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Category: Immunology, inflammation, infectiology and microbiology

Focusing on Viral Load to Understand Progression to Severe COVID-19

Posted on by Graziella Cara

SARS-CoV-2 infected cell © Sébastien Eymieux and Philippe Roingeard, INSERM – Université de Tours

What are the factors predicting progression to severe forms of COVID-19? One year into the pandemic, this question remains a key research subject, and one that scientists from Inserm and Université de Paris decided to explore further by studying the link between viral kinetics and disease progression. This research is based on data from the Inserm-sponsored French COVID cohort, and has been published in PNAS.

While some patients infected with SARS-CoV-2 only have mild symptoms of COVID-19, a minority will go on to develop severe forms of the disease. A better understanding of the factors that determine this progression is essential if we are to improve their treatment and reduce mortality.

A team led by Inserm researcher Jérémie Guedj at the IAME laboratory (Inserm/Université de Paris) analyzed the biological data of 655 patients hospitalized for SARS-CoV-2 infection, and who were participants in the French COVID cohort.

The aim was to help elucidate the link between viral kinetics – the amount of virus present in the nasopharyngeal compartment over time – and the progression of the disease.

Their study has highlighted two essential points. The first is that the older the patient, the longer he or she takes to eliminate the viral load from the nasopharyngeal compartment. The second is that this viral dynamic is associated with mortality.

While viral load is certainly not the only factor in progression to severe disease and death, it does play an important role. Although COVID-19 is often described as an inflammatory disease, these virological aspects must also be taken into account in the treatment and support of hospitalized patients.

As a consequence, this research also highlights the need for continued research into the development of antiviral treatments.

In particular, the scientists used modeling to show that shortening the time to viral clearance by administering treatment upon hospitalization could significantly improve prognosis, especially in the most elderly.

Covid-19: Understanding Early Immune Response

Posted on by Graziella Cara

Cellule infectée par le SARS-CoV-2. © Sébastien Eymieux et Philippe Roingeard, INSERM – Université de Tours

As the COVID-19 pandemic continues, scientists are making significant headway in understanding the transmission of the SARS-CoV-2 coronavirus and the immune response it triggers at the time of infection. Researchers from Inserm, the Paris hospitals group AP-HP and Université de Paris, in collaboration with Rockefeller University in New York, have provided new data on the very early stages of immune response. Their findings have been published in Journal of Experimental Medicine.

Understanding the immune response against SARS-CoV-2 is essential if we are to know who is at risk of developing severe forms of COVID-19 and how to treat them effectively. While many studies have been conducted in patients in the advanced stages of infection, when they are already showing signs of severity, little is known about the very early stages of immune response against the virus.

Thanks to close collaboration between the Inserm teams of Ali Amara, virologist, and Vassili Soumelis, immunologist at Saint-Louis Research Institute (Université de Paris/Inserm/AP-HP), a study published in the Journal of Experimental Medicine was able to characterize innate immune response[1] within 24 to 48 hours following contact with the SARS-CoV-2 virus.

The researchers used immune cells called “plasmacytoid predendritic cells” as a model of innate immune cells that play an essential role in antiviral immunity by producing large amounts of interferon-alpha[2].

They reconstructed the early immune response to the virus by placing these model cells in contact with primary strains of SARS-CoV-2 isolated from patients with COVID-19.

Analysis of this in vitro reconstituted response showed that SARS-CoV-2 induced effective and complete activation of the plasmacytoid predendritic cells. These then produced large amounts of interferon-alpha (the first line of defense against viruses) and differentiated into dendritic cells capable of activating T cells (which correspond to specific immunity cells). The researchers were also able to show that this activation of the plasmacytoid predendritic cells was partially inhibited by hydroxychloroquine, which would call for caution in the use of this molecule.

In the second part of the study, the teams collaborated with Jean-Laurent Casanova’s team from the Imagine Institute (Inserm/Université de Paris/AP-HP) and Rockefeller University in New York, in order to study the response of plasmacytoid predendritic cells from patients with genetic deficits for certain important genes of innate immunity. The objective was to clarify the molecular mechanisms involved in the response of these immune cells to SARS-CoV-2.

These experiments performed on samples obtained directly from patients showed that the response of plasmacytoid predendritic cells is dependent on UNC93B and IRAK-4, two important molecules of innate antiviral immunity. This research as a whole makes it possible to clarify early immune response to SARS-CoV-2 as well as some of its molecular determinants.

The study suggests that the immune system is naturally armed to respond to SARS-CoV-2 and that defects in the response of plasmacytoid predendritic cells, particularly in the early production of interferon-alpha, may contribute to the infection progressing to a severe form.

 

[1] Innate immunity is the body’s first line of defense and is triggered as soon as the body is exposed to a bacterium or virus (such as SARS-CoV-2). The innate immunity cells can contribute to the total destruction of the detected microbes or present them to the mechanisms of acquired immunity to facilitate their destruction by specific mechanisms (T and B cells).

[2] Interferons are cytokines (proteins) whose production is induced following viral, bacterial or parasitic infection, or the presence of tumor cells. While their main function is to interfere with viral replication, they also have an antibacterial and antiproliferative action, as well as an activating effect on other immune cells.

Discovery stops testing Remdesivir against Covid-19 for lack of evidence of its efficacy

Posted on by Graziella Cara

©hal-gatewood-AypaEmWVH8I-unsplash

The Discovery trial was originally launched in March 2020 by Inserm to evaluate possible treatments for COVID-19. Its European expansion (Discovery Europe) was made possible by the EU-RESPONSE[1] project funded by the European Commission (see details in the box below). On January 13th, 2021, the Discovery Europe trial Data Safety Monitoring Boards (DSMB) evaluated an interim report based on 776 patients of whom 389 received remdesivir and 387 received standard of care. The efficacy of the treatment was evaluated after 15 days and measured on the WHO-7-point ordinal scale. As a result of the evaluation, the DSMB recommended that patient recruitment be suspended.

This recommendation was based on lack of evidence of efficacy of remdesivir after 15 days and a very low probability to conclude with the inclusion of additional participants. There was also no evidence for treatment efficacy at day 29 (on the same scale or on mortality), nor in the analysis restricted to moderate-risk participants at day 15. This recommendation has been endorsed by the Discovery Europe Steering Committee.

Discovery researchers are now collecting and monitoring data on all participants enrolled in the clinical study in order to publish their detailed scientific findings in a peer reviewed scientific journal.

The Discovery Europe trial will continue in 80 centres from 14 European countries and will soon launch the clinical evaluation of a combination of two monoclonal antibodies. Beside the deployment of vaccines, it remains paramount to provide strong evidence for adding effective medicines for the treatment of patients affected by Covid-19.

 

The Discovery trial was originally launched in March 2020 by Inserm to evaluate possible treatments for Covid-19. An agreement was signed with the WHO Solidarity trial so that it became an add-on trial of Solidarity. Discovery is now part of the EU-RESPONSE project (Discovery Europe), funded through Horizon 2020, the EU’s research and innovation programme. It is a multicentre adaptative randomized platform trial for the evaluation of the clinical and virological efficacy, as well as the safety, of candidate treatment versus standard of care in hospitalized adult patients with laboratory confirmed Covid-19. The initial set of tested treatments includes lopinavir/ritonavir, lopinavir/ritonavir plus IFN-b-1a, hydroxychloroquine, and remdesivir. The primary endpoint is the clinical status at day 15, measured on the WHO 7-point ordinal scale..

In June 2020, the DSMBs of Solidarity recommended to stop the hydroxychloroquine arm for futility concern as well as both lopinavir/ritonavir containing arms for futility and safety concern. In July 2020, continuing the evaluation of remdesivir, approved for conditional marketing authorisation in the European Union, was felt important because more data were needed to fully assess its efficacy.

[1] https://cordis.europa.eu/project/id/101015736

A New Mechanism Involved in the Development of Persistent Bacterial Infections

Posted on by Graziella Cara

Staphylococcus aureus bacteria (in green) adhering to keratinocytes (in red). © Inserm/Tristan, Anne

 

So-called “persistent” bacterial infections constitute a major public health problem and are linked to significant failures of antibiotic treatments. Researchers from Inserm and Université de Rennes 1, in collaboration with a team based in Switzerland, have identified a new mechanism to explain the persistence of Staphylococcus aureus. Their research has been published in Nature Microbiology.

In this context, persistence denotes the ability of bacteria to survive high doses of antibiotics without actually becoming resistant. They become persistent by slowing their growth – a bit like going into “hibernation” – to protect themselves from antibiotic treatments. The presence of such antibiotic-tolerant bacteria represents a major public health problem. When the intake of antibiotics is stopped, some of the bacteria “wake up” and are liable to multiply again, presenting a very high risk of relapse or of developing a chronic bacterial infection.

Many of the mechanisms leading to the formation of persistence remain unknown. In their study, the Inserm and Université de Rennes 1 researchers at the Bacterial Regulatory RNAs and Medicine laboratory focused on Staphylococcus aureus. This bacterium is the leading pathogen responsible for nosocomial infections (infections contracted in hospital) and is also implicated in many cases of food poisoning.

Fighting chronic bacterial infections

In their study, the researchers focused on a Staphylococcus aureus non-coding RNA, i.e. one that is not translated into proteins.

They have shown that once positioned on the ribosomes[1] of the staphylococci, this RNA (referred to as SprF1 antitoxin) reduces protein synthesis during the growth of the bacterium (the aforementioned “hibernation” phenomenon). This mechanism promotes the formation of persistent staphylococci that become insensitive to antibiotics.

“We have revealed an RNA-guided molecular process in which the interaction between this SprF1 RNA and the ribosome is involved in the formation of antibiotic-tolerant bacteria, which are themselves largely implicated in chronic staphylococcal infections,” emphasizes Brice Felden, the professor at Université de Rennes 1 who supervised this work.

These findings also make it possible to envisage a new class of anti-infectives that target persistent bacteria, and thus new treatments for chronic Staphylococcus aureus infections. “Based on these results, we want to develop molecules that fight the persistent bacteria by targeting the SprF1 antitoxin. This strategy is therefore aimed at supplementing the therapeutic arsenal available to clinicians, who find themselves confronted with an increasing number of cases of chronic bacterial disease,” declares Marie-Laure Pinel-Marie who coordinated this research.

These findings have been the subject of a European patent application.

 

[1] Particles present in all cells that are the “factories” for making proteins.

Study – Particularly active antibodies to act as a barrier to SARS-CoV-2

Posted on by Graziella Cara

Colorized image of human bronchial cells (blue) infected with SARS-CoV-2 virus (orange). © Institut Pasteur. Image by Rémy Robinot, Mathieu Hubert, Vincent Michel, Olivier Schwartz & Lisa Chakrabarti, colors by Jean Marc Panaud

Teams from the Pitié-Salpêtrière AP-HP hospital, Sorbonne University, Inserm and the Pasteur Institute have carried out work to study the role that IgA-type antibodies play in the protection of body against Covid-19 in the mucous membranes, in particular respiratory. This work in press in Science Translational Medicine , and which is the subject of a pre-publication on Monday, December 7, 2020 on the website of the journal Science Translational Medicine , shows that the IgA antibody response plays a key role in neutralizing the early and particularly effective SARS-CoV-2 virus.

IgA-type antibodies play an essential role in the protection of the organism at the level of the mucous membranes, in particular respiratory. It therefore made sense to study this particular antibody response in patients infected with the SARS-CoV-2 virus. Researchers and clinicians affiliated with the CIMI Research Center (Sorbonne University and Inserm) in collaboration with several clinical departments of APHP-Sorbonne University and teams from the Institut Pasteur, show that the IgA response plays a key role in neutralizing the early and particularly effective SARS-CoV-2 virus.

Somewhat surprisingly, IgA antibodies are often even the first detectable virus specific antibodies. An unusual profile since immunological dogma wants the IgM response to be dominant when encountered with an unknown pathogen. The stimulation induced by the virus induces a very large expansion of young cells secreting IgA antibodies (plasmablasts) which circulate between the blood and the mucous membranes in which they are able to reside. However, this IgA antibody response is slowly declining, including in the saliva.

The teams in charge of this work show that in the first weeks following infection, IgA type antibodies do most of the work of neutralizing the virus.

The level of these antibodies decreases rapidly in the blood, becoming weakly detectable in most people 30 days after the onset of symptoms. However, these antibodies remain detectable and active in saliva longer (up to 73 days after the onset of symptoms) even though this level of local protection also seems to decline slowly. In a subgroup of patients having presented a mild ambulatory form, it is indeed reported that approximately 6 months after the counting, saliva no longer exerts a neutralizing power on the virus.

In conclusion, this work highlights the powerful protective nature of IgA. It raises the question of the possible role of secretory IgA in limiting the transmission of the virus.

It will therefore be interesting to assess to what extent the various vaccines which will soon be widely available could induce, or not, a systemic IgA response, or even mucosal.

If necessary, it may be considered to eventually include local stimulation in our vaccine strategies, for example in the form of local nebulizations.

Published Now in the New England Journal of Medicine: The Initial Results of the Solidarity/Discovery Clinical Trial

Posted on by Léa Surugue

©Adobe Stock

Back at the start of the pandemic, Inserm, through its REACTing consortium, set up Discovery: a European clinical trial to evaluate the efficacy of four antiviral drugs repurposed for the treatment of patients hospitalized with COVID-19 (remdesivir, hydroxychloroquine, lopinavir and interferon beta-1a). In parallel, the World Health Organization (WHO) set up Solidarity, a major consortium of clinical trials also aimed at testing the efficacy of these four treatments. Discovery then joined forces with Solidarity to help supply it with robust and rigorous data. The initial results of Solidarity have now been published in the New England Journal of Medicine.

Launched in March 2020 under the aegis of Solidarity – the World Health Organization (WHO) global clinical trials – Discovery is a clinical trial to study efficacy and safety. It is the only large-scale European academic trial of COVID-19 treatments.

Focusing on patients hospitalized with severe COVID-19 in France and other European countries, this trial is both randomized (the treatments are randomly assigned to the participants) and open-label (the patients and their caregivers know which treatment they have been allocated). The data obtained in Discovery form part of the data analyzed within the framework of Solidarity and have been presented in the study by the New England Journal of Medicine.

The analysis covers 11,330 adult patients in 405 hospitals across 30 countries and includes Solidarity’s “daughter trials” (with one of the main contributors being Discovery). The patients were assigned to different groups in order to receive one of the following regimens:

  • Remdesivir + standard of care
  • Hydroxychloroquine + standard of care
  • Lopinavir + standard of care
  • Interferon (or interferon and lopinavir) + standard of care
  • Standard of care that is given to all patients hospitalized with severe COVID-19

The results suggest that none of these treatments have an effect on the clinical improvement of patients. None of them significantly reduce overall mortality, the risk of having to initiate mechanical ventilation, or the duration of hospitalization.

However, within the framework of Solidarity and Discovery, it has nevertheless been decided to continue enrolments in the remdesivir group. Indeed, the meta-analysis presented in the study suggests that although mortality is not reduced in the mechanically ventilated patients in intensive care having received remdesivir, it does show that remdesivir may slightly reduce mortality in the subgroup of hospitalized patients who do not require mechanical ventilation. In addition, while a scientific consensus is emerging as to the lack of efficacy of the other therapeutic combinations tested in Solidarity, data published in other studies remain contradictory on the subject of remdesivir.

The decision by the Discovery investigators to continue enrolments in this group has therefore been made with the aim of obtaining new data in order to decide one way or the other on the utility of remdesivir in severe COVID-19.

Discovery has received funding from the European Commission and is currently enrolling patients hospitalized for severe COVID-19 in five European countries (other European countries will soon follow and are awaiting regulatory approvals).

Deciphering the energetic code of cells for better anticancer therapies

Posted on by Graziella Cara

 

 

 

 

 

 

© Olivier Cabaud

A procedure that may help personalise anticancer therapies has just been developed by the CNRS, Inserm, and Aix-Marseille University scientists at the Centre d’Immunologie de Marseille-Luminy, in association with colleagues from the University of California San Francisco and the Marseille Public University Hospital System (AP-HM), with support from Canceropôle Provence–Alpes–Côte d’Azur. Their patented technique1 reveals the energy status of cells, an indicator of their activity. It is presented in Cell Metabolism (1 December 2020).

Immunotherapies are a promising anticancer arsenal and work by mobilizing the immune system to recognize and destroy cancer cells.2 Currently, however, only a third of patients respond to immunotherapies: the tumour environment can be hostile to immune cells, depriving them of their source of energy, which diminishes treatment efficacy. The energy status of the various types of immune cells is a marker of their activity, and particularly of their pro- or antitumour action. To boost the effectiveness of immunotherapies, it is thus essential to have a simple method for characterising the energy profiles of immune cells from tumour samples.

SCENITH1 is just such a method. Developed by scientists working in Marseille and San Francisco, it identifies energy sources on which the different cells in the tumour are dependent and, most importantly, the specific needs of immune cells in this hostile environment.

It uses the level of protein synthesis, a process responsible for half of cellular energy consumption, as an indicator of a cell’s energy status. The biopsy sample is separated into subsamples that are each treated with an inhibitor of a metabolic pathway through which cells produce energy. Levels of protein synthesis are then measured using a flow cytometer,3 which also makes it possible to differentiate types of cells in the sample and identify cell surface markers targeted by therapies. The SCENITH method thus identifies the energy status of each immune or cancer cell within the tumour, its energy sources, and the metabolic pathways it relies upon.

The scientists behind SCENITH have already begun working with clinical research teams to better understand how it might be used to predict patient treatment response.4 They seek further collaborations of this kind to determine profiles associated with different responses to immuno- and chemotherapy. SCENITH seeks to enable personalised treatment for each patient that exploits the strengths of the immune response and the weaknesses of the tumour.

 

  1. SCENITH: Single Cell ENergetIc metabolism by profilIng Translation inhibition. Patent: PCT/EP2020/060486
  2. The 2018 Nobel Prize in Physiology or Medicine was awarded for the discovery of immunotherapeutic mechanisms. Find out more about immunotherapy: https://news.cnrs.fr/articles/cancer-the-immunotherapy-revolution.
  3. A flow cytometer is an apparatus that can be used to evaluate each sample cell’s size or shape, or any other cell component or function affecting the intensity of the fluorescent stains employed.
  4. Lopes N, et al. Metabolism and function of γδ T cell subsets in the tumour microenvironment. Nature Immunology (In press).

The SCENITH project received support from Canceropôle Provence–Alpes–Côte d’Azur, the French National Cancer Institute (INCa), France’s Sud regional authority, and INSERM Transfert.

Find out more:

Food Emulsifiers Increase Pathogenicity of Certain Bacteria and Risk of Intestinal Inflammation

Posted on by Graziella Cara

Certain bacteria of the intestinal microbiota (shown in red) are able to penetrate the normally sterile mucus layer (shown in green). © Benoit Chassaing

Diet is believed to play a role in triggering intestinal inflammation that can lead to the development of certain conditions, such as Crohn’s disease. Researchers from Inserm, CNRS and Université de Paris have shown that the emulsifiers present in many processed foods could have a harmful impact on specific bacteria in the gut microbiota, leading to chronic inflammation. Their findings have been published in Cell Reports.

The prevalence of chronic inflammatory bowel disease is increasing in all countries of the world and is thought to affect nearly 20 million people. Characterized by inflammation of the wall of part of the digestive tract, these conditions include Crohn’s disease and ulcerative colitis.

Several factors, both genetic and environmental, have been implicated in explaining the intestinal inflammation associated with these diseases. For several years, Inserm researcher Benoît Chassaing and his team at Institut Cochin (Inserm/CNRS/Université de Paris) have studied the role of diet, particularly the impact of certain additives such as emulsifiers.

Widely used by the food industry in many processed products, the purpose of emulsifiers[1] is to improve texture and extend shelf life. For example, lecithin and polysorbates ensure the smooth texture of mass-produced ice cream and prevent it from melting too quickly once served.

In previous studies based on animal models, the researchers had already shown that the consumption of dietary emulsifiers negatively alters the microbiota in such a way as to promote inflammation.

Moreover, in mouse models where the microbiota had been comprised of a low diversity of bacteria, they observed that the animals were protected against the negative effects of certain emulsifiers.

This led to their hypothesis that the emulsifiers would impact only specific bacteria, which are harmless under “normal” conditions but have the potential to cause disease. It is only in the presence of emulsifiers that these bacteria would be able to promote the development of chronic intestinal inflammation and its associated diseases.

E. coli as a model

As part of their study published in Cell Reports, the researchers used two mouse models: one without a microbiota and the other with a simple microbiota containing only eight species of bacteria. They colonized them with a strain of Escherichia coli (“AIEC bacteria”) associated with Crohn’s disease.

The researchers were interested in the effects of two emulsifiers administered following the colonization of the mice by the AIEC bacteria. Although the consumption of the emulsifiers had no harmful effects on the animals in the absence of these bacteria, they observed the development of chronic intestinal inflammation and metabolic deregulation when they were present. The presence of both the AIEC bacteria and the emulsifier was necessary and sufficient to induce chronic intestinal inflammation.

Further analysis revealed that when these bacteria were in contact with the emulsifiers, they over-expressed groups of genes that increased their virulence and propensity to induce inflammation. “We were able to identify a mechanism by which dietary emulsifiers can promote chronic intestinal inflammation in people who harbor certain bacteria, such as AIEC bacteria, in their digestive tract,” says Benoît Chassaing , who coordinated the study.

The next step is to list all the bacteria that have the same effects in contact with these food additives.

In the longer term, studies to identify and stratify patients according to the composition of their microbiota and risk of inflammation could be set up with the aims of taking a preventive approach and implementing personalized nutritional recommendations. People with specific microbiotas, sensitive to emulsifiers, could benefit from such recommendations.

“And while it is illusory to think that we can banish emulsifiers from our diet, the models and methodologies we have developed here will also allow us to test the action of several types of emulsifiers on the microbiota in order to identify those without harmful effects, and thus encourage their use,” concludes Chassaing.

 

[1] An emulsifier is a compound that has an affinity for both water and oil and allows the different phases of a compound to remain mixed together.

COVID-19 Vaccines: 25,000 Volunteers Needed for Large-Scale Clinical Trials in France – Registration Now Open

Posted on by Léa Surugue

 

International research is being mobilized in order to develop safe and effective vaccines for COVID-19. Around thirty vaccine candidates are at the clinical evaluation stage, with some undergoing Phase 3 trials to demonstrate their efficacy. At the request of the Ministry of Solidarity and Health and the Ministry of Higher Education and Research, France – drawing on the excellence of its clinical research in vaccination – has taken steps to help evaluate the most promising vaccine candidates with the deployment of the COVIREIVAC platform. Driven by Inserm, COVIREIVAC federates 24 Clinical Investigation Centers (CICs) located in university hospitals across France, in close collaboration with the College of Teachers in General Practice. The clinical operational aspects of the various university hospitals are coordinated by the Paris Hospital Group AP-HP. Today, COVIREIVAC opens the registration process for volunteers to participate in the first large-scale clinical trials in France.

To make these trials possible, COVIREIVAC is looking for 25,000 volunteers aged 18 or over and has launched the registration and information website www.covireivac.fr. Developed with the support of Public Health France and the Medicines Agency (ANSM), it aims to provide the most accurate information possible on vaccine development so that potential volunteers can make an informed decision.

Join the fight

Volunteers in COVID-19 vaccine trials have a role to play in fighting the pandemic, moving research forward and thus contributing in the medium term to their own protection and that of their fellow citizens – particularly the most vulnerable. Becoming a volunteer also means participating in a scientific challenge alongside the scientific and medical community.

If you are interested in volunteering, simply pre-register at www.covireivac.fr and complete a preliminary health questionnaire. Volunteers will then be contacted according to the needs of the various trial protocols (age, pre-existing conditions, geographical location), following which they can either confirm or withdraw their agreement to participate in the specific trial for which they have been called. It is also possible that they may never be called.

French research, a key player in developing safe and effective vaccines

Two vaccine clinical trials are currently ongoing in France: a Phase 1 trial in healthy subjects for a vaccine developed by Institut Pasteur in collaboration with CEPI, Themis and MSD which has begun at Cochin Hospital (Paris Hospital Group AP-HP), and a trial in healthcare workers on the contribution of the BCG vaccine to boosting systemic immunity and protection against COVID-19, which is coordinated by AP-HP.

Two types of large-scale clinical trial are envisaged in France. The first is Phase 2 trials to closely study the ability of vaccines to produce an immune response (immunogenicity) in elderly people, whose immune system is generally weakened despite being most at risk of developing severe forms of the disease. The second is Phase 3 trials for the large-scale study of the efficacy and safety of promising vaccine candidates, depending on the intensity of the virus’ circulation in France in the months to come.

These clinical trials could start between October and the end of the year, depending on the evolution of the epidemic and the ongoing discussions with industry.

“Good clinical trials are crucial for the development of safe and effective vaccines. As researchers and doctors, we are all committed to rigorous evaluation that will provide the health authorities with the essential data to guarantee the quality of the vaccines developed. What wenow need is volunteers to mobilize alongside us,” emphasizes Odile Launay, Professor of Infectious and Tropical Diseases at Université de Paris, coordinator of Cochin-Pasteur CIC at Cochin Hospital (AP-HP), and coordinator of COVIREIVAC.

In addition to the follow-up and monitoring of the volunteers during the trials, a specific system for monitoring participants will be set up by the platform at the end of the trials, in conjunction with primary care doctors and ANSM. This monitoring will therefore make it possible to track the safety of the vaccines over the long term.

COVIREIVAC, a “one-stop shop” for France

The COVIREIVAC platform is working in close collaboration with the Scientific Committee for COVID-19 Vaccines, chaired by Inserm Research Director and CARE Committee member Marie-Paule Kieny. The clinical trials conducted will focus on the most promising vaccines, selected by the Scientific Committee.

New Whooping Cough Vaccine In Development

Posted on by Lea Roy

Boîte de pétri contenant une Culture de Bordetella pertussis, l’agent causal de la coqueluche.

Culture of Bordetella pertussis, the causative agent of whooping cough ©Inserm/Locht, Camille

A research team from Inserm, Lille University, Lille University Hospital, CNRS, and the Institut Pasteur of Lille, as part of the Lille Immunity and Infection Center, in partnership with ILiAD Biotechnologies, is developing a new vaccine against whooping cough. The researchers are using the whole bacterium, which has been genetically modified to render it nontoxic, in the hopes of compensating for the efficacy failures of the current vaccine. The new vaccine is intended to induce a lasting immune response and block transmission between individuals. New research published in The Lancet Infectious Diseases presents phase 1 results of the clinical trials for this vaccine, which show satisfactory tolerance and an effective response in adults.

Whooping cough is a respiratory illness caused by Bordetella pertussis bacteria. It is highly contagious and can be fatal to infants. Vaccination is recommended for both infants and their families.

The first whooping cough vaccines were developed in the 1950s. These “inactivated” vaccines involved injecting bacteria that had been inactivated by heat or chemical treatments. The vaccines were effective, but they presented the disadvantage of inducing some localized and generalized adverse effects that were bothersome but not serious. A second generation of more easily tolerated vaccines was developed, this time based on the use of just a few bacterial proteins.

These vaccines have been in use in industrialized nations since the 2000s; but in less than ten years it became apparent that whooping cough infection rates in the general population were rising despite vaccination. The current vaccines do indeed provide effective protection from the illness, but their effect lasts only 3 to 5 years and they do not sufficiently block the transmission of bacteria between individuals.

Inserm research director Camille Locht and his team from the Lille Immunity and Infection Center (Inserm/Lille University/Lille University Hospital/CNRS/Institut Pasteur of Lille) together with ILiAD Biotechnologies are working on a new whooping cough vaccine that will be more effective than current vaccines. Like first-generation vaccines, the new vaccine, referred to as BPZE1, relies on whole bacteria but in this case the bacteria are still alive. BPZE1 is, in fact, a “live attenuated” vaccine, meaning that it contains a live infectious agent but whose pathogenic potential is genetically attenuated (rather than having been inactivated by heat).

One of the major challenges of perfecting BPZE1 was finding a way to improve tolerance, which was poor with the first vaccines. After identifying and describing the toxicity genes responsible for the pathological effects of whooping cough, the researchers were able to genetically modify the bacteria to obtain a strain that lacked toxicity, from which BPZE1 was developed. The vaccine is administered via nasal route in the form of an inhalable suspension, which reproduces the natural route of infection and consequently improves the duration of efficacy.

“This vaccine triggers local immunity in the respiratory tract by mobilizing innate immunity, enabling a rapid response,” explains Locht. “Furthermore, the bacteria are quickly eliminated after being introduced into the nasal cavity, which limits transmission. We hope that the effect of BPZE1 will last for at least two decades.”

After satisfactory preclinical trials in animals, the researchers conducted a phase 1 trial in humans to determine whether tolerance was satisfactory and if a response occurred at three different doses of the vaccine with a single nasal administration. The trial was conducted on 48 participants, aged 18 to 32, presenting few antibodies specific to Bordetella pertussis bacteria. They were divided into three groups, one for each of the three doses. In each group, 12 individuals received the vaccine and 4 received a placebo. Nasal and blood samples were taken on six occasions during the first month, then six months later, and, finally, one year later, to check whether the vaccine was present in the mucosa and determine whether a specific immune response had taken place.

The highest dose triggered the production of specific antibodies, which were still present one year later in 100% of the volunteers (the rate was 80% at the lowest dose). Furthermore, all three doses were tolerated well, with adverse effects equivalent to those reported in the placebo groups.

The researchers were encouraged by these results and have begun phase 2 clinical trials in 300 volunteers. “If this vaccine passes all the steps in development, it may be used initially for adults who care for infants, to protect the infants from the possibility of transmission,” Locht specifies. “Use in vulnerable individuals and infants is planned, but this will require additional safety data that it may take a long time to obtain,” he concludes.

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