The first Scientific Days of ANRS | Emerging Infectious Diseases
The first Scientific Days of ANRS | Emerging Infectious Diseases were held on March 15 and 16, 2022 in Paris. This symposium was an opportunity to present the actions of this new agency to the national and international scientific community in order to encourage the coordination, animation and promotion of cross-disciplinary and collaborative research. The presence of major scientific figures, as well as the representatives of the agency's supervisory bodies: Frédérique Vidal, Minister of Higher Education, Research and Innovation, Olivier Véran, Minister of Solidarity and Health, and Gilles Bloch, Inserm CEO, made these meetings between research stakeholders a singular event.
These two days allowed the invited experts to share and exchange on the pathologies within the scope of the agency : HIV/AIDS, viral hepatitis, STIs, tuberculosis and emerging infectious diseases, particularly SARS-CoV-2. Surveillance, prevention, research into therapeutic targets and strategies, development of innovative prophylaxis and organization of care accessibility are the main areas necessary for the control of epidemics. These approaches were the focus of the presentations made during these two days, summarized below.
In his introduction, Chikwe Ihekweazu (Hub for Pandemic and Epidemic Intelligence, WHO) drew parallels between the current COVID-19 crisis and the HIV and Ebola epidemics, highlighting the accelerated response by research – particularly the development of vaccines within one year. However, research must accompany policy decisions. This is the objective of the World Health Organization (WHO) Hub for Pandemic and Epidemic Intelligence, based in Berlin and created in 2021 to improve analysis of the data flow and help countries make informed decisions on the management of epidemics. Research data must also be made as accessible as possible in an attempt to reduce inequalities between the countries of the Global North and South: 'ANRS and its international partners will certainly play a major role here in the future,' he added.
Moderated by Françoise Barré-Sinoussi (Institut Pasteur) and Marc Bourlière (Saint-Joseph Hospital,SESSTIM), this session reiterated that one of the agency’s priorities is translational research into the remission and cure of HIV and viral hepatitis. Michaela Müller-Trutwin (Institut Pasteur) recounted the difficulties in finding a curative treatment for HIV, namely the existence of viral reservoirs, the major genetic variability of the virus and its immune evasion strategies. Numerous multidisciplinary research studies focus on inhibiting viral rebound and reducing the viral reservoir, with the ANRS RHIVIERA consortium being a good example of this. Müller-Trutwin presented the results of recent studies in simian models which control the virus and the conclusions of the ANRS Visconti cohort of patients who control HIV infection after treatment interruption. The data collected tend to show the key role of the natural killer (NK) cells and how their education is involved in maintaining antiviral response. Proof-of-concept clinical studies are ongoing to develop novel immunotherapies, which will pave the way for possible remission.
Jennifer Gorwood (Karolinska Institute) presented another major challenge in HIV research: that of reducing the viral reservoir contained in adipose tissue. By studying the role of viral proteins and integrase inhibitors in adipocyte dysfunction, the development of adipose fibrosis and insulin resistance, new avenues have been identified to reduce adipose reservoir size and improve patient care.
The persistence of the viral reservoir is also a key problem encountered in the search to achieve functional remission from hepatitis B virus (HBV) infection. In the form of cccDNA minichromosomes maintained in host liver cells, this viral reservoir slows recovery. Fabien Zoulim (Lyon 1 University, Hospices Civils de Lyon, CRCL) described the molecular players involved in its maintenance and replication. Various molecules and gene editing strategies are being studied in an aim to neutralise the viral reservoir by inactivating its replication.
Immunotherapy and the restoration of immune responses in the hepatic compartment by stimulating innate responses and remodelling adaptive responses were also discussed. As part of the IP-Cure-B project, a preclinical study is evaluating the efficacy of TLR8 agonist treatment in chimeric mouse models with humanised liver. Priyanka Fernandes (Institut Pasteur) presented her results showing functional validation of the various murine models used in the study and recruitment of NK cells in the liver and spleen of the treated mice.
An overview of the ongoing research and the progress made in identifying novel therapeutic targets and strategies gives hope of achieving a functional cure for hepatitis B within the coming decade.
At present, genomic data combined with epidemiology represent a fundamental response to emerging infectious diseases – a response on which public health decisions are based. The second session of the day, moderated by Geneviève Chêne (Santé publique France (French public health agency)) and Nicolas Meda (Joseph Ki-Zerbo University) was devoted to the surveillance of epidemics and to the contributions of research in response to health crises worldwide.
Deborah Williamson (Doherty Institute, University of Melbourne) illustrated the crucial contribution of genomics in tracing the chains of transmission and characterising the subpopulations of various pathogens (responsible for syphilis, Japanese encephalitis and COVID-19). These examples serve as a reminder that sequencing alone is insufficient without the epidemiological and clinical data to put it into context. The sharing of this data and the equity in the capacity to collect it pose significant challenges to the global and concerted response to emergences.
Xavier de Lamballerie (Aix-Marseille University, IRD, UVE) presented the EMERGEN consortium for the deployment in France of a SARS-CoV-2 genome surveillance system for public health and research purposes. Taking an interdisciplinary approach, this project coordinated by Santé publique France (French public health agency) and ANRS | Emerging Infectious Diseases enables effective monitoring of the epidemic situation in France. Mobilising the consortium stakeholders increased the number of sequences described from 3 000 in 2020 to 450 000 in 2021. In addition, 16 projects in various research areas (experimental activities and animal models, cohort, modelling, wastewater analysis, etc.) were funded by the consortium to acquire new knowledge on the variants of SARS-CoV-2.
The COVID-19 pandemic highlighted the difficulties experienced by some African countries in monitoring the progression of SARS-CoV-2 on their territories. In response to this need, the AFROSCREEN consortium was created in 2021 to build the sequencing capacities of 13 African countries: Benin, Burkina Faso, Cameroon, Central African Republic, Côte d'Ivoire, Democratic Republic of the Congo, Ghana, Guinea, Madagascar, Mali, Niger, Senegal and Togo. With the support of the French Development Agency (AFD) and ANRS | Emerging Infectious Diseases, and in partnership with Institut Pasteur, IRD and the laboratories in these 13 countries, the objective of the project is to deploy two genomic methods: PCR screening for mutations/variants of interest and sequencing in partner laboratories. Dramane Kania (MURAZ Centre, Bobo-Dioulasso, National Institute of Public Health, Burkina Faso) explained that since January 2022 the laboratories have all been operational in terms of PCR screening and that training in sequencing is ongoing in six countries.
Arlette Simo-Fotso (IRD, CEPED) then presented the PHIA surveys – population surveys evaluating the impact of HIV – deployed in 16 African countries. By mapping the incidence of the virus, evaluating the efficacy of the actions taken, and incorporating biological, epidemiological and sociological data, these national surveys were able to highlight the progress made in controlling HIV. They have also led to the improved screening of children and have shown the need for biomarkers to more accurately monitor the dynamics of the virus in these countries.
Created in response to epidemic emergency situations, these projects reinforce the territories’ epidemiological and genomic surveillance. These structural mechanisms are intended to be sustainable for a more effective response to future crises.
The third session, devoted to global health, sexual health and prevention, was moderated by François Dabis (University of Bordeaux, ISPED, COREVIH) and Hugues Fischer (TRT-5 CHV).
Kevin Fenton (Commander of the British Empire (CBE), Regional Director London - Office for Health Improvement and Disparities, London) began by providing an overview of the inequalities revealed by the COVID-19 crisis in the United Kingdom. The data presented show a greater impact of the epidemic on ethnic minorities. These disparities can be explained in particular by social factors affecting individual exposures (work, housing, family, etc.) and the populations’ adherence to prevention and vaccination measures. These findings have led to Public Health England drawing up recommendations in order to restore trust in the health authorities, particularly through the deployment of local systems and community actions.
Anne Gosselin (INED) also addressed the value of an approach that involves community stakeholders in research projects in order to more effectively target and include immigrants – who are strongly affected in France by HIV and hepatitis B and C. She reiterated the results of the ANRS projects Parcours and VESPA 2, showing the high risk of acquiring HIV after migration, because precariousness (housing, legal status, etc.) is an aggravating factor of exposure to HIV. Immigrants are also more exposed to the risk of treatment failure (poor adherence or comorbidities) and discrimination. Community associations and stakeholders must be involved in all stages of research for the most exposed populations.
This research has shown the importance of taking social inequalities into account for an equitable and effective response to epidemics, particularly in the area of sexual health. As the presentation by Nathalie Bajos (Inserm, IRIS) highlighted, inequalities stem from a social context structured by relationships of dominance related to gender, sexual orientation, class, and ethnic group. Taking an intersectional approach, in order to understand these relationships of dominance simultaneously, enables a deeper understanding of social realities and a more effective adaptation of public prevention and care policies.
Regarding the prevention of HIV and STIs, Jean-Michel Molina (University of Paris and Saint Louis and Lariboisière Hospitals AP-HP) presented the various research projects on pre-exposure prophylaxis (PrEP) conducted under the aegis of ANRS: the IPERGAY (2012) and PREVENIR (2017-2020) studies on the impact of PrEP in men who have sex with men (MSM) in the Paris region (Île-de-France). Studies are planned for the evaluation of novel PrEP strategies involving alternative or long-acting molecules. Several studies are being launched as part of PREVENIR, particularly regarding Chemsex (use of recreational drugs during sexual activity). An STI component is also envisaged with DOXYVAC, evaluating the efficacy of PrEP with doxycycline (for syphilis and bacterial STIs) and the Bexsero® vaccine (for gonorrhoea).
With the ANRS CohMSM cohort, PrEP is also one of the research areas of ARCAD SANTE PLUS in Mali, for the follow up of MSM in West Africa. Bintou Dembélé Keita (ARCAD SANTE PLUS, Mali) presented the tangible contributions made by community-based research to sexual health services in Mali. The research carried out there since 1994 has improved the efficacy of the strategies to prevent HIV and STIs in key populations: female sex workers and MSM. Armed with its findings, the association is advocating for the legal facilitation of medical care, the reduced stigmatisation of key populations, and their inclusion among the vulnerable groups in the HIV/AIDS law.
To conclude, Pierre Delobel (University of Toulouse, Toulouse University Hospital, Infinity) reported on the progress of the new French recommendations for the treatment of HIV infection, viral hepatitis and STIs. Envisaged for the end of 2022, these recommendations constitute a necessity in terms of public health and support for healthcare professionals and patients alike.
The fourth session, moderated by Martine Peeters (Inserm, IRD, University of Montpellier) and Jérôme Nigou (CNRS, University of Toulouse), devoted to tuberculosis and emerging infectious diseases, presented an overview of the ongoing research to meet the specific needs of each epidemic. Improved epidemiological surveillance, access to diagnostics, identification of therapeutic targets and the development of innovative vaccine strategies are all necessary areas of research in the response to emergences.
Tuberculosis remains one of the deadliest infectious diseases. Diagnostic difficulties, the few novel molecules developed and treatment resistance represent major challenges for researchers in their efforts to end the epidemic by 2030 in accordance with the United Nations Sustainable Development Goals.
The presentation by Claudia Denkinger (Heidelberg University Hospital) focused on the need for sensitive and specific diagnostic tools for tuberculosis. Until now limited to sputum, the types of analysable samples must be diversified (aerosols, oral cavity swabs, sweat, blood, stool and urine) in order to more effectively target the populations affected, especially children. Priorities for deploying these tests in the field include the portability and reduced costs of the devices. The use of computer-analysed portable X-rays, the detection and analysis of circulating free DNA, and antigen tests based on the model of those developed for COVID-19 are therefore being studied. In addition, to improve the efficacy of care protocols, approaches to characterise resistance (genome sequencing, drug susceptibility testing) need to be devised and implemented more broadly in tuberculosis.
The emergence of treatment-resistant Mycobacterium tuberculosis subpopulations is a major challenge facing epidemiological and basic research. The presentation by Alain Baulard (Inserm, Institut Pasteur, CIIL, Lille) detailed both the diversity of the causes and the dynamics of drug resistance in M. tuberculosis. The molecules used to treat tuberculosis are 'prodrugs,' which are administered as inactive forms and then activated by mycobacterial enzymes. Resistance to these prodrugs can be mediated by mechanisms that are innate (low expression of these enzymes) or acquired (mutations responsible for their inactivation). This distinction paved the way for the development of innovative therapies based on the administration of transcriptional regulators to increase production of the enzymes that activate prodrugs and thereby the susceptibility of the bacteria in vitro and in vivo in murine infection models. In response to acquired resistance, 'booster' molecules, which call upon recently described alternative enzyme activation pathways, are also under clinical development.
Marie Jaspard (Alima, Coral, Inserm, BPH) highlighted a new paradigm in the monitoring of Ebola epidemics regarding the long-term transmission of the virus and relapses as starting points for resurgences. She mentioned two studies conducted in the Democratic Republic of the Congo: EVISTA, a prospective cohort, and PALM, a clinical study evaluating the efficacy of three treatments (antivirals and monoclonal antibodies), each of which has around 700 patients. These studies show the urgency of designing new therapeutic protocols capable of penetrating viral reservoirs and the importance of supportive care (symptoms control, biological monitoring of blood glucose, electrolytes, etc.). In addition, a correlation has been demonstrated between the mortality of patients and their viral load upon admission to treatment centres. Marie Jaspard also mentioned the need for post-exposure prophylaxis for contacts who are at high risk of transmitting the virus.
Lassa fever, responsible for 500 to 1 000 cases each year in West Africa, is a haemorrhagic fever for which no effective treatment or vaccine is currently available. A prospective cohort, LASCOPE, was initiated in order to obtain more information on its clinical and biological parameters. More particularly, this research has clarified the mortality associated with Lassa fever – which represents 12% of patients hospitalised with the disease – as well as its impact on renal function. At a time when various studies are challenging the efficacy of ribavirin – the treatment currently used, the SAFARI phase II clinical trial in Nigeria is currently evaluating the potential of an alternative: favipiravir.
Alongside the efforts to develop treatments for Lassa fever, the search for vaccines for it is also making headway. Mathieu Mateo (Institut Pasteur, UBIVE, Lyon) presented the results of his preclinical study, on a simian model, of the vaccine MV-LASV, which is composed of two antigens (glycoprotein and nucleoprotein). This candidate showed good short and long-term immune responses as well as cross-protection against seven different strains of the virus. A phase I clinical trial has commenced and its results are expected soon.
The ArboFrance group, a multidisciplinary and multi-institutional network of researchers in human and animal arbovirology created under the aegis of REACTing in 2019, was presented by Anna Bella Failloux (Institut Pasteur). Its objectives are to create a watch and alert system for both ANRS | Emerging Infectious Diseases and the health authorities, strengthen and facilitate interactions between surveillance and research teams in mainland France and the overseas territories, assist in setting up research projects while promoting a multidisciplinary One Health approach, and provide the national community with scientific-research-based expertise that supports public policy. Its activities have, for example, led to the creation of a cohort studying factors predictive of severe dengue in all French overseas territories and the establishment of a platform for seroprevalence of arboviruses in blood donors in mainland France. The network now has a Strategic Orientation Committee, a Steering Committee and an Expert Committee.
One of the preferred approaches to the control of arboviruses is to better understand the mechanisms and factors affecting viral colonisation of the mosquito vector. Ottavia Romoli (Institut Pasteur) presented her research on the mosquito microbiota, as well as a protocol developed for obtaining germ-free mosquitoes based on the use of auxotrophic bacteria. This innovative approach has added to our knowledge of the role of bacteria in mosquito development and forms the basis of a study aimed at understanding the role of the microbiota in the transmission of arboviruses.
Studies on SARS-CoV-2 pathogenicity showed that serious forms of the disease are partially related to host factors, notably due to a deregulated immune response during infection. Rémi Planès (InvivoGen, IPBS) presented his research on the description of an innate immune mechanism at play during the in vitro infection of a model of primary lung epithelial cells. What this study revealed was pyroptosis (a highly inflammatory form of programmed cell death) of cells infected following the recognition of viral molecules by the NLRP1 sensor. This induced cell death appears to be an antiviral mechanism, as cells expressing NLRP1 produce fewer infectious viral particles. In addition, overactivation of this pathway may be associated with the severity of the disease, as pyroptosome markers are enriched in patients with severe forms of it.
The description of the various immune mechanisms, innate and acquired, provides a better understanding of the pathogenicity of the virus and the maintenance of vaccine immunity. Research by Yanis Feraoun (CEA, IDMIT) showed non-specific innate immune memory induced following vaccination with the Modified vaccinia virus Ankara (MVA) vector in a macaque model. This innate immune memory, whose link to the adaptive response remains to be elucidated, should be considered when designing and evaluating vaccine strategies using this vector.
Isabelle Dimier-Poisson (University of Tours, INRAE) presented another innovative vaccine approach, this time in the form of a nasal spray for COVID-19 consisting of antigens (Spike and stable antigens) encapsulated in nanoparticles that adhere to the mucous membranes. Preclinical testing had demonstrated the efficacy of this candidate vaccine in terms of immune response and early neutralisation of the virus in the nasal cavities, thereby reducing the risk of transmission. The results of the preclinical rodent tests showed cross-protection for all the variants tested. Funds are currently being raised in order to commence clinical trials in the near future.
This session, moderated by Marie-Paule Kieny (Inserm) and Jean-François Delfraissy (National Consultative Ethics Committee for health and life sciences (CCNE), COVID-19 Scientific Advisory Board) questioned the place of antivirals in the COVID-19 therapeutic arsenal, the role of modellers in public health decision-making and, more generally, the responsibility of researchers to society in times of crisis.
Although the viral component appears to play a minor role in COVID-19 complications, Florence Ader (Claude-Bernard University and University Hospital Lyon, CIRI) presented the added value of antiviral treatments for immunocompromised populations, which are more likely to develop severe forms of the disease. It appears important to go beyond the repurposing of existing molecules and develop new specific antiviral strategies (direct-acting antivirals and monoclonal antibodies) to attenuate the impact of COVID-19. These treatments should be included as part of recommendations, which can be adapted according to the populations concerned and the emerging variants.
Mathematical modelling plays a key role in the development of public health recommendations made during the health crisis. Vittoria Colizza (Inserm, IPLESP) reiterated the fundamentals underpinning this recent discipline in the field of infectious diseases. Modelling is an attempt to analyse past events in order to develop scenarios for the development of future situations. It also aims to understand the key parameters and mechanisms of epidemic progression, as well as test the impact of public health interventions. The collection of high-quality data is fundamental to the accuracy of the models proposed and must take place in collaboration with stakeholders on the ground. Furthermore, the models have limitations which must be taken into account when interpreting them, one of which is the unpredictable nature of human behaviours. For all of these reasons, the onus is on the researchers to be clear in their communications to the public authorities and general population in order to promote the correct understanding of mathematical models.
Jeremy Farrar (Wellcome Trust) also strongly advocated for the responsibilities of the scientific community towards civil society. During this period of health crisis, in which uncertainties are exacerbated, it is essential to strive for greater equality and transparency in access to scientific data. Research players must be vocal in promoting scientific methods and they must embody a desire to act for the common good. Since the factors behind the emergence of diseases (climate change, trade globalisation, etc.) are not controlled, COVID-19 is unlikely to be the last of the health crises to be weathered by the populations. This requires us to collectively devise sustainable solutions for increasing our agility in response to future crises and for cementing trust between science and society.
The first ANRS | Emerging Infectious Diseases scientific colloquium has highlighted the flagship activities of the agency and its partners in researching and fighting HIV, viral hepatitis, STIs, tuberculosis and emerging infectious diseases. 'ANRS has done a lot of work in HIV and hepatitis: its historical operating model needs to be applied to emerging infectious diseases,' reiterated Sharon Lewin (Peter Doherty Institute for Infection and Immunity, Australia and Chair of the Scientific Advisory Board of ANRS | Emerging Infectious Diseases). The various presentations also highlighted the richness provided by research on emerging diseases applicable to the historical themes in terms of surveillance, sequencing and modelling.
This colloquium was an opportunity to bring together many multidisciplinary, multi-institutional and industry-based colleagues and partners.For Gilles Bloch, Inserm CEO: 'these communities, which are consolidating themselves, represent a remarkable potential for excellence and hope for the preparation of future crises,'. The projects presented during this two-day event show the involvement of ANRS in funding research, and also 'the intensity of the work in terms of strategic reflection to structure the response to ongoing and future health crises,' praised Gilles Bloch.
International partnerships were widely represented, reflecting the desire to build more equitable health, 'an essential dimension for the building of global health,' reiterated French Solidarity and Health Minister, Olivier Véran. 'International openness is necessary to the study of emergences ' stated Yazdan Yazdanpanah, in order to enrich projects with experiences that are closer to the realities on the ground and enable responses that are concerted and effective. The spotlight was also on young researchers, French and international, with the objective of establishing 'real mentoring between the most experienced and youngest generations,' emphasised Olivier Véran, because 'they are the agency’s future,' affirmed Yazdan Yazdanpanah.
Les partenariats internationaux ont été largement représentés, montrant une volonté de construire une santé plus équitable, "une dimension indispensable pour construire la santé globale", rappelle Olivier Véran, ministre des Solidarités et de la Santé. "L'ouverture à l'international est nécessaire à l'étude des émergences", indique Yazdan Yazdanpanah, pour enrichir les projets d'expériences plus proches des réalités de terrain et permettre des ripostes concertées et efficaces. Les jeunes chercheurs français et internationaux ont également été mis en lumière lors de ces Journées scientifiques, avec pour objectif de mettre en place "un vrai compagnonnage entre les générations les plus expérimentées et les plus jeunes", souligne Olivier Véran, car "ce sont eux le futur de l'agence", affirme Yazdan Yazdanpanah.
The richness of the discussions, the enthusiasm of the participants and speakers, as well as the sheer number of projects and scientific achievements presented, show that 'the agency’s vitality and ambitions have remained undiminished since the day it was founded,' to quote Gilles Bloch.