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.

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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.

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Thanks to antiretroviral therapies, it is possible to grow old with HIV under control. However, this chronic infection may not leave cognitive function unscathed. That is why Alain Makinson (Translational Research on HIV and Infectious Diseases unit, Montpellier University Hospital, Université de Montpellier, Inserm, IRD) and his team were interested in exploring the development of neurocognitive impairment (NCI), such as diminished attention, memory and motor capacity, in patients living with HIV in the ANRS EP58 HAND 55-70 study. In their latest research, published in Clinical Infectious diseases, the scientists describe the results of their observations of 200 people living with HIV enrolled in six French centers. The data collected from these patients were then compared, using the same neurocognitive evaluation methods, with those of a control population of 1,000 people of the same age, sex and education taken from Constances – a cohort recruited from the general population, with over 200,000 volunteers. The researchers reveal that among those living with HIV between the ages of 55 and 70, the risk of developing mild (and in some cases, symptomless) neurocognitive impairment increases by 50%.

Thanks to antiretroviral therapies, people living with the human immunodeficiency virus (PLHIV) can bring it under control. However, while HIV is no longer their major cause of death – having decreased substantially since the advent of these therapies – other risks must be considered. Several recent studies have highlighted the increased prevalence of neurocognitive impairment (NCI) in PLHIV compared with uninfected individuals – an increase that is all the more pronounced in those whose virus is not controlled. However, this NCI could also be caused by cardiovascular factors or the onset of depression, which is more common in this population.

In order to try to determine the nature of the link between living with HIV and developing NCI (such as diminished attention, memory and motor capacity), Alain Makinson and his coworkers studied the data of 200 PLHIV, between 55 and 70 years of age, whose HIV was under control and who were enrolled between January 2016 and October 2017 in the ANRS EP58 HAND (HIV-Associated Neurocognitive Disorder) study. Each patient was compared with five HIV-uninfected individuals of the same age, sex and education, from Constances – a cohort recruited from the general population. The same methods were used for both populations when performing the cognitive tests and collecting the study data. All in all, 1,200 people took part in this study.

Although the impairments observed in the study were either mild or without apparent symptoms (i.e. with zero to low impact on daily activities despite abnormal test results), those living with HIV were more affected by NCI: 35% versus 24% for the control group.

The risk of developing NCI is therefore 50% higher for HIV-infected individuals compared with HIV-uninfected individuals, all other criteria being equal (age, sex and education).

Despite these highly robust results, a causal link between living with HIV and developing NCI cannot be established – for which there are several possible hypotheses. One is that HIV infection and its treatments cause recurrent brain inflammation. Another is that the complications associated with the immune deficiency can affect cognition before antiretroviral treatment is initiated, but without the subsequent deterioration occurring more rapidly in comparison with the general population. Finally, seropositivity could be associated with other risk factors (particularly drug use), which are difficult to measure fully in the two populations of this study.

The authors wish to continue to follow the same population over a longer period in order to better define the causes of NCI in this aging population and test the hypothesis of accelerated cognitive aging in PLHIV – particularly given that very few studies with a control group are available. Testing the brain inflammation hypothesis by collecting certain specific blood biomarkers represents another avenue for the team to explore in its quest to elucidate the mechanisms behind NCI.

Fibroblast infected with the chikungunya virus. © Inserm/Thérèse Couderc/Marie-Christine Prévost/Marc Lecuit

Chikungunya is an infectious disease caused by a mosquito-borne virus transmitted to humans. First detected in Africa, the virus has been responsible for recent epidemics in the Americas, Asia and the Indian Ocean – particularly the Reunion Island. Chikungunya is characterized by high fever and intense joint and muscle pain that can last for several months. The mechanisms of infection of human cells with the virus remain very poorly understood. Led by Ali Amara in collaboration with Marc Lecuit researchers from Inserm, Institut Pasteur, CNRS and Université de Paris have identified a protein that is crucial in order for the virus to replicate within its target cells. This research, published in the journal Nature, opens up therapeutic avenues in the fight against chikungunya.

Originally from Africa, chikungunya is aptly named. It derives from a word in the Kimakonde language, meaning “to become contorted”, because the severe muscle and joint pains endured by the patients prevent them from moving normally or performing their daily activities.

While the clinical manifestations of the disease are well understood, the mechanisms by which the virus infects human cells and multiplies remain poorly elucidated. Several studies had already identified certain host cell factors implicated in the replication of the virus. However, none had succeeded in explaining why the virus preferentially targets the muscle and joint cells, causing these clinical signs.

Researchers from Inserm, CNRS and Université de Paris led by Dr. Ali Amara at the AP-HP Saint-Louis Hospital Research Institute in Paris, in collaboration with Marc Lecuit’s team from Institut Pasteur, Inserm and Université de Paris, have identified that the FHL1 protein is a key cellular factor for the replication and pathogenesis of chikungunya. FHL1 is a molecule present mainly in the muscle cells and fibroblasts, the preferred targets of the virus. Usually, FHL1 contributes to healthy muscle physiology and it is now thought to be diverted from that function by the virus to ensure its replication in the target cells.

To conduct this study, Amara’s team used the CRISPR-Cas9 technology to systematically screen the genome of human cells in order to identify the host factors necessary for viral replication. In doing so, it isolated the gene coding for the FHL1 protein. The team then conducted a series of experiments showing the incapacity of the virus to infect cells whose FHL1 expression had been abolished.

In addition, the researchers have shown that the virus was incapable of multiplying within cells derived from patients suffering Emery-Dreifuss muscular dystrophy – a rare genetic disease. This muscle disease is the result of mutations of the FHL1 gene responsible for the breakdown of the FHL1 protein. The researchers have shown that the cells of these patients are resistant to the virus.

Finally, the researchers performed in vivo experiments in mice whose Fhl1 gene was invalidated. They have shown that these animals are totally resistant to infection and do not develop the disease, whereas the virus multiplies and causes major muscle lesions in mice expressing a functional FHL1 protein. These observations demonstrate that the FHL1 protein plays a key role in chikungunya virus replication and pathogenesis.

The precise role played by FHL1 in the viral infection is not fully understood. The researchers have discovered that FHL1 interacts with a viral protein known as nsP3. It is when binding to this that FHL1 participates in the replication of the virus.

“We now want to understand this interaction in molecular detail. The next step is to define why FHL1 is so specific to the chikungunya virus, and to decipher its mechanism of action at the molecular level. Elucidating the molecular structure of the FHL1-nsP3 complex could represent a major step forward in the development of antivirals that block the replication of the virus“, emphasize Ali Amara and Laurent Meertens, the Inserm researchers in charge of the study.

At present, only symptomatic treatments are available for patients infected with chikungunya.

Escherichia coli © Inserm/Cloup, Emilie/Nougayrede, Jean-Philippe

For more than a century, the Nissle 1917 strain of the bacterium Escherichia coli has been used as a probiotic to treat gastrointestinal disorders. However, this bacterium also produces a toxin, colibactin, which has deleterious effects on host DNA and might cause colon cancer. It is therefore crucial to understand the mechanisms at play in the strain if we wish to limit undesirable side effects. In a recent study, researchers at INRA, INSERM, the University of Toulouse III – Paul Sabatier, and ENVT managed to decipher certain pathways by which Escherichia coli Nissle 1917 produces both beneficial and toxic compounds. They then successfully created a modified strain with the same probiotic properties but an unactivated version of the toxin. This work was published on September 23, 2019, in PLOS Pathogens.

A German doctor discovered the bacterial strain that became known as Escherichia coli Nissle 1917 during World War 1. There had been an outbreak of dysentery in a group of soldiers; only one remained unafflicted. The doctor, Alfred Nissle, isolated the strain from this soldier and used it to treat other soldiers. Since then, E. coli Nissle 1917 has been used as a probiotic to treat various gastrointestinal disorders.

In 2006, researchers at INRA, INSERM, the University of Toulouse III – Paul Sabatier, and ENVT discovered that the genome of E. coli Nissle 1917 contained a group of genes that jointly encode a toxin: colibactin. In certain E. coli strains, colibactin acts as a virulence factor and can promote colon cancer. Until now, researchers had been unable to decouple the strain’s probiotic properties from its toxic side effects. It was therefore necessary to delve into the mechanisms underpinning both the strain’s synthesis of beneficial compounds, which make it a probiotic, and its synthesis of harmful compounds, notably colibactin, which can have negative impacts.

In a new study, this same team of researchers uncovered the important role played by the protein ClbP. It is an enzyme that has a key function in the strain’s probiotic action but that also activates colibactin. 

Using this discovery, the scientists were able to create a strain in which a tiny relevant portion of the enzyme was modified. This strain had the same probiotic properties as the original but could not activate colibactin, negating its toxicity. In vivo assays in mice confirmed the functionality of the new strain. Mice infected with Salmonella typhimurium (one of the bacteria that can cause dysentery) developed less severe symptoms of salmonellosis when treated with the modified E. coli Nissle 1917 strain.

This research underscores the importance of taking a closer look at the bacteria that we use as probiotics. Indeed, like traditional medications, they can have side effects.

Illustration of the experimental approach © INRA, INRA, Eric Oswald

WHO©C. Onuekwe

The World Health Organization (WHO) recommends a single dose of the yellow fever vaccine for individuals aged 9 months or older living in or traveling to areas at risk of disease transmission, but there is a lack of data on its long-term efficacy when administered to infants. José Enrique Mejía, Inserm researcher at Unit 1043 Center for Pathophysiology of Toulouse Purpan and Cristina Domingo from the Robert Koch Institute in Berlin have recently shown that around half of children initially protected by the vaccination at 9 months of age lose that protection within the next 2 to 5 years, due to disappearance of the neutralizing antibodies. This research has been published in The Lancet Infectious Diseases.

Yellow fever is a viral infection spread by various species of mosquito and is rife in 34 countries in Africa and 13 in Latin America. Infection may be asymptomatic and go unnoticed or, on the contrary, it may progress rapidly to severe illness with fever, headache, muscle pain, nausea, vomiting and fatigue. The virus attacks the liver cells, often causing jaundice from which the disease gets its name. Severe bleeding occurs in 25 to 50 % of cases, with high levels of mortality observed 7 to 10 days after the onset of symptoms.

Since 2013, WHO recommends a single dose of the vaccine for life-long protection. This recommendation is based on proof of long-term efficacy, in vitro and in vivo, established in adults and children over 2 years of age.

Their study verified whether children to whom the vaccine was administered at around 9 months of age were still protected several years later. The team studied two cohorts, one from Mali (587 children) and the other from Ghana (436 children), in whom the levels of specific antibodies to the yellow fever virus had been measured 4 weeks after vaccination. They then repeated the measurement several years later, with findings from previous studies enabling them to estimate that levels above 0.5 IU/ml should protect children from infection.

In the Malian cohort, 4.5 years after vaccination, only half of the children continued to present levels of antibodies above 0.5 IU/ml. And 19.3 % presented detectable antibodies but at levels below this recommended threshold (<0.5 IU/ml). The proportion of children seropositive for these antibodies was therefore 69.7 % as opposed to 96.7 % just after vaccination.

In the Ghanaian cohort, 2.5 years after vaccination, only around 30 % of children continued to be protected against infection and 11.7 % continued to present specific antibodies but in low concentrations (<0.5 IU/ml). All in all, 39.4 % of the children were considered seropositive as opposed to 72.7 % just after vaccination.

Irrespective of the differences in vaccine efficacy between these two groups, which could be explained by ethnic and environmental factors (urban/rural population, seasonality of vaccination, diet, exposure to other infectious agents, etc.), the results in both cases show a substantial fall – practically by half – in the levels of protective antibodies in the years following vaccination, and which predict the absence of protection against infection for large numbers of children.

“Our data suggest that a booster may be necessary when the 1^st vaccination is performed in 9-12-month-olds, but we will need more precise knowledge of the decrease in antibodies over time. Maintaining immunity to the virus during childhood and in adulthood is fundamental for obtaining vaccine coverage beyond the threshold of 80 % of the population in order to prevent the risk of epidemic”, concludes Mejía.