Menu

When Stress Weakens the Immune Defenses

Cytomegalovirus (CMV) infection in a human being. In red and green, the natural killer (NK) cells try to make their way to the infected cell. Inserm/Jabrane-Ferrat, Nabila

In previous years, various studies have established a link between psychological stress and reduced immune defenses, but the mechanisms involved remained poorly elucidated. Sophie Ugolini, Inserm Research Director at the Center of Immunology Marseille-Luminy, and her colleagues at CNRS and Aix-Marseille Université have recently shown that such a link is to a large extent mediated by a type of receptor that binds to stress hormones: the β2-adrenergic receptor. Their findings have been published in Journal of Experimental Medicine.

For several years now, the scientific community has been interested in the effects of psychological stress on health. Studies have shown that when infection strikes, stress is linked to reduced immune defense system efficacy. With her team, Sophie Ugolini, Inserm Research Director at the Center of Immunology Marseille-Luminy (Inserm/CNRS/Aix-Marseille Université), has sought to explain the biological mechanisms behind this phenomenon. The researchers focused on receptors expressed on the surface of many of the body’s cells (including the immune cells) and which are specific to the stress hormones adrenaline and noradrenaline – the β2-adrenergic receptors.

To study their role, the team first reproduced a situation of chronic stress in mice by administering for seven days a molecule which, like the stress hormones, stimulates the β2-adrenergic receptors. They then exposed the animals to a virus from the herpes family, cytomegalovirus MCMV. The mortality rate of the “stressed” mice having received the molecule proved to be much higher than that of the untreated mice (90% versus 50%).

The researchers then evaluated the animals’ resistance to infection in the absence of these receptors. This involved taking mice that are genetically modified to be devoid of β2-adrenergic receptors and exposing them to cytomegalovirus. In these animals, the stress hormones could no longer bind to β2 receptors and as a consequence could no longer act. They presented much greater resistance to the viral infection (90% survival versus only 50% for the control mice). These initial findings therefore suggest that stimulation of the β2-adrenergic receptors by the stress hormones is responsible for the weakening of the immune system in situations of psychological stress.

 

Towards new therapeutic avenues

In order to better understand the mechanisms involved, the team also analyzed the immune response of the mice devoid of β2-adrenergic receptors. They observed an increased production of inflammatory cytokines – molecules produced by the immune cells which promote the elimination of viruses.

The researchers discovered that the β2-adrenergic receptors most particularly inhibit the response of certain immune cells, known as natural killer (NK) cells. Stimulated by the stress hormones, the β2-adrenergic receptors prevent the NK cells from producing a particular type of cytokine required in order to eliminate viruses.

We have confirmed in an experimental setting that the stress hormones that bind to the β2-adrenergic receptors reduce immune response, which involves a decrease in the production of certain inflammatory cytokines required to eliminate viruses”, specifies Ugolini. According to the researcher, this study could open up new therapeutic avenues. “By targeting the β2-adrenergic receptor, it would in some disease settings be conceivable to deactivate the immune brakes triggered by states of stress”, she concludes.

Buruli Ulcer: New Diagnostic Avenues for a Neglected Disease

Recent studies have shown that Mycobacterium ulcerans infection causes the aggregation of immune cells (B cells) around the infected areas. Using fluorescent staining, a mouse spleen section shows B cells (in blue) and two sub-populations of T cells (in green and red). Credits: CIML/INSERM/CNRS/Mailfert, Sébastien/Chasson, Lionel

 

Buruli ulcer is the world’s third most common tropical mycobacterial disease after tuberculosis and leprosy. Caused by Mycobacterium ulcerans, it leads to the destruction of skin tissue and the development of large ulcers which can affect entire limbs right down to the bone. Researchers from Inserm, Université de Nantes, Université d’Angers and CNRS at the Nantes-Angers Oncology and Immunology Research Center (CRCINA) studied the rare cases of spontaneous healing from this disease in order to better understand its mechanisms. In addition to publishing their findings in the journal Science Advances, the team has filed a patent, opening up avenues for the deployment of hitherto inexistent diagnostic tools.

 

Buruli ulcer is a disease caused by Mycobacterium ulcerans (M.ulcerans), whose mode of transmission to humans is still not known. This bacterium produces a toxin called mycolactone which destroys skin cells and prevents the immune system from mounting an effective response, leading to the propagation of disease-characteristic ulcers on the limbs. Incapacitating and stigmatizing, Buruli ulcer affects children and adolescents most particularly. This little-known this disease is especially prevalent in West and Central Africa and has a very poor diagnostic and therapeutic arsenal. The World Health Organization (WHO) has classified it as a neglected tropical disease. Antibiotic treatment is effective if the disease is diagnosed quickly, although this is not yet possible in the majority of cases.

As part of a study published in Science Advances[1], a team led by Inserm researcher Estelle Marion at Nantes-Angers Oncology and Immunology Research Center (Inserm/Université de Nantes/Université d’Angers/CNRS) used mice to investigate the phenomenon of spontaneous healing that is observed in around 5% of infected patients.

Until now, research into Buruli ulcer focused on whole-body immune response. However, recent skin tissue studies have revealed that Mycobacterium ulcerans infection causes the aggregation of immune cells (B cells) around the infected areas. With this in mind, the researchers decided to focus on local immune response, at the site infected by the bacterium.

B cells produce a family of antibodies known as immunoglobulins (Ig). The major subgroups are IgA – found mainly in the mucous membranes and epidermis, IgM – present on the surface of the lymphocytes and for which a high count is synonymous with an ongoing infection, and IgG – the most numerous, which circulate primarily in the blood and eliminate foreign bodies encountered there.

Towards a diagnostic avenue

The researchers worked with two types of mice – one with the ability to spontaneously heal from Mycobacterium ulcerans infection, the other without. They began by studying immune reaction during infection, including during the spontaneous healing process, by analyzing skin samples from the area close to the infected site.

In both types of mouse, the level of cutaneous immunoglobulins increases during infection, but not to the same extent. In those unable to heal, IgM predominate, whereas in those able to heal, IgG predominate.

The researchers showed that these IgG bind to the toxin mycolactone. They went on to discover that only the mice that heal produce a very particular sub-type of IgG, IgG2a – capable of neutralizing the action of mycolactone. Finally, the researchers discovered the presence of the latter in the tissues of patients infected with M. ulcerans.

 “This study suggests for the first time that the body could efficiently respond to Mycobacterium ulcerans infection thanks to the production of antibodies that are capable of recognizing and neutralizing the toxin secreted by the mycobacterium. Although therapeutic avenues are still a long way off, this research offers new diagnostic ones”, concludes Inserm researcher Estelle Marion, who led this study.

According to the priorities issued by WHO, the team is envisaging the development of a quick and simple diagnostic test strip, based on the detection of antibodies recognizing mycolactone, thereby indicating M. ulcerans infection.

[1] This research was funded by Fondation Raoul Follereau, the French National Research Agency, the Pays de la Loire region, Université d’Angers, and Inserm (ATIP – Avenir Program).

Influenza: combating bacterial superinfection with the help of the microbiota

Section of lungs infected with influenza virus with a major inflammation which results in a marked infiltration of neutrophil polynuclear cells, dark cells. © Inserm/Si-Tahar, Mustapha

Researchers from the CNRS, INSERM, the Institut Pasteur de Lille, INRAE (France) and from Brazilian (Belo Horizonte), Scottish (Glasgow) and Danish (Copenhagen) laboratories have shown for the first time in mice that perturbation of the gut microbiota caused by the influenza virus favours secondary bacterial superinfection. Published in Cell Reports on March 3, 2020, these results open up new prospects for the prevention and treatment of bacterial pneumonia, a major cause of death in elderly or vulnerable people infected with the influenza virus.

Influenza and its complications continue to be a significant public health concern as well as a major social and economic burden. Vaccination campaigns, together with the discovery of new antiviral therapies, provide preventive and therapeutic solutions. However, impairment of defence mechanisms against secondary bacterial infections, which considerably worsen the clinical picture of people with influenza, remains a major problem.

Specializing in the field of pulmonary immunity, a team led by François Trottein, a CNRS researcher at the Lille Centre for Infection and Immunity (CNRS/INSERM/Institut Pasteur de Lille/University of Lille/CHU Lille), focused on the gut microbiota, well known for their key role in many physiological processes, including immune defence mechanisms. Scientists have shown that, in mice, influenza temporarily alters the composition and metabolic activity of the gut microbiota, probably due to reduced food consumption during illness. During influenza, the production of short-chain fatty acids by the bacteria of the microbiota is also diminished. The team has now shown that these fatty acids remotely favour the bactericidal activity of macrophages present in the lungs.  Perturbation of the intestinal microbiota by influenza thus compromises lung defences, particularly against Streptococcus pneumoniae, the leading cause of bacterial pneumonia in humans.

The researchers also showed that this sensitivity to bacterial superinfection can be corrected by treatment with acetate, one of the main short-chain fatty acids produced by the microbiota. Their work could have practical applications for the well-being of infected patients, who would be better protected against influenza-related complications.  This work was made in collaboration with scientists from the Micalis Institute (INRAE/AgroParistech/Université Saclay), the Lille Inflammation Research International Center (INSERM/Université de Lille/CHU Lille), the Laboratory of Design and Application of Bioactive Molecules (CNRS/University of Strasbourg), the Molecular Virology and Immunology Unit (INRAE) and GenoScreen (Lille), the Universidade Federal de Minas Gerais (Belo Horizonte, Brazil), the Institute of Molecular, Cell and Systems Biology (Glasgow, Scotland) and the Department of Pharmacology (University of Copenhagen, Denmark). This discovery represents a major breakthrough in the understanding of the mechanisms behind bacterial superinfections in influenza patients. It could lead to the development of new nutritional and/or therapeutic strategies to better control bacterial infections.

Egypt, Algeria and Republic of South Africa, main gates for coronavirus importation in Africa

©chuttersnap

Egypt, Algeria and Republic of South Africa are the African countries most at risk for coronavirus COVID-19 importation in the continent, due to high air traffic with the contaminated Chinese provinces. But these countries are also among the best equipped on the continent to quickly detect and deal with new cases. In other African countries, the risk of importation is lower, but health organization deficiencies raise concerns about rapid spread. This modeling work carried out by Vittoria Colizza, Inserm research director, and her team from Unit 1136 Pierre Louis Institute of epidemiology and public health (Inserm / Sorbonne University), in collaboration with the Université libre de Bruxelles, the Oxford Martin Programme on Pandemic Genomics and the University of California Los Angeles, is published in The Lancet.

The COVID-19 coronavirus continues to spread in China and cases have been reported in more than 25 countries. The African continent was spared for a long time until a first case was recently reported in Egypt. Vittoria Colizza, research director at Inserm (French Institute for Health and Medical Research), and her team from Unit 1136 Pierre Louis Institute of Epidemiology and Public Health (Inserm / Sorbonne University), in collaboration with the Université libre de Bruxelles, the Oxford Martin Programme on Pandemic Genomics and the University of California Los Angeles, assessed the risk of importing the virus into Africa, country by country, and the capacities of each of them to detect and deal with it.

The researchers evaluated the risk of the virus importation according to the number of cases declared by each chinese province and according to air traffic between the three main airports of each of these provinces (except Hubei due to flights suspension) and each African country. Moreover, they analyzed the potential of each country to face the risk of the spread of a contagious disease using WHO data and official data.

Each country makes a mandatory annual declaration to the WHO of its resources to deal with an epidemic (State Parties self-assessment Annual Reporting SPAR). It includes twenty-four items weighted into an overall score between 0 and 100, 100 showing a strong preparedness to face an epidemic. These indicators are legislation, adherence to WHO standards, laboratory skills, medical staff, emergency organization, food safety, level of equipment in healthcare centers and public communication.

The researchers also took into account the IDVI score (for Infectious Disease Vulnerability Index), also noted out of 100, 0 corresponding to an extreme vulnerability and 100 to the lowest vulnerability. The IDVI takes into account factors not directly linked to the health system but which can influence the response to an epidemic: the size of the population, the socio-economic level or even political stability. Thus, high IDVI and SPAR scores are predictive to an efficient response in case of virus importation.

The results show that Egypt, Algeria and Republic of South Africa are the countries most at risk of importing the virus to Africa due to high trade exchanges with China. On the other hand, their SPAR and IDVI scores are among the best on the continent, letting expect effective detection and containment of the virus. Other countries as Nigeria, Ethiopia, Sudan, Angola, Tanzania, Ghana and Kenya, are at lower risk of virus importation but their SPAR and IDVI scores are lower, raising fears of the non-detection of possible imported cases and of local or even national spread.

Finally, the researchers clustered the African countries at risk into three groups according to the influence of the Chinese provinces in these countries. Thus, a first group including 18 countries will be more vulnerable in the event of a major epidemic in the province of Beijing, a second comprising 7 countries will be more exposed in the event of a strong growth of the epidemic in the province of Guangdong and a third group of two countries is risking virus importation only from Fujian province.

“This work will allow the international community to make projections and plans according to the evolution in China. It also alerts the countries most exposed to the need of being prepared for the possible introduction of the virus. We can see how hard it is to quickly detect imported cases, as even well prepared developed countries missed some of them. For several poorly equipped African countries, the risks are significant of not having sufficient organization and infrastructure for detection, containment and urgent care, raising fears of a risk of epidemic on the continent”, concludes Vittoria Colizza.

Malaria: Vaccine clinical trial for Pregnant Women yields promising results

©Benoît Gamain. Gestational malaria is associated with low birth weight for the baby and an over-risk of neonatal mortality.

Malaria infection during pregnancy represents a major public health problem in the regions endemic for the disease, substantially increasing the risks to mothers and their unborn children. For newborns, malaria is linked to low birth weight and an excess risk of mortality. To protect this population, a team of researchers from Inserm and Université de Paris led by CNRS Research Director Benoît Gamain is developing a vaccine at the French National Institute of Blood Transfusion (INTS). Called PRIMVAC, the vaccine has undergone a clinical trial to study its safety and collect preliminary data on its ability to induce an immune response. The results of this clinical trial sponsored by Inserm[1] have been published in the prestigious journal Lancet Infectious Diseases.

According to the World Health Organization, malaria is responsible for over 400,000 deaths each year. Despite the progress made in fighting the disease in recent decades, some populations remain particularly vulnerable. One such population is pregnant women.

In the areas of the world where malaria is endemic, people acquire immunity throughout their childhood, meaning that they are generally protected against its most severe outcomes once they reach adulthood. However, pregnant women are an exception because the red blood cells infected with the Plasmodium falciparum parasite responsible for malaria accumulate in the placenta, promoting anemia and gestational hypertension. The disease is also linked to a higher risk of spontaneous abortion, premature birth and intrauterine growth delays which lead to low birth weight and a high rate of neonatal mortality. In Sub-Saharan Africa, 11 million pregnant women were infected with malaria in 2018, with around 900,000 of their babies born underweight.

To tackle this public health problem, a team of researchers from Inserm and Université de Paris led by CNRS Research Director Benoît Gamain has spent the past two decades developing a vaccine for gestational malaria. The goal is to prevent the deaths of up to 10,000 mothers and 200,000 babies each year. “Developing an effective vaccine for young women before their first pregnancy is a priority if we are to reduce malaria-related mortality. An effective strategy could focus on a population similar to that targeted by HPV vaccination, for example, before the women become sexually active”, emphasizes Benoît Gamain.

A safe and effective vaccine

Called PRIMVAC, the vaccine had recently been produced in large quantities in accordance with current regulations. In a clinical trial published in Lancet Infectious Diseases, the researchers provide data on its safety and ability to induce an appropriate immune response, up to 15 months after the initial vaccination.

The vaccine was evaluated in 68 non-pregnant women aged 18 to 35 at the Cochin Pasteur Clinical Investigation Center in Paris, then at the National Center for Research and Training on Malaria (CNRFP) in Ouagadougou, Burkina Faso. The participants were randomly assigned to 4 cohorts, receiving the vaccine at various doses, on 3 occasions over a period of 3 months. These women were then monitored for 15 months in order to identify and treat any side effects and study the immune response induced by the vaccination.

Antibody (green) of a vaccinated volunteer binding to the surface of a human red blood cell infected with the Plasmodium falciparum parasite (blue). Credits: Inserm/Chêne, Arnaud et Semblat, Jean-Philippe

The results of this study show that PRIMVAC is well tolerated. In addition, the researchers have shown that vaccine can produce an immune response, with the production of antibodies in 100% of women vaccinated after only two injections. The antibodies produced are capable of both recognizing the parasitic antigen on the surface of the infected red blood cells and inhibiting their adhesive capacity, which is responsible for their accumulation in the placenta.

“We were able to show that the vaccine is well tolerated, at all the tested doses. The side effects observed were mainly pain at the injection site. We also revealed that the quantity of antibodies generated by the vaccine increases after each vaccination and that they persist for several months. It therefore appears that the vaccine has the capacity to trigger a lasting and potentially protective immune response”, underlines Gamain.

Studying this immune response on the longer term will be the subject of future clinical trials. The researchers want to continue monitoring the 50 Burkinabe volunteers in order to evaluate whether the immune response induced by the vaccination is maintained until their first pregnancy.

 

[1] The trial was coordinated by the Cochin Pasteur Clinical Investigation Center in Paris and the EUCLID/F-CRIN clinical trials platform in Bordeaux in collaboration with the National Center for Research and Training on Malaria (CNRFP) in Ouagadougou, Burkina Faso, and the European Vaccine Initiative (EVI). Funding: Federal Ministry of Education and Research, through the development bank KfW, Germany; Inserm, and National Institute of Blood Transfusion (INTS), France; Irish Aid, Department of Foreign Affairs and Trade, Ireland.

Coronavirus: A Model Estimating Importation Risk to Europe

 ©chuttersnap

Could the coronavirus epidemic that has hit China spread to Europe? A pertinent question given the new cases being announced by the Chinese authorities, of which eight have already been exported to other countries. An Inserm team led by researcher Vittoria Colizza at Pierre Louis Institute of Epidemiology and Public Health (Inserm/Sorbonne Université) has modeled the potential spread of 2019-nCoV in order to orient prevention and surveillance policies. A model which comes with one caveat: derived from research, its purpose is not to make predictions but rather be used as a theoretical tool to aid public decision-making.

Update on 31 January 2020 :

As the situation is unfolding quickly, the following figures may also change, depending on the number of confirmed cases in and outside China. Vittoria Colizza’s model, based on the most recent figures up to 30 january, is now published on Eurosurveillance

To follow the evolution of the number of cases, you can visit  GISAID.

Just two weeks after announcing the discovery of a new virus from the coronavirus family responsible for severe pneumonia, there were 571 confirmed cases in China. In an effort to contain this epidemic whose death toll currently stands at 18, the Chinese authorities have taken drastic measures – particularly restrictions on travel from the province of Hubei, where the city of Wuhan is located.

Many questions continue to remain unanswered as to the origin of this new virus, 2019-nCoV, and about the capacity of the epidemic to spread to other regions of the world – particularly Europe. In the space of two weeks, eight cases have already been exported from China to Japan, South Korea, USA, Thailand and Taiwan.

From the start of the epidemic, Inserm researchers under the aegis of the research group REACTing have been working to model its potential dissemination.

Led by Inserm researcher Vittoria Colizza at the Pierre Louis Institute of Epidemiology and Public Health (Inserm/Sorbonne Université), a team is now able to propose a model to anticipate a potential arrival of the epidemic in Europe in order to guide surveillance and prevention measures. However, it is important to note that this model in no way constitutes a prediction of the future number of cases in France and Europe, but rather a theoretical tool to aid public decision-making.

Air traffic flows from China

When developing their model, the researchers focused on those Chinese provinces reporting more than ten cases. Their estimations of the risks of these cases being exported are based on January 2019 data on air traffic from these regions to Europe produced by the OAG – a world leader in flight data collection.

What is the risk of at least one case being imported to Europe in the next two weeks? The team addressed this question by preparing two scenarios: one of a low risk of dissemination and the other of a high risk.

The low-risk scenario is based on the situation (seven cases exported from China) prior to the flight ban by the Chinese government. It estimates the risk of at least one case being imported to Europe if seven cases are exported from the Chinese provinces affected in the next two weeks.

 

The high-risk scenario proposes an estimation of the same risk if three times more cases are exported from China. “It is an arbitrary choice but one which reflects the fact that the number of Chinese cases is on the increase, making it possible to anticipate the case of a greater number of infected people being exported”, emphasizes Colizza.

 

 

According to the researchers, the risk of at least one case being imported to Europe is 33% in the first scenario and 70% in the second. Given the flows of air traffic, the countries most exposed would be Germany and the UK. The risk of an infected passenger arriving in France is 5% in the first scenario and 13% in the second and would mainly be concentrated around the airports serving Paris. “Our findings are not predictions, they simply make it possible to pinpoint where the risk is located and where prevention and surveillance need to be stepped up”, states Colizza.

PREVAC-UP: The Partnership for Research on Ebola Vaccination extends follow-up and builds research capacity against deadly disease

PREVAC – Landréah Conakry vaccination centre. Credits : Inserm/Delapierre, Patrick

Public health efforts successfully stopped human-to-human transmission of Ebola virus in West Africa in 2016 after the worst Ebola outbreak in history.  However, the threat of the disease is still real, as the recent Ebola outbreaks in the Democratic Republic of the Congo (DRC) have shown. Thus, pursuing and intensifying efforts to develop a safe and effective vaccination strategy against Ebola virus disease, with durable protection in all populations, including children, is vital.

Since August 2018, the DRC has been battling its worst Ebola outbreak, and the world’s second largest such outbreak, with more than 2200 lives lost and more than 3300 confirmed infections to date. This ongoing crisis highlights again the continued urgent need to develop safe and effective vaccines against the Ebola virus.

This goal has been the priority for the Partnership for Research on Ebola Vaccination (PREVAC)[1], an international consortium that recently received additional funding to scale up its research in West Africa as part of a new project known as PREVAC-UP. This initiative aims to evaluate the long-term safety, as well as the durability of humoral and cellular immune responses, of three different Ebola vaccine regimens previously tested by the consortium. PREVAC-UP will assess these factors for 5 years after vaccination.

The study will also evaluate the effect of co-infections, such as malaria and helminths, on the immune response to vaccination. An integrative statistical analysis of the immune response will be used to explore the mechanism of action of the vaccines and to identify early correlates of durable antibody induction. “This programme is expected to significantly impact Ebola prevention and control in adults and children in Africa. The study will also strengthen the capacity for science relevant to the development and evaluation of new vaccines in sub-Saharan Africa”, Dr Yazdan Yazdanpanah, PREVAC Principal Investigator, says.

The project is co-funded by the European and Developing Countries Clinical Trials Partnership (EDCTP2) programme supported by the European Union[2]. Besides the EDCTP2 grant, PREVAC-UP benefits from co-funding from Inserm, the NIAID, the LSHTM and the COMAHS, as well as host country support from Liberia, Sierra Leone, Guinea and Mali.

PREVAC results expected in 2020

PREVAC-UP follows up on the work already carried out by the PREVAC[3] consortium since March 2017 in West Africa. Working in Liberia, Guinea, Sierra Leone and Mali, the team conducted a randomised, placebo-controlled, multicentre Phase 2 trial – one of the largest Ebola vaccine trials to date – using the recently WHO prequalified rVSVΔG-ZEBOV-GP vaccine from Merck, Sharpe & Dohme, Corp.[4], and an investigational two-dose vaccine regimen (Ad26.ZEBOV, MVA-BN-Filo) developed by Janssen Vaccines & Prevention B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, in collaboration with Bavarian Nordic.

The aim was to study the safety and immunogenicity over 12 months of three different vaccination strategies involving these vaccines in adults and children one year and older. In total, PREVAC enrolled 4789 people from the 4 countries, with the enrolment of 2802 participants (1401 adults and 1401 children) in the main phase of the trial completed in December 2018. The first results on immunogenicity at 12 months after vaccination are expected in the summer 2020.  Importantly, the retention rate of the participants is very high (95% after 12 months). “This reflects the great commitment of all the local professionals and shows the high level of collaboration between all the partners involved in the project as well as the interest in the population to receive an Ebola vaccine, and successful community engagement strategies”, Dr. Yazdanpanah says.

PREVAC-UP will now bring much needed additional data on these different vaccination strategies, helping to promote the safest and most efficient approach to protect vulnerable populations in countries threatened by Ebola.

 

[1] To learn more about PREVAC on Inserm’s website : https://www.inserm.fr/en/news-and-events/news/ebola-already-more-than-2000-people-included-in-prevac-immunization-trial

[2] PREVAC-UP Partner Organizations 

Institut national de la santé et de la recherche médicale (Inserm)*, France ; Centre National de Formation et de Recherche en Santé Rurale (CNFRSR)*, Guinea ; Institut Bouisson Bertrand* (IBB)/ Centre de Recherche et de Formation en Infectiologie (CERFIG) France/ Guinea ; London School of Hygiene & Tropical Medicine (LSHTM)*, United Kingdom ; University of Sierra Leone, College of Medicine and Allied Health Sciences (COMAHS)*, Sierra Leone ; Alliance for International Medical Action (ALIMA)*, France ; Inserm-Transfert SA*, France ; National Institute of Allergy and Infectious Diseases (NIAID), USA ; Université des Sciences, des Techniques et des Technologies de Bamako (USTTB)*, Mali ; Ministry of Health (Centre pour le Développement des Vaccins –Mali)*, Mali ; National Public Health Institute of Liberia (NPHIL), Liberia

*EDCTP grant agreement signatories.

[3] Inserm’s participation in PREVAC is in part through a subcontract with Leidos Biomedical Research, Inc. which operates the Frederick National Laboratory for Cancer Research on behalf of the National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

The PREVAC UP project is funded by the European and Developing Countries Clinical Trials Partnership (EDCTP2) programme supported by the European Union and the UK Department of Health & Social Care (Grant number RIA2017S – 2014 -PREVAC-UP). Besides the EDCTP2 grant, PREVAC-UP benefits from co-funding from Inserm, the NIAID, the LSHTM and the COMAHS as well as host country support from Liberia, Sierra Leone, Guinea and Mali.

[4] The rVSVΔG-ZEBOV-GP vaccine (sold under the name ERVEBO®) was awarded prequalification status by the WHO in November 2019. It is now licensed in the USA and in Europe.

A Vaccine Against Chronic Inflammatory Diseases

The colon viewed using a confocal microscope, showing the microbiota bacteria (in red), the intestinal mucous (green), the intestinal cells (purple) and their DNA (blue). Credits: Benoît Chassaing

In animals, a vaccine modifying the composition and function of the gut microbiota provides protection against the onset of chronic inflammatory bowel diseases and certain metabolic disorders, such as diabetes and obesity. This research was conducted by the team of Benoît Chassaing, Inserm researcher at Institut Cochin (Inserm/CNRS/Université de Paris), whose initial findings have been published in Nature Communications.

Chronic inflammatory bowel diseases, such as Crohn’s and ulcerative colitis, are linked to abnormalities of the gut microbiota in humans and in animals. The subjects concerned generally present reduced bacterial diversity in their intestinal flora along with excessive levels of bacteria that express a protein called flagellin, which favors their mobility. This enables them to penetrate the layer of mucous that covers the intestinal wall and is usually sterile. The purpose of this layer is to form a bacteria-resistant wall between the internal digestive tract and the rest of the body, thereby protecting it from the risk of inflammation linked to the presence of the billions of bacteria of the intestinal flora.

Previous research had already shown that antibodies are naturally found within this mucous layer, some of which are directed against flagellin. This means that the body spontaneously develops immune protection against flagellin, making it possible to control the presence of the bacteria that express it. With the aim of reducing the risk of chronic inflammation, Inserm researcher Benoit Chassaing and his colleagues had the idea of stimulating this anti-flagellin antibody production in order to reduce the presence of the bacteria that express flagellin in the gut microbiota.

As described in their study published in Nature Communications, the researchers administered flagellin to mice intraperitoneally, thereby inducing a marked increase in the anti-flagellin antibodies, particularly in the intestinal mucosa. The researchers then applied a protocol in order to induce chronic intestinal inflammation, whereupon they observed that immunizing against flagellin gave the animals significant protection from intestinal inflammation. In addition, detailed analysis of their microbiota and intestines revealed not just a reduction in the levels of bacteria that strongly express flagellin but also their absence in the intestinal mucosa, as opposed to the unvaccinated group.

Given that excess flagellin in the gut microbiota has also been linked to metabolic disorders such as diabetes and obesity, the researchers tested their vaccine strategy in mice exposed to a high-fat diet. Whereas the unvaccinated animals developed obesity, the vaccinated animals were protected.

This vaccine strategy can be envisaged in humans, because such abnormalities of the microbiota have been observed in patients with inflammatory and metabolic diseases. With this in mind, we are currently working on a means of locally administering flagellin to the intestinal mucosa“, explains Chassaing. The researchers are considering, for example, the possibility of developing ingestible flagellin-filled nanoparticles. Finally, in addition to the preventive aspect, they now wish to test this vaccination in curative mode, in animals already presenting chronic inflammatory disease or metabolic disorders.

Influenza : the Reasons for Low Vaccine Coverage Among Pregnant Women

Adobe/Stock

A study carried out by Béatrice Blondel (Inserm Obstetrical, Perinatal and Pediatric Epidemiology Research Team – Université de Paris) and Odile Launay (CIC Cochin Pasteur – AP-HP) reveals that seasonal influenza vaccine coverage remains particularly low among pregnant women in France (7.4% for the 2015-16 season). Despite risks of severe complications, expectant mothers are often not offered the vaccine during their prenatal monitoring or, if they are, a large majority declines it. The findings of this study have been published in Human Vaccines and Immunotherapeutics.

Since 2012, the French health authorities recommend that all pregnant women be vaccinated against influenza. Data from the scientific literature suggest that they and their newborns run a higher risk of developing severe complications of the disease.

Nevertheless, vaccine coverage of pregnant women in France continues to remain low, with Inserm researcher Béatrice Blondel and her colleagues estimating it at 7.4% for the 2015-16 season. To obtain this figure, the team used data from the National Perinatal Survey – a large-scale study periodically conducted by Inserm in France since 1995 to evaluate the health of mothers and their newborns in addition to medical practices during pregnancy and birth.

Over 12,000 women that had given birth in March 2016 agreed to participate. “The fact that they had given birth in March was relevant for our study because their pregnancy coincided with the ‘flu epidemic and the entire vaccination period, meaning that the vaccination measures were totally applicable to them“, emphasizes Blondel.

The women were interviewed to find out not just whether they had been vaccinated against the disease during their pregnancy, but also which care provider had performed their prenatal monitoring. In addition to estimating vaccine coverage, the researchers analyzed the factors that favor vaccination, as well as the reasons why a large majority of women had not made use of it.

 

Lack of knowledge and suspicion of vaccination

 An analysis of the sociodemographic characteristics of the study participants reveals that the pregnant women most likely to be vaccinated are aged between 30 and 34, have a higher level of formal education, and are more likely to work in the healthcare sector.

In addition, those whose main care provider during the pregnancy was a general practitioner also have a higher level of vaccine coverage. “The problem in France is that the principal professionals responsible for prenatal monitoring, namely the OB-GYNs and midwives, have not taken up this question and have not systematically incorporated vaccination in the prenatal monitoring process”, specifies Blondel.

The study suggests that effective interventions should be conducted to raise awareness of influenza vaccination among medical professionals and pregnant women. Indeed, only one quarter of the mothers interviewed said that they had been offered the vaccination during their prenatal monitoring, which was then declined by 70% of them. Targeted campaigns to remind pregnant women that they are one of the populations at risk and to incite care providers to offer the vaccine could have a positive impact. In this context, given the numerous and widely-dispersed care providers involved in prenatal monitoring, the professional associations could play a decisive role in these interventions.

“Women also need to be made aware of the known benefits of the vaccination. While vaccine hesitancy is particularly strong in the French population as a whole, the principle of precaution in regards taking medication is very firmly rooted in the behavior of pregnant women. The cumulation of these two attitudes helps to explain the low vaccine coverage. Nevertheless, the inclusion of pregnant women in the 2019 national vaccine campaign should encourage improved adherence of health professionals and these women”, concludes Blondel.

Towards a Drug to Combat a Severe Intestinal Disease in Children, Immunocompromised Patients

3D structure of the enzyme with the molecule AN3661 shown against the background of the intestine of an immunocompromised mouse infected with Cryptosporidium. ©Fabrice Laurent and Christopher Swale.

Researchers from Inserm and INRA working in the teams of Mohamed-Ali Hakimi (Institute for Advanced Biosciences – Inserm U 1209 / CNRS JRU 5309 / UGA) and Fabrice Laurent (INRA) have recently discovered a new candidate drug to control cryptosporidiosis, a severe intestinal disease in children, immunocompromised patients, and young ruminants. Beyond this disease, their research represents an opportunity to discover new therapeutic avenues for related infections, such as toxoplasmosis and malaria. Their findings have been published in Science Translational Medicine.

Cryptosporidiosis is a diarrheal disease caused by Cryptosporidium, a microscopic parasite that develops in the intestine of numerous mammals – notably humans. This intestinal parasite is mainly spread through contaminated drinking or pool water, where it can survive for several days in the presence of chlorine, or through contact with infected animals. Over the past 20 years, infection with Cryptosporidium has been recognized as a common cause of waterborne disease in humans. According to a recent study by the US Centers for Disease Control and Prevention (CDC), the number of Cryptosporidium epidemics is even on the increase. In humans, it causes acute and sometimes fatal diarrhea in the most vulnerable populations, including young malnourished children and immunocompromised patients (for example, those infected with HIV). The therapeutic arsenal is currently very limited and in some cases ineffective in eliminating this parasite.

This study conducted by the researchers from Inserm and INRA reveals the discovery of a candidate drug called AN3661, which drastically reduces not just Cryptosporidium infection but also that of Toxoplasma, the parasite responsible for toxoplasmosis.

The study teams have revealed the mechanism of action of this molecule by elucidating the three-dimensional structure of its target, called CPSF3, in Cryptosporidium. AN3661 binds to the heart of the enzyme CPSF3, thereby preventing the maturation of the messenger RNA, a process essential to the parasite’s survival. Preclinical tests using an animal model show remarkable efficacy in vivo with single-dose treatments of the infection in immunocompromised or baby mice.

This major discovery paves the way for new therapeutic strategies and innovations to fight not just cryptosporidiosis but also other related infections, such as toxoplasmosis and malaria.

fermer