications?