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Month: December 2022

Trial on safety and immunogenicity of Ebola vaccines yields promising results

Posted on by Graziella Cara

© Inserm/Patrick Delapierre, 2018

Ebola epidemics occur periodically in various sub-Saharan African countries. While vaccines exist and have already received WHO Prequalification[1] against the Zaire ebolavirus species, it is essential to pursue and intensify efforts to supplement the available data to develop a safe and effective Ebola vaccine strategies in adults and children alike. The PREVAC international consortium (see box), which includes scientists from Inserm and from institutions in Africa, USA and UK, has published the results of a large-scale randomized clinical trial in West Africa in the New England Journal of Medicine. These results confirm the safety of three different vaccine regimens, and suggest that an immune response is induced and maintained for up to 12 months.

In a context where many sub-Saharan African countries regularly face Ebola outbreaks, vaccines are seen as a central tool to fight the spread of the disease. Since 2019, two vaccines have obtained WHO Prequalification against the Zaire ebolavirus species: the vaccine rVSVΔG-ZEBOV-GP developed by Merck, Sharpe & Dohme, Corp., and the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen from Johnson & Johnson.

Beyond these advances, research on Ebola vaccines must continue. Indeed, additional data is needed in order to establish the most appropriate recommendations regarding the use of these vaccines, in different categories of the population.

 

Three Vaccine Regimens Tested

This is the goal of the PREVAC international consortium. Starting in 2017, a vast, multicenter, randomized, placebo-controlled, phase 2 trial mobilized African, European and US research teams working together in Liberia, Guinea, Sierra Leone, and Mali.  It is one of the largest Ebola vaccination trials to date – conducted with both adults and children aged 1 year and older.

The trial aimed to measure the rapidity, intensity and durability of the immune responses generated by three different Ebola vaccine regimens, involving the vaccines mentioned above. It also evaluated the safety and tolerability of the various products administered.

 

  • The first vaccine regimen tested consisted of injecting one dose of ZEBOV followed 56 days later by one dose of MVA-BN-Filo.
  • The second regimen consisted of injecting one dose of rVSVΔG-ZEBOV-GP.
  • Finally, the third regimen started with one dose of rVSVΔG-ZEBOV-GP followed 56 days later with the same vaccine as a booster.

 

In total, the trial included 1400 adults and 1401 children between 1 and 17 years of age, who were randomized into several groups to test and compare the three regimens versus placebo.

The data obtained suggest that all three regimens are safe and well-tolerated in adults and children.  After vaccination and within the 7 days that followed, the majority of the participants reported pain at the injection site and other minor symptoms (fever, muscle and joint pain, headache, etc.), which generally disappeared after 7 days.

The three regimens also generated a rapid increase, after 14 days, of the amount of antibodies directed against the virus, with a peak at between 1 and 3 months after the first vaccination. While it’s not yet possible to say whether this immune response prevents infection, current scientific literature suggests a strong correlation between the amount of these antibodies and the level of protection against the virus. These antibodies were detected up to 12 months after the first injection.

“The data collected during this clinical trial are valuable because they help confirm the safety and potential efficacy of the available vaccines, making it possible to refine the vaccination recommendations during both Zaire ebolavirus epidemic and inter-epidemic periods, in populations at risk,” explains the trial’s principal investigator, Yazdan Yazdanpanah.

 

“This trial is marked by a high participant retention rate thanks to the unwavering involvement of all the professionals in the field, and the population’s adherence to the research that led to these results,” explains principal investigator Mark Kieh.

 

“The PREVAC trial is a real example of success for international research in emerging and re-emerging infections. We show that with solid collaboration founded on strong partnerships, we can advance Ebola research in the areas of the world most affected by the disease,” emphasizes H Clifford Lane, NIAID Deputy Director for Clinical Research and Special Projects.

 

The work of the PREVAC consortium in West Africa continues, thanks in part to a European funding from the EDCTP supported by the European Union. Participants will be followed up over a 5-year period to assess the long-term safety of vaccines and the durability of the immune response. It is crucial to obtain such data, which will shed light for example on whether or not it is necessary to provide a vaccine booster to individuals who are already vaccinated.

 

About PREVAC

Partnership for Research on Ebola Vaccinations (PREVAC) is an international consortium that conducts research in West Africa to assess the safety and efficacy of Ebola vaccination.

The project is co-funded by Inserm, NIAID, LSHTM, and COMAHS and is supported by Guinea, Liberia, Mali, and Sierra Leone. In-field support from the NGO ALIMA has also been crucial to foster the population’s adherence to the research and to monitor the volunteers. The companies Merck and JnJ provided the vaccines used in the trial.

The project received additional funding to continue monitoring volunteers over the long term (PREVAC-UP project) via the European and Developing Countries Clinical Trials Partnership (EDCTP2) program supported by the European Union.

 

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

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) program 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.

[1] Prequalification means that a vaccine meets WHO standards of quality, safety, and efficacy. Based on this recommendation, United Nations agencies and Gavi, the Vaccine Alliance, can procure the vaccine for the countries where there is a high level of risk.

2022 Inserm Prizes: Forming a Common Front for Our Health

Posted on by Graziella Cara

Prix Inserm 2022

© Inserm

 

“Awarding the Inserm Prizes is a key point in the Institute’s life, enabling us to showcase the various talents of our staff and the great wealth of the research we conduct to form a common front for the health of our fellow citizens. But it is also an opportunity to emphasize our involvement at the heart of society, our commitment to scientific research that is effective, ethical and accessible to as many people as possible,” states Inserm CEO, Gilles Bloch.

This year, the Inserm Prizes are awarded to five individuals whose results and commitment to high-quality research demonstrate scientific excellence and the Institute’s central place in society. The Inserm 2022 Grand Prize goes to Olivier Delattre, an oncopediatrician whose work has led to major discoveries in childhood cancers.

 

Olivier Delattre, Inserm Grand Prize

Prix Inserm 2022

Olivier Delattre © Inserm/François Guénet

“Once a pediatrician, always a pediatrician,” may well be the expression that best describes Olivier Delattre’s commitment. Director of the Cancer, heterogeneity, instability and plasticity unit (unit 830 Inserm/Institut Curie), this researcher began his career by studying medicine, during which he developed an interest in pediatrics. His time with the Pediatric oncology department of Institut Curie in Paris encouraged him to specialize in childhood cancers and study biology alongside his work as a doctor.

In the early 1990s, he decided to focus entirely on research with the aim of improving the understanding, diagnosis and treatment of pediatric cancers – so he joined Inserm. In 1992, he was involved in a world first when his team identified and characterized the genes responsible for Ewing sarcoma, a form of bone cancer that occurs in children. This was followed by a series of discoveries with significant advances in the understanding of rhabdoid tumors, which are rare and very aggressive cancers.

In 2018, which represents another key step in his career, he founded the SIREDO center (for Care, innovation & research in childhood, adolescent & young-adult oncology) at Institut Curie in Paris, which he has been leading ever since. An initiative that brought together within the same place healthcare and research teams dedicated to solid tumors affecting the under-25s. In this pioneering center, the aim is to collaborate more effectively and ensure that basic research can quickly benefit patients.

It is this desire to always go further to serve the health of young patients and their families, by continuing to work tirelessly to better understand and treat their diseases, which has earned Delattre the Inserm Grand Prize.

 

Valérie Gabelica, Research Prize

Valérie Gabelica © Inserm/François Guénet

Mass spectrometry, an analytical chemistry tool more than a century old, has been given a new lease of life thanks to work by Valérie Gabelica and her team.

A researcher at ARNA (unit 1212 Inserm/CNRS/Université de Bordeaux), this chemist has developed with her colleagues an innovative method that combines mass spectrometry and circularly polarized light to improve the study of the structure of nucleic acids (DNA and RNA) and how they interact with other molecules. It is understanding these interactions that will help research to discover new medicines, for example.

A long-term endeavor, which offers biomedical research valuable new tools and demonstrates the importance and excellence of the interdisciplinary research conducted at Inserm.

 

Valérie Crépel, Innovation Prize

Valérie Crépel © Inserm/François Guénet

Temporal lobe epilepsy is the most common form of epilepsy in adults. In 2005, Valérie Crépel, Inserm research director at the Mediterranean Institute of Neurobiology in Marseille, showed that kainate receptors of glutamate, a key neurotransmitter of the nervous system, were involved. Shortly afterwards, her colleague Christophe Mulle discovered that these receptors are a key element in the origin of this epilepsy in the hippocampus and a potential therapeutic target.

With the support of Inserm Transfert, Inserm’s subsidiary for tech transfer, the scientists filed a first patent in 2013. The project continued to develop, resulting in the creation of Corlieve Therapeutics in 2019. This start-up then became a subsidiary of Dutch biotech uniQure in 2021. The years of research in epilepsy and the efforts to create value have paid off in leading to the clinical trial of a treatment in patients.

 

Justine Bertrand-Michel, Research Support Prize

Justine Bertrand-Michel © Inserm/François Guénet

Trained chemist Justine Bertrand-Michel has dedicated her entire career to supporting researchers. Since 2021, she has masterfully led the MetaToul platform, the largest in France, with 6 teams, 40 engineers, 23 analysis systems and 4 robots.

This metabolomics platform analyzes metabolites, the compounds derived from the metabolism of all living things: glucose, amino acids, nucleotides, etc.

This work is her passion and requires a thorough understanding of the challenges faced in order to offer services, develop methods and train new staff – while keeping the budget balanced.

 

Priscille Rivière, Opecst-Science and Society Prize

Priscille Rivière © Inserm/François Guénet

Deputy director of the Inserm Scientific information and communication department, Priscille Rivière works to ensure the clear, transparent and rigorous dissemination of science to the general public.

The COVID-19 pandemic has brought with it an increase in health misinformation.

The initiatives set up by Rivière with the communications team – from the Canal Détox series to the development of the Cellule Riposte network of researchers to answer media questions – now enable Inserm to play a role in the more global fight against fake news. And build a trust-based dialogue between scientists and citizens, to improve the health of all.

The Inserm Prizes

The Grand Prize pays tribute to a French scientific research player whose work has led to remarkable progress in our knowledge of human physiology, treatment and health research more generally.

The Research Prize honors a researcher, lecturer-researcher or clinician-researcher whose work has particularly marked the fields of basic research, clinical and therapeutic research, and public health research.

The Innovation Prize is awarded to a researcher whose work has been the subject of entrepreneurial value creation.

The Research Support Prize is awarded to an engineer, technician or administrative worker for significant achievements in the support of research.

Finally, the Opecst-Science and Society Prize honors a researcher, engineer, technician or administrative worker who stands out in the field of research promotion and through their ability to be in dialogue with society and attentive to the health questions of its citizens.

ASD: Towards a Better Understanding of the Molecular Mechanisms of Autism

Posted on by Graziella Cara

autisme

Images showing the human brain anatomy in two axial slices obtained by MRI (left), then the corresponding molecular images showing a larger number of mGluR5 receptors in the brain of an adult subject with ASD (right) compared to a control subject (middle). © Laurent Galineau

 

While great progress has been made in recent years in the understanding of autism spectrum disorder (ASD), its underlying molecular mechanisms remain fairly poorly documented. Several hypotheses have been put forward regarding the possible dysfunction of certain neurotransmitters in the brain, but rigorous scientific studies are still lacking in order to validate them. In a new publication, researchers from Inserm and Université de Tours at the Imaging & Brain unit have shown that specific receptors of glutamate, one of the most important neurotransmitters in the nervous system, are expressed in large quantities in the brains of adults with ASD. However, this overexpression of the receptors does not occur at earlier stages of development. The study, sponsored by Tours university hospital and published in Molecular Psychiatry, paves the way for a better understanding of ASD to help refine therapeutic research.

Autism spectrum disorder (ASD) is caused by neurodevelopmental particularities and affects around 700 000 people in France. This term brings together a large variety of clinical realities and as such a large variety of specific individual needs. The development of treatments that specifically target severe autism-related disorders has long been hampered by a piecemeal understanding of the underlying molecular and genetic mechanisms.

At present, those affected may therefore use treatments for potential comorbidities such as sleep disorders or epilepsy, but there is no therapeutic solution to improve behavioral disorders or the associated alterations in social interactions.

One avenue put forward to explain the development of ASD is dysfunction of glutamate – the main excitatory neurotransmitter of the central nervous system. Studies have recently suggested that glutamate receptors called mGluR5 (see inset) are expressed in increased quantities in certain brain regions in people with ASD.

mGluR5 and glutamate

mGluR5 is a receptor that is abundantly expressed in the central nervous system and particularly in the cerebral cortex, hippocampus, lateral septum, dorsal striatum, and nucleus accumbens, which are all brain regions involved in cognition, motor control and emotivity.

mGluR5 belongs to a subgroup of eight receptors that are activated by glutamate, the main excitatory neurotransmitter of the central nervous system.

Pharmacological intervention on these receptors, particularly mGluR5 blockade, is already being evaluated for various disorders such as anxiety, depression, schizophrenia, Parkinson’s disease, and addictions.

Compensatory mechanism

In order to further understand the molecular mechanisms of ASD, Frédérique Bonnet-Brilhault’s team at the Imaging & Brain unit (unit 1253 Inserm/Université de Tours) sought to better characterize glutamate dysfunction in the brains of adults with ASD.

They started by quantifying the glutamate levels in the cingulate cortex of 12 adults with ASD and 14 adults without ASD (referred to as “control” participants), using several methodological approaches. Next, they looked at the expression of the mGluR5 receptors in the participants’ brains.

The scientists observed that the glutamate levels varied widely in the adults with ASD. However, they found that the quantity of mGluR5 receptors expressed was particularly high in the brains of all these individuals, compared to the controls.

Then, to better understand how the quantity of mGluR5 varies at different stages of development, the team also quantified these receptors in the brains of young rats, grouped into animal models of ASD and “control” animals.

Their analyses show that the quantities of mGluR5 in the “ASD rats” and the “control rats” did not differ during childhood. However, in adolescence, larger quantities of these receptors were present in certain brain regions of the “ASD rats”.

The fact that mGluR5 receptors are expressed in large quantities in the adult human participants with ASD, but not at the earliest stages of development in the animal models, suggests that the overexpression of these receptors is not a cause of this disorder, but rather a consequence that emerges progressively throughout life.

“Our findings suggest that the changes in the quantity of mGluR5 receptors expressed during development could be a compensatory mechanism for the early dysfunction in the brain communication systems, rather than a primary element that causes the development of ASD,” explains Bonnet-Brilhault.

At a time when research in adults with ASD is a real priority, this work points to the need to understand the development trajectory of each individual with ASD to distinguish the causes of the adaptation mechanisms.

An overview of ASD

“Typical” autism, described by the child psychiatrist Leo Kanner in 1943, is now part of much broader group, known as Autism Spectrum Disorder (ASD), a term that takes better account of the diversity of the situations. ASD is characterized by:

  • alterations in social interactions
  • communication problems (language and non-verbal communication)
  • behavioral disorders: a restricted and repetitive repertoire of interests and activities (stereotypies: tendency to repeat the same movements, words, or behaviors)
  • unusual sensory reactions

ASD can also be associated with other conditions, such as anxiety disorders, sleep problems, motor function deficits, or epilepsy.

Within this wide range of clinical diversity, it is important to identify the “strengths” or “talents” that may result from this atypical brain development. The development of therapies must therefore target what corresponds to the individuals’ complaints while preserving their specific characteristics.

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