Against Whooping Cough and Its Transmission, a New Safe and Effective Nasal Vaccine

coqueluche - Colonies de Bordetella pertussis

Colonies of Bordetella pertussis, the agent of whooping cough, on an agar plate. © Camille Locht/Inserm

Highly infectious and potentially life-threatening in infants, whooping cough, caused by the bacterium Bordetella pertussis, continues to circulate to a large extent throughout the world. Although the vaccines currently used protect against the onset of symptoms, they have limited durability and cannot prevent bacterial infection resulting in transmission between individuals. An international research team including Camille Locht, Inserm research director at the Center for Infection and Immunity of Lille (Inserm/Institut Pasteur de Lille/Université de Lille/Lille University Hospital/CNRS), has demonstrated, in a phase 2 clinical trial, the efficacy and safety of a nasal vaccine for whooping cough in adults. The results of their study, sponsored by ILiAD Biotechnologies and to be published in The Lancet, suggest that this new vaccine, BPZE1, which is potentially capable of preventing bacterial colonization of the respiratory tract, constitutes a valuable asset when it comes to breaking the epidemic chains of transmission of the disease.

Whooping cough is an infectious respiratory disease caused by the bacterium Bordetella pertussis. Highly contagious, it is known for causing fatal complications in infants.

Since the late 1990s, although the Tdap vaccine[1] has been used in industrialized countries mostly to fight whooping cough, the immunity it provides decreases over time, requiring the administration of boosters. In addition, although it helps to prevent the onset of symptoms, it does not prevent infection by the bacterium itself or its transmission to others. Therefore, whooping cough epidemics persist throughout the world, despite high rates of vaccination.

The development of a new whooping cough vaccine, called BPZE1, aims to make up for the shortcomings of Tdap in order to better fight these epidemics. A particularity of this “live attenuated” vaccine (containing an attenuated version of the bacterium) is that it is administered nasally, thereby mimicking the natural modes of transmission and colonization of Bordetella pertussis in the mucous membranes of the respiratory tract.

An international research team including Camille Locht, Inserm research director at the Center for Infection and Immunity of Lille (Inserm/Institut Pasteur de Lille/Université de Lille/Lille University Hospital/CNRS), in collaboration with the company ILiAD Biotechnologies, conducted a study to evaluate the efficacy and safety (non-toxicity) of BPZE1 in a phase 2 clinical trial with 300 healthy adult US participants.

In this study, the participants were divided into two groups: the first group received one nasal dose of BPZE1 and one intramuscular dose of placebo and the second group received one intramuscular injection of Tdap and one nasal dose of placebo. Three months later, half the participants from each of the two groups received one dose of BPZE1 (to simulate an attenuated natural infection), while the other half received intranasal placebo.

The research team found that, while the Tdap vaccine induced the secretion of high levels of Bordetella pertussis immunity markers in the blood, BPZE1 induced consistent immunity in both the nasal mucosa and the blood. In addition, within 28 days of the second nasal administration, 90% of the participants having initially received BPZE1 had no bacterial colonies in the nose. In the remaining 10%, colonization was low (fewer than 260 colonies per mL of mucus). In comparison, 70% of the patients vaccinated with Tdap had significant nasal bacterial colonization (nearly 14,325 colonies per mL).

Moreover, the research team did not see any serious adverse side effects from vaccination during the study.

Therefore, according to Locht, “the benefit/risk profile of BPZE1 is favorable: just one nasal administration induces safe and well-tolerated strong and long-lasting immunity, in both the blood and respiratory tract. And unlike Tdap, BPZE1 protects the mucous membranes from colonization by the bacterium”.

Indeed, given that Bordetella pertussis infects the respiratory tract and multiplies in its mucosa, immunity at this level could be essential in preventing epidemics of whooping cough.

“As this bacterium is highly infectious to humans, it is critical that a vaccine does not only target the prevention of disease but also the transmission of its causative bacterium and the speed at which the body eliminates it,” adds Locht, “which makes BPZE1 a relevant tool for preventing whooping cough infections and reducing the epidemic chains of transmission.”

Given that the participants in the aforementioned study were all adults over the age of 18, another study is ongoing to evaluate the efficacy and safety of BPZE1 in school-age children, as schools are a critical location for transmission of the disease.

More About the Development and Evaluation of BPZE1

In 2008, the European project CHILD-INNOVAC was launched under the auspices of Inserm in collaboration with 10 European partners, with the aim of developing an innovative nasal vaccine against whooping cough. This was the context for the development and patenting of the BPZE1 vaccine by a team from Inserm and Institut Pasteur de Lille led by Inserm research director and project coordinator, Camille Locht. In 2014, the research team published in PLOS ONE the first work evaluating the efficacy and safety of BPZE1 in a phase 1 clinical trial, following examination of the data by an Independent Data Monitoring Committee. An agreement was then reached between the Inserm Transfert platform, tasked with creating value from the intellectual property related to BPZE technology, and ILiAD Biotechnologies, in order to continue the development and evaluation of the vaccine. In 2020, a new phase 1 study conducted in collaboration with ILiAD Biotechnologies, and published in The Lancet Infectious Diseases, reinforced the clinical results from 2014 on the vaccine’s efficacy and safety.

[1] Tdap is an “acellular” vaccine, which does not contain whole bacteria but only certain proteins derived from Bordetella pertussis, which have the particularity of triggering a blood immune response. It combines vaccines against whooping cough, diphtheria, and tetanus, and is administered in France in three intramuscular doses to infants at 2, 4, and 11 months of age. Three boosters are recommended at around 16 months, 11 years and 26 years of age. Although better tolerated, it is more expensive and less effective than the whole cell pertussis vaccine (that contains the inactivated bacteria), which is still being used today in many low- and middle-income countries.

A New Milestone in the Development of an Effective Allergic Asthma Vaccine

asthmeMicroscopic visualization of lung sections from a mouse model of house dust mite asthma, with hematoxylin and eosin staining showing bronchial obstruction and white blood cell infiltration around the bronchi in the unvaccinated group (left) but not in the vaccinated group (right). © Dr Eva Conde.

To combat allergic asthma, which affects millions of people worldwide, scientists from Inserm, CNRS and Université Toulouse III-Paul Sabatier at the Infinity laboratory[1], Institut Pasteur and French company NEOVACS are developing and testing a new vaccine. In their previous study, the teams had shown it to be effective in producing antibodies capable of neutralizing human immune proteins that play a key role in triggering allergic asthma, cytokines IL-4 and IL-13. The results, published in Allergy, pave the way for the organization of a clinical trial.

Asthma is a chronic disease that affects around 4 million people in France and 340 million worldwide. Allergic asthma, which accounts for around 50% of asthma cases, is characterized by inflammation of the bronchial tubes and respiratory discomfort caused by the inhalation of allergens, most often dust mites.

This exposure to dust mites and other allergens triggers the overproduction of antibodies called immunoglobulin E (IgE) and proteins called type 2 cytokines (particularly interleukin-4 (IL-4) and IL-13) in the airways. This phenomenon leads to a cascade of reactions resulting in hyperresponsiveness of the respiratory tract, overproduction of mucus, and eosinophilia (when there are too many eosinophils, a type of white blood cell, in the airways).

At present, inhaled corticosteroids are the gold standard for controlling asthma. However, in the case of severe allergic asthma, this treatment is not always sufficient. Therapeutic monoclonal antibody treatments are then required in order to target the IgE or the IL-4 and IL-13 pathways. However, these are very costly and require patients to inject for years or even throughout their lives.

For several years now, Inserm research director Laurent Reber and his colleagues at the Infinity laboratory in Toulouse, along with Pierre Bruhns’ team at Institut Pasteur, have been working in collaboration with French company NEOVACS to develop a vaccine to open up new therapeutic avenues for patients with severe allergic asthma.


A Vaccine Effective Against Human Cytokines

In a previous study, the researchers had showed the efficacy in mice of a conjugate vaccine [2] called Kinoïde® (see box). The results suggested that this vaccine induced the sustained production of antibodies directed specifically against murine IL-4 and IL-13, as well as a reduction in the symptoms of allergic asthma in those animals.

Following these encouraging early data and in order to envisage clinical trials in humans, it was necessary to develop a vaccine that is also capable of neutralizing human IL-4 and IL-13 cytokines. In order to test the efficacy of this new vaccine, the scientists this time used a model of house dust mite allergic asthma in “humanized” mice, whose genes encoding murine cytokines IL-4 and IL-13 were replaced with the respective human genes.

Again, the results are promising: vaccination induced a major antibody response, capable of neutralizing human IL-4 and IL-13 cytokines, with no reduction in the efficacy of the vaccine, up to three months after injection (time corresponding to the total duration of this study).

A significant effect on asthma symptoms was also observed: in the animals studied, vaccination was associated with reduced IgE and eosinophilia levels as well as reduced mucus production and airway hyperreactivity.

 “This study provides proof of concept of the vaccine’s efficacy in neutralizing human proteins that play a key role in allergic asthma, bringing us closer to its testing in humans. We are currently in discussion with the various project partners regarding the set-up of these clinical trials,” concludes Reber.

“Vaccination against allergic asthma represents the hope of a long-term treatment for this chronic disease and the prospect of reducing allergy symptoms related to other factors, since this vaccine targets molecules involved in different allergies,” points out Pierre Bruhns, head of the Antibodies in Therapy and Pathology unit at Institut Pasteur.


 How Does This Vaccine Work?

Kinoïde® uses a technology that combines the recombinant cytokines IL-4 and IL-13 with a carrier protein called CRM197 (the non-pathogenic mutated form of the diphtheria toxin, used in many conjugated vaccines).

This protein is highly immunogenic, in that it is capable of provoking a major immune response. When exposed to the CRM197 contained in the vaccine, the immune system starts to produce antibodies directed not just against this protein, but also against the cytokines IL-4 and IL-13. This helps control the overproduction of these proteins, which are key in allergic asthma, and more generally in any allergic reaction.

In addition to allergic asthma, IL-4 and IL-13 are involved in many other allergic conditions, including atopic dermatitis and food allergy. Ongoing preclinical studies in the laboratories of the various partners aim to demonstrate that this vaccine can also induce a protective response against these major allergies. 


[1] Toulouse Institute for Infectious and Inflammatory Diseases (Inserm/CNRS/Université Toulouse III)

[2]conjugate vaccine  is a vaccine containing an antigen associated with a protein to increase its efficacy

New data of efficacy of a Meningococcal B Vaccine and a Preventive Antibiotic in Reducing the Risk of Sexually Transmitted Bacterial Infections and proven efficacy of the MVA-BN Vaccine Against Mpox

This study, sponsored and funded by ANRS | Emerging Infectious Diseases in partnership with Roche[1], was conducted by a research team from the Paris Public Hospitals Group AP-HP, Université Paris Cité, Inserm, and Sorbonne Université in collaboration with the associations AIDES and Coalition PLUS. It demonstrates the efficacy of both a meningococcal B vaccine in reducing the risk of gonorrhea infection and the use of the antibiotic doxycycline as a preventive treatment against sexually transmitted infections, when taken within 72h after sex. Following the first mpox cases in France, the study scope was expanded, adding the possibility to observe the efficacy of the Modified Vaccinia Ankara (MVA-BN) vaccine against the mpox virus responsible for the epidemic that emerged in 2022.

In recent years, France has seen an increase in sexually transmitted infections (STIs), including bacterial infections such as syphilis, chlamydia and gonorrhea, which particularly affect men who have sex with men (MSM). It was this population which has been mainly affected by the mpox epidemic, which emerged in France in May 2022.

The ANRS DOXYVAC trial was designed to evaluate interventions aimed at preventing these infections. It has been ongoing since January 2021 in MSM using PrEP to prevent HIV infection and highly exposed to the risk of STIs and having presented at least one STI during the year prior to their participation in it[2].


The ANRS DOXYVAC trial aims to measure the efficacy of an antibiotic and a vaccine in preventing bacterial STIs in MSM.

Enrollment was stopped early and the two interventions were proposed to all participants following the promising results with doxycycline in the U.S. study DOXYPEP and at the recommendation of the data and safety monitoring board following an interim analysis requested by them.

The study is evaluating the efficacy of post-exposure prophylaxis (PEP)[3] for bacterial STIs that combines the antibiotic doxycycline and vaccination with Bexsero® against meningococcus B[4]. Between January 2021 and July 2022, 502 MSM volunteers living in the Paris region were randomly assigned to into four groups: the first receiving doxycycline PEP to be taken within 72h after condomless sex; the second receiving vaccination with Bexsero®; the third a combination of these two interventions; and the fourth none of the two interventions.

The volunteers had a median age of 39 years, a median of 10 sexual partners in the last 3 months and received a median follow-up of 9 months. They were monitored and tested every 3 months for symptoms of gonorrhea, chlamydia and syphilis infections.

The researchers compared the incidence of a first episode of chlamydia or syphilis infection between the group that received doxycycline and the group that did not and found it to be 5.6 and 35.4 per 100 person-years[5], respectively (84% reduction in the risk of chlamydia or syphilis infection). As for the incidence of a first episode of gonorrhea infection in these same groups, this was found to be 20.5 and 41.3 per 100 person-years (51% reduction). After 3 months, the incidence of a first episode of gonorrhea infection in the Bexsero®-vaccinated group and the unvaccinated group was 9.8 and 19.7 per 100 person-years (51% reduction). No severe adverse effects relating to these two procedures were observed.

“The use of doxycycline for post-exposure prophylaxis has shown itself to be effective in reducing the incidence of both chlamydia and syphilis infection. This antibiotic has also had a significant impact, just like the meningococcal B vaccine, on the incidence of gonorrhea infections. This is the first time that a vaccine has shown an effect on a sexually transmitted bacterial infection,” concludes Prof. Jean-Michel Molina (Université Paris Cité and Department of Infectious Diseases at Hôpital Saint-Louis and Lariboisière, AP-HP, and Université Paris Cité), the study’s coordinating investigator.

Follow-up of the participants will continue until the end of 2023 to ensure that these prevention strategies, which have now been offered to all the participants, are effective in the medium term.

This study, which forms part of a global prevention effort, combines several risk reduction measures (repeated screening for HIV and STIs, vaccination against hepatitis A and B, distribution of condoms and gels). The participants also have the possibility to benefit from community support, therapeutic education, or both.


Beyond bacterial STIs, DOXYVAC has made it possible to analyze the impact of the MVA-BN vaccine on the incidence of the mpox virus rapidly after the appearance of the first cases.

In France, the first cases of infection with the mpox virus appeared in May 2022. For the first time, the risk of human-to-human transmission of this virus through sexual contact has been observed. It has therefore been recommended since July 11, 2022 that the vaccine be used as a protective measure for multi-partner MSM.

In view of this observation, the research teams considered it necessary to include in DOXYVAC a component dedicated to studying the vaccine impact on the incidence of mpox virus in MSM taking PrEP, given that these volunteers are at risk of developing mpox. Among the 502 participants in DOXYVAC, the researchers analyzed, in this specific component, the information regarding 472 people whose data were available before and after May 8, 2022. These participants had reported having a median of 10 partners in the previous 3 months, and 20% had received a smallpox vaccine in childhood.

The researchers compared the pre-epidemic (i.e. until May 8, 2022) characteristics of the 77 volunteers having contracted mpox to the “control” volunteers who had not had the virus. They found that the cases of mpox affected younger people (37 vs. 40 years) who had had more sexual partners in the previous 3 months (7 vs. 5), and among whom fewer had been vaccinated against smallpox in childhood (4% vs. 23%). In people who did not have mpox infection, the proportion having had more than 10 partners over a 3-month period had decreased between the pre-epidemic and epidemic periods (up to and after May 8, 2022).

The incidence of mpox virus infection was 67.4 per 1 000 person-months between May 9 and July 10. It fell to 24.4 per 1 000 person-months between July 11 (date from which it was possible to get vaccinated) and September 20. The research team found that simply being vaccinated against the mpox virus in 2022 was associated with a reduced risk of developing the disease with an efficacy of 99%; the impact of behavioral change was limited in this highly vaccinated population (87%).

“This vaccine provides a high level of protection against the mpox virus,” explains Prof. Jade Ghosn (Université Paris Cité, Department of Infectious and Tropical Diseases of Bichat-Claude-Bernard Hospital AP-HP), DOXYVAC co-investigator and the researcher behind the implementation of the study’s “mpox” component.

AIDES, which has developed numerous risk reduction tools during the mpox crisis and participated in providing community support in these studies, welcomes these results.

For Camille Spire, president of the association, the emergence of new effective tools to add to the existing prevention arsenal is to be welcomed, especially since during the mpox crisis we have noted a high level of vaccine uptake by the people exposed to the virus. We will work to ensure that the effective accessibility of these tools is supported by public policies in terms of the fight against STIs”.

Vincent Leclercq, managing director of Coalition PLUS adds: “in order to achieve their full potential, these prevention tools must reach all the populations at which they are targeted. However, access to vaccines and medicines is too often restricted to the richest countries. We have seen it with the mpox epidemic: only the countries of the North have been able to set up vaccination campaigns”.


[1] Roche Molecular System and Roche Diagnostics France provided – free of charge – the kits, consumables and reagents needed to detect Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium.

[2] These men are participants in the HIV infection prevention cohort ANRS PREVENIR.

[3] Post-exposure prophylaxis (PEP) is the use of preventive treatment in people who have recently been exposed to a risk of disease transmission to prevent them from developing it.

[4] Meningococcus B (Neisseria meningitidis) is a bacterium that can cause meningitis. It is close to gonococcus (Neisseria gonorrhoeae).

[5] X per 100 person-years: this means that out of 100 patients followed up for one year, there is a probability of observing X events (in this case an STI).

Discovery of a circovirus involved in human hepatitis

circovirus_ illustration

© Adobe Stock

Scientists from the Institut Pasteur, Necker-Enfants Malades Hospital (AP-HP), Inserm in the Imagine Institute, Université Paris Cité and the Alfort National Veterinary School (EnvA) have identified a previously unknown species of circovirus, provisionally named human circovirus 1 (HCirV-1). Circoviruses are a family of small, highly resistant DNA viruses that were initially identified in 1974 in various animal species, where they can cause respiratory, renal, dermatological and reproductive problems. HCirV-1 is a novel virus that is distant from known animal circoviruses. It was shown to be implicated in damage to the liver of a patient undergoing immunosuppressive treatment. This discovery of the first circovirus in humans, linked to hepatitis, was published in the journal Emerging Infectious Diseases on January 3, 2023.

Although the transmission of animal viruses to humans is regularly reported in the scientific literature, it is rare for a novel virus to be identified in a patient in Europe. But as part of a recent study, scientists and physicians have identified the first circovirus involved in human hepatitis.

The patient had unexplained chronic hepatitis, with few symptoms. She had received a heart-lung transplant 17 years earlier and had been monitored regularly since. We had access to a large number of samples over several years and were therefore able to identify this novel virus, which was completely unexpected,” explains Marc Eloit, last author of the study, Head of the Institut Pasteur’s Pathogen Discovery laboratory and a Professor of Virology at the Alfort National Veterinary School (EnvA). His laboratory specializes in the identification of pathogens in patients suspected of severe infection of unknown cause.

In March 2022, in collaboration with the Department of Clinical Microbiology at Necker-Enfants Malades Hospital (AP-HP), the pathological tissue samples of this 61-year-old female patient receiving immunosuppressive treatment, whose hepatitis had no identifiable cause, were sequenced to search for microbial sequences. The RNA (ribonucleic acid) sequences extracted from the tissues were analyzed and compared with those of known microbes.

The aim is to identify sequences of interest among all the sequences obtained, which is like searching for a needle in a haystack!” continues the scientist Marc Eloit.

These thousands of RNA sequences were analyzed in parallel using mNGS (metagenomic next-generation sequencing) high-throughput sequencing techniques and sophisticated algorithms. After ruling out common etiologies, the analysis led to the identification of a previously unknown species of circovirus, provisionally named human circovirus 1 (HCirV-1). No other viral or bacterial sequence was found.

The involvement of HCirV-1 in the hepatitis was then demonstrated by analyzing samples taken from the patient in previous years as part of her post-transplant treatment. The results showed that the HCirV-1 viral genome was undetectable in the blood samples from 2017 to 2019, then that its concentration peaked in September 2021. Viral replication in liver cells was demonstrated (2 to 3% of liver cells were infected), pointing to the role of HCirV-1 in liver damage: once the virus has used the resources in the liver cell to replicate, it destroys the cell.

From November 2021 onwards, following antiviral treatment, the patient’s liver enzymes returned to normal levels, indicating the end of hepatic cytolysis.

Diagnosing hepatitis of unknown etiology remains a major challenge, as shown by the cases of acute hepatitis reported in children in the United Kingdom and Ireland last April and signaled by WHO.

We need to know the cause of the hepatitis, and especially whether or not it is viral, to be able to offer suitable treatment and monitor patients effectively. The identification of this novel virus that is pathogenic in humans, and the development of a test that can be performed by any hospital laboratory, offers a new tool for diagnosing and monitoring patients with hepatitis,” stresses Anne Jamet from the Department of Clinical Microbiology at Necker-Enfants Malades Hospital (AP-HP), who is also affiliated with Inserm and co-last author of the study.

Although some circoviruses are pathogenic for animals and vaccines can be administered, especially in pigs, this is the first known circovirus to be pathogenic for humans. The patient’s symptoms remained mild; the virus was able to be identified because she was being closely monitored following her combined transplant. The origin of the virus – whether it is circulating in humans or of animal origin – has yet to be identified, and the source of infection (contact, food, etc.) remains unknown. Following their discovery, the scientists developed a specific PCR test that is now available for etiological diagnosis of hepatitis of unknown origin. A serological test is also being developed.

These results show the value of this type of sequencing analysis in identifying novel or unexpected pathogens. It is always important for clinicians to know whether or not an infection is viral so that they can adapt the treatment accordingly. It is also crucial to be able to identify a novel pathogen when an infection remains unexplained and to develop a diagnostic test, because any new case of human infection with an emerging pathogen may potentially signal the start of an outbreak,” concludes Marc Eloit. The test is available for the medical community and can now be easily performed for other cases of unexplained hepatitis.

Dengue and Zika Viruses: Towards a Better Understanding of the Mechanisms of Transmission

moustique Aedes aegypti

The Aedes aegypti mosquito is the main vector of dengue, Zika virus infection, chikungunya, and yellow fever. © Adobe Stock

Aedes mosquitoes are the principal vectors of dengue and other arboviruses, including Zika, for which no vaccines or antiviral treatments currently exist. Understanding the factors that influence the transmission of arboviruses from mosquitoes to humans is therefore a priority because it could guide the implementation of public health measures that could limit or even prevent epidemics. In a new study, a team of researchers from Inserm, CNRS and Université de Strasbourg at the Institute of Molecular and Cellular Biology, in collaboration with the Federal University of Minas Gerais in Brazil, described the virome (the totality of the viruses) present in 800 mosquitoes collected in six countries across four continents. The scientists show that out of the 12 viruses identified, two of them do not infect humans but increase the potential for transmission of dengue and Zika. The mechanism involved reveals the existence of a new cellular factor hijacked by arboviruses in mosquitoes. Their findings have been published in Nature Microbiology.

Among the infectious viral diseases transmitted by mosquitoes, the frequency of dengue is the fastest growing worldwide, and is currently responsible for 400 million new infections each year. This increase in the number of cases of dengue, as well as other diseases caused by viruses transmitted by mosquitoes (arthropod-borne viruses), such as Chikungunya and Zika, reflects the geographic expansion of the principal vector mosquitoes, Aedes aegypti and A. albopictus, particularly due to globalization and climate change.

The virological surveillance of adult Aedes mosquitoes using metagenomic analysis[1] can lead to the early identification of circulating arboviruses and thus contribute to improving public health measures. In addition to arboviruses, these surveillance methods have identified a large number of insect-specific viruses in Aedes mosquitoes. Although they do not infect mammals, these viruses are likely to impact the dynamics of arbovirus transmission to humans.

This is the context for the research by a team of scientists from Inserm, CNRS and Université de Strasbourg, in which they characterized the full virome of Aedes mosquitoes on a global scale.

Using a high-throughput RNA sequencing technique[2] coupled with bioinformatics analysis according to a method developed in their laboratory, the researchers made an inventory of the viruses present in Aedes mosquitoes worldwide. They worked with a network of collaborators, the majority of whom are participating in the European consortium ZIKAlliance[3], to collect over 800 mosquitoes at 12 different sites in six countries across four continents. This enabled them to identify 12 circulating viruses, present in these mosquitoes, five of which had previously never been described.

Two of these 12 viruses, Phasi Charoen-like virus (PCLV) and Humaita Tubiacanga virus (HTV)[4], attracted the researchers’ attention because of their high levels of prevalence (they were present in over half of the samples). These two viruses were either not present or present only to a small extent in the samples from Africa, where there are few cases of dengue, in comparison with Asia or South America, where there are many.

To find out whether PCLV and HTV could affect the transmission of dengue, the scientists looked at Caratinga, a small city in south-east Brazil, where dengue is endemic and for which they have an archived collection of the RNA of over 500 mosquitoes collected there over a one-year period. This analysis of samples collected in the field revealed an interaction between HTV and PCLV with the dengue virus, with those mosquitoes infected with HTV and PCLV being three times more likely to also be infected with dengue.

The scientists then confirmed this observation in the controlled environment of Strasbourg’s insectarium, showing that the introduction of HTV and PCLV into laboratory mosquitoes increased replication of the dengue (DENV) and Zika (ZIKV) viruses. Higher levels of these viruses shorten the extrinsic incubation period, which is the time required for infected mosquitoes to become infectious. By using mathematical modelling, the researchers suggest that this greater infectious capacity could multiply the risk of dengue and Zika transmission by five when HTV and PCLV are present.

These findings all raise the question of the mechanism by which HTV and PCLV affect DENV and ZIKV replication. The researchers tried to find some explanations.

By studying gene expression in dengue-infected mosquitoes, in both the absence and presence of HTV and PCLV, the scientists discovered the major role of histones (proteins that combine with DNA to compact it and form chromatin), and particularly histone H4. Their findings show that the dengue virus uses histone H4 to multiply in mosquitoes. HTV and PCLV, through a mechanism that has yet to be determined, maintain the expression of histone H4 in infected mosquitoes, thereby promoting this multiplication of the dengue virus.

“A better understanding of the molecular mechanisms that govern the interaction between these three viruses seems essential for the continuation of our research. Understanding what promotes the transmission of the Zika and dengue viruses could make it possible to propose more effective strategies to reduce the transmission of the virus to humans, and to limit or even prevent epidemics,” concludes João Marques, newly recruited Inserm research director and last author of the study.


[1] Method of studying the genetic content of samples from complex environments taken from nature, here from mosquito samples.

[2] Sequencing of a very large number of different molecules within the same sample

[3] ZIKAlliance is a multinational and multidisciplinary research consortium of 54 partners worldwide, coordinated by Inserm. ZIKAlliance is funded by the European Union’s Horizon 2020 research and innovation program.

[4] Virus discovered by the same team during previous research.

A Bacterium to Protect the Microbiota from the Harmful Effect of Food Additives

microbiote colon

Section showing the interaction of the microbiota and the intestinal epithelium in the colon. In blue, the mucus secreted by the intestinal epithelium in protection against the microbiota. In pink, the epithelial cell nuclei. © Noëmie Daniel/Inserm

Emulsifiers are food additives that are used to improve texture and extend shelf life. They are found in many processed products (ice cream, packaged cakes, sauces, etc.) despite having demonstrated harmful effects on intestinal balance. In a new study, scientists from Inserm, CNRS and Université Paris Cité at Institut Cochin in Paris sought to counteract these effects by using Akkermansia muciniphila, a bacterium naturally present in the intestine, to repopulate and thus strengthen the intestinal epithelium. The addition of this bacterium to the gut microbiota is thought to prevent the damage caused by the consumption of emulsifiers. These data, published in Gut, confirm the growing potential of Akkermansia muciniphila as a probiotic.

Emulsifiers are consumed by millions of people every day and are among the most widely used additives in the food industry. Something that is not surprising given that they improve the texture of foods and extend their shelf life. For example, emulsifiers such as lecithin and polysorbates ensure the smooth texture of mass-produced ice cream and prevent it from melting too quickly once served.

Previous studies by the team of Benoît Chassaing, Inserm researcher at Institut Cochin (Inserm/CNRS/Université Paris Cité), have shown the consumption of certain emulsifiers to lead to alterations of the gut microbiota[1] and how it interacts with the digestive system. Such alterations lead to chronic gut inflammation and metabolic dysregulation. More specifically, this research has shown the consumption of food emulsifiers to induce the ability of certain elements of the microbiota to come into close contact with the epithelium, which is the first line of defense of the digestive tract and usually sterile.

 In this new study, the researchers wanted to counteract the harmful effects caused by the consumption of emulsifiers by reinforcing the intestinal epithelium. To do this, they focused more specifically on the bacterium Akkermansia muciniphila, which, being naturally present in the intestine has already been shown to have an impact on the interactions of the microbiota with the rest of the body.

It is also known that the quantity of this bacterium is reduced when emulsifiers are consumed.

In the study, groups of mice were fed emulsifying agents as part of their diet, which for some of them was supplemented with a daily dose of Akkermansia muciniphila. The scientists saw that while the consumption of food emulsifiers was sufficient to induce the chronic inflammation associated with metabolic alterations and high blood glucose, the mice receiving Akkermansia muciniphila were totally protected against such effects. The administration of Akkermansia muciniphila was also sufficient in preventing all molecular alterations normally induced by the consumption of emulsifying agents, including the encroachment of bacteria into the wall of the epithelium.

“This research supports the notion that using Akkermansia muciniphila as a probiotic could be an approach to maintaining metabolic and intestinal health in the face of modern stressors such as emulsifiers that promote chronic gut inflammation, and the resulting harmful consequences. Furthermore, this suggests that colonization of the intestine with Akkermansia muciniphila could be predictive of individual propensity to develop intestinal and metabolic disorders following the consumption of emulsifiers: the greater the presence of the bacterium, the more likely the individual is protected from the harmful effects of food additives on the microbiota,” explains Chassaing, the last author of the study.


[1] All of the microorganisms – non-pathogenic (commensal) bacteria, viruses, parasites, and fungi – that live in the intestine.

Trial on safety and immunogenicity of Ebola vaccines yields promising results

© 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.



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.

Tuberculosis: children hospitalized with severe pneumonia in high-incidence countries should be screened for TB

© Copyright TB-Speed

Tuberculosis affects 1 million children each year; less than half of them are diagnosed and treated for the disease, which leads to more than 200,000 deaths. In a new study, researchers and clinicians from the TB-Speed consortium funded by global health agency Unitaid and led by the University of Bordeaux, in collaboration with the French Research Institute for Sustainable Development (IRD) and MU-JHU (a research collaboration between Makerere University and John Hopkins University in Uganda), showed that screening for tuberculosis at the time of hospital admission was feasible in children with severe pneumonia.

In addition, screening with a molecular test called Xpert Ultra improved the diagnosis of tuberculosis in children in countries with high incidence of the disease. The results of the study argue for a more systematic use of the Xpert Ultra in these children, especially in those suffering from severe acute malnutrition. They also confirm the importance of tuberculosis as a cause of severe pneumonia. These findings were published on November 15th, 2022 in The Lancet Infectious Diseases.

In countries with a high incidence of tuberculosis, the disease can be a cause of severe pneumonia and can contribute to mortality in young children. Usually the diagnosis of tuberculosis is considered only in children presenting with prolonged symptoms, those failing antibiotic courses prescribed for community-acquired pneumonia, or those with a history of contact with an adult with tuberculosis disease. Thus, many tuberculosis cases are missed or diagnosed with delays, which can result in poor outcomes and death.

However, young children presenting with tuberculosis-related severe pneumonia can have acute symptoms and would not be considered as presumptive tuberculosis cases. In this context, the TB-Speed consortium made the hypothesis that a tuberculosis screening in young children admitted with severe pneumonia with immediate treatment initiation for those who tested positive could reduce mortality of severe pneumonia related to tuberculosis.

TB-Speed Pneumonia is the first large-scale international cluster-randomized trial to assess the effect of doing systematic molecular tuberculosis detection in addition to the World Health Organization WHO standard of care in children admitted with severe pneumonia. The study, funded by Unitaid and the Initiative, and sponsored by INSERM, was conducted in 16 tertiary hospitals across six countries with high tuberculosis incidence (Cote d’Ivoire, Cameroon, Uganda, Mozambique, Zambia and Cambodia).

It aimed to assess the impact on mortality of adding systematic molecular tuberculosis detection using the Xpert MTB/RIF Ultra (Ultra) assay performed on one nasopharyngeal aspirate and one stool sample to the standard of care recommended by the World Health Organization for children with severe pneumonia (that includes antibiotics course, oxygen when indicated and treatment of HIV infection and severe malnutrition). Hospitals were randomly selected to start molecular testing and the flow was organized in order to reduce time to results to 3 hours. All children with Ultra positive results were immediately started on tuberculosis treatment. Children were followed for 12 weeks after enrolment.

2570 children were enrolled in the study (1401 in the control arm and 1169 in the intervention arm) between March 2019 and March 2021. 95% of children had nasopharyngeal aspirates and 80% had stools collected and tested with Ultra.

Although this tuberculosis screening intervention did not lead to a reduction in 12-week all-cause mortality as compared to the standard of care, it increased the rates of tuberculosis detection and microbiological confirmation and reduced the time to treatment initiation.

In addition, mortality and tuberculosis diagnosis rates were four to five times higher in children with severe acute malnutrition as compared to those without severe acute malnutrition. The study also showed that collecting and testing nasopharyngeal aspirates and stool samples with Xpert MTB/RIF Ultra in highly vulnerable children was highly feasible and well tolerated.

Efficacy of a Meningococcal B Vaccine and a Preventive Antibiotic in Reducing the Risk of Sexually Transmitted Infections

Vaccination © Adobe Stock

The ANRS DOXYVAC trial, conducted by a research team from the Paris public hospitals group (AP-HP), Université Paris Cité, Inserm and Sorbonne Université in collaboration with AIDES and Coalition PLUS, demonstrates the efficacy of both a meningococcal B vaccine in reducing the risk of gonorrhea infection and the use of doxycycline as preventive intervention for sexually transmitted infections when taken within 72h after sexual intercourse. In the wake of these results and taking into account the recommendations of the data and safety monitoring board, the scientific leaders and sponsor have decided to discontinue the trial and recommend the provision of both interventions to all its participants. This study is sponsored and funded by ANRS | Emerging Infectious Diseases in partnership with Roche[1].

According to World Health Organization (WHO) estimates, over 374 million people each year are diagnosed with a sexually transmitted infection (STI), which includes bacterial infections such as syphilis, chlamydia and gonorrhea. These bacterial infections particularly affect young people, men who have sex with men (MSM), and ethnic minorities. They are responsible for impaired quality of life and can cause serious side effects during pregnancy with congenital syphilis, risks of infertility in women and globally increase the risk of HIV infection.

In recent years, an increase in these STIs has been observed in France, particularly among MSM, making them a major public health problem for which new means of prevention must be developed.

Over the past few years, several research teams worldwide have been studying the efficacy of antibiotics used as prophylaxis in reducing the risk of STIs. This concept of post-exposure prophylaxis was first evaluated in the ANRS IPERGAY trial, which demonstrated that doxycycline, when used within 72h after sexual intercourse, led to an approximately 70% reduction in the risk of infection with chlamydia and syphilis.

In parallel, a certain number of epidemiological studies have reported in recent years that people receiving the Bexsero® meningococcal B[2] vaccine may have a reduced risk of gonorrhea infection by around 30%[3].

ANRS DOXYVAC differs from the other trials by the evaluation in a prospective, randomized trial of the combination of post-exposure prophylaxis with doxycycline and vaccination with Bexsero®. This study has been conducted since January 2021 in MSM, highly exposed to the risk of STIs and having presented at least one STI in the year prior to their participation in it. These men also participate in the ANRS PREVENIR cohort for the prevention of HIV infection whose results have recently been reported in The Lancet HIV and which showed that taking PrEP on demand was as effective and safe as its daily administration in preventing HIV infection.

ANRS DOXYVAC therefore forms part of a global, combined prevention framework in association with other risk reduction measures (repeated HIV and STI screening, hepatitis A and B vaccinations, distribution of condoms and gel) and with the possibility of community support or therapeutic education. Over 500 volunteers living in the Paris region[4] were randomly assigned to four groups: one receiving post-exposure prophylaxis with doxycycline, the other vaccination with Bexsero®, the third a combination of the two interventions, and the fourth neither of the two interventions.

Following the results of the US DOXYPEP study – presented at the International AIDS Conference in July 2022 in Montreal – and following an analysis of the data on the incidence of STIs among the ANRS DOXYVAC study participants, conducted at the request of the data and safety monitoring board, it was found that:

  • The doxycycline group presented a significant reduction in the risk of syphilis and chlamydia infections. The incidence of gonorrhea infections was also significantly reduced.
  • The meningococcal B vaccine group presented a significant reduction in the risk of gonorrhea infection.

According to the recommendations of the data and safety monitoring board, the scientific leaders and ANRS | Emerging Infectious Diseases, as sponsor, have therefore decided to stop the study in its current form in order to make doxycycline and the meningococcal B vaccine available to all ANRS DOXYVAC participants, following validation by the regulatory and ethical authorities. The follow-up of the participants will continue until the end of 2023 to ensure that these prevention strategies are effective in the medium term.

The results of the study have been submitted for presentation at an international congress in early 2023.

According to the study’s coordinating investigator, Prof. Jean-Michel Molina (Department of Infectious Diseases at Saint-Louis and Lariboisière Hospitals AP-HP, and Université Paris Cité) :

the concept of biomedical prophylaxis at the time of exposure to the risk of sexually transmitted infections as part of an expanded prevention offering is therefore validated. We owe this to all the study volunteers without whom it would not have been possible to demonstrate this efficacy.” He adds: “however, the efficacy observed must not overshadow the fact that condoms remain the cornerstone of STI prevention in general. It is by adding together all the prevention tools that have proved themselves that we will be able to effectively control STIs and achieve the WHO and UNAIDS objective for 2030, which is to reduce their incidence by 90%.

It is a major step forward in the fight against STIs. The results of ANRS DOXYVAC should bring about changes to the national and international recommendations for the prevention of these diseases. This research project in its collaborative form with the associations AIDES and Coalition PLUS is showing particular promise when it comes to the future implementation of the recommendations.” affirms Prof. Yazdan Yazdanpanah, Director of ANRS | Emerging Infectious Diseases.


[1] Roche Molecular System and Roche Diagnostics France provided – free of charge – the kits, consumables and reagents needed to detect chlamydia, neisseria and mycoplasma.

[2] Meningococcus B (Neisseria meningitidis) is a bacterium that can cause meningitis. It is close to gonococcus (Neisseria gonorrhoeae).

[3] Observational studies conducted in New Zealand, USA, Australia and Canada.

[4] The participants were enrolled at the following hospitals of the Paris public hospitals group (AP-HP): Saint-Louis, Tenon, Pitié-Salpêtrière, Bichat Claude-Bernard, Saint-Antoine, Hôtel-Dieu, Necker, Garches, and Lariboisière.

Highly Effective Memory B Cells Localized in the Lungs

Researchers showed that memory B cells can be localized in the lungs. © Adobe Stock

How can we increase the efficacy of vaccines used to protect against viral respiratory diseases such as influenza and COVID-19?  Scientists from Inserm, CNRS and Aix-Marseille Université at the Center of Immunology Marseille-Luminy are opening up new prospects in the field, with the triggering of memory B cells directly in the lungs looking to be a promising avenue. At present, the vaccines are administered intramuscularly and do not trigger the appearance of these cell populations. This research, which enhances fundamental knowledge in the field of immunology, has been published in the journal Immunity.

Memory B cells are immune cells produced primarily in the lymph nodes and spleen following infection. They persist for a long time in these regions and retain the memory of the infectious agent. If the body is confronted with the same agent in the future, these cells are immediately mobilized and rapidly reactivate the immune system for effective protection of the individual.

Following extensive research into these memory B cells, researchers discovered three years ago that they could also be localized in the lungs. The team led by Inserm researcher Mauro Gaya and his colleagues from the Center of Immunology Marseille-Luminy (AMU/CNRS/Inserm) and the Center for Immunophenomics (AMU/CNRS/Inserm) went further in order to describe the nature and functioning of this specific immune cell population.

The aim was to better understand these cells and their involvement in the long-term immune response against respiratory infections. For this, the scientists worked with two mouse models of infection: the influenza and Sars-CoV-2 viruses.


“Bona fide” and “bystanders”

They used fluorescent markers to track the appearance of memory B cells after infection, following which they performed a single-cell transcriptome analysis[1]. “These techniques enabled us to precisely localize these cells in the lungs of our animal models and describe their gene expression profile cell by cell to study their function,” explains Gaya.

Approximately ten weeks after inoculation of the virus and after its elimination from the body, the team observed the formation of groups of memory B cells in the bronchial respiratory mucosa, in a strategic position allowing them to be directly in contact with any new virus entering the lungs.

Furthermore, this research suggests that there are two subpopulations of memory B cells expressing different genes, known as “bona fide” and “bystanders”, with the “bona fide” cells having a particular affinity for the virus that triggered their appearance. In the event of new encounters with this pathogen, they immediately differentiate into plasma cells[2] and secrete highly specific antibodies against the virus.

Conversely, the “bystanders” do not directly recognize the virus but bind thanks to a specific receptor to the immune complexes formed by the antibodies that are produced by the “bona fides”.

The “bystanders” can therefore enable cross-reactions by increasing the response of different “bona fide” populations against several types of viruses. “What we have is a two-tier system that enables a synergistic effect and increases the efficacy of the anti-viral memory response in the lungs,” explains Gaya.

In addition to advancing fundamental knowledge in immunology, the research team sees in these findings a longer-term way of improving the efficacy of influenza or COVID-19 vaccines.

These findings could in fact form the basis for new research into the way vaccines are administered. “The hypothesis is that by intranasal vaccination, we could mimic the natural entry pathway of the virus, mobilize these lung memory B cells to block the virus as soon as it reaches the respiratory tract in the event of an infection. In this way, we could combat severe forms and also better protect against infection,” concludes Gaya.


[1] Single-cell transcriptome analysis: a technique used to study the genes expressed in each cell of a sample

 [2] Plasma cells:B cells that have reached a stage of terminal differentiation during which they produce antibodies