Many different fields of the highly recognized fundamental research pursued at the Institut Pasteur are connected to vaccinology or immunotherapy. These include pathogen identification and characterization, structural analysis, in silico approaches, analysis of mechanisms to potentially enhance antigen immunogenicity and/or delivery or to identify specific immunotherapy targets, effects of microbiota on immune responses, and epidemiology before and after vaccine implementation. Results in these areas have allowed scientists to generate efficient vaccines, vaccine technologies, and immunotherapies that are used today or are currently under investigation. A key aim of the Initiative is to further foster fundamental and transversal research tackling the detailed understanding of pathogens, mechanisms, and interplay with the host, a basis for identifying novel approaches, targets, and technologies for vaccines and immunotherapies.
Teams and Projects:
Laboratory: Philippe Bousso
In collaboration with the Vaccine Research Institute, we are taking advantage of intravital imaging approaches to gain new insights into the mode of action of HIV candidate vaccines and of broadly neutralizing antibodies (bNabs). We focus our research on early changes in immune cell dynamics, signaling pathways and metabolic activity after vaccine administration with the aim to delineate new strategies to improve vaccine efficacy.
Group: Nienke Buddelmeijer
My group asks how bacterial lipoproteins become acylated by fatty acids derived from membrane phospholipids and how this influences their function both in light of physiology and in the interaction with the signalling components of the host innate immune system. Lipoproteins are efficient antigens in vaccine development due to their adjuvant characteristics, where triacylated antigens are more efficient than diacylated antigens.
Group: Alexandre Chenal
Fundamental research: biophysical and MS-based approaches
Unit: James Di Santo
We have created a series of innovative ‘humanized’ mouse models that generate robust human immune responses in vivo. These ‘Human Immune System’ (HIS) mice can be used to assess immunogenicity of candidate vaccines and to demonstrate efficacy of novel therapeutics (including immunomodulators, monoclonal antibodies, etc.) in a pre-clinical setting. HIS mice can be infected with a variety of pathogens (HIV, HBV, HCV) thereby creating human disease models to study pathogenicity as well as novel therapeutic approaches with an aim for ‘cure’. This work in performed in collaboration with research units directed by Olivier Schwartz, Hugo Mouquet, Philippe Bousso (Institut Pasteur) and Yves Lévy (Univ. Créteil, Labex VRI).
Unit: Gérard Eberl
Analysis of the microbial and genetic determinants of response to vaccination
We have demonstrated that the symbiotic microbiota sets the reactivity of the immune system early in life. If this ontogenic regulation is perturbed, the immune system develops increased reactivity, which leads to higher susceptibility to inflammatory pathologies, but possibly also to increased reactivity to infection and vaccination. We are now assessing the impact of this early life cross-talk between microbiota and immune system, in combination with the genetic background, on the efficacy and pathogenicity of vaccination later in life.
Unit: Jost Enninga
Our team develops approaches that provide precise information on the localization of pathogens in the context of challenged host cells. These approaches have been used to identify molecules and pathways that alter pathogen localization and the induced host responses. These modulations can be used to improve vaccination strategies as well as immune therapies.
Group: Molly Ingersoll
Treatment for urinary tract infection (UTI) relies upon antibiotics, which only treat acute UTI, do not prevent recurrence, and are not efficacious against rapidly disseminating multidrug resistant uropathogenic E. coli (UPEC). We are identifying novel treatment strategies targeting host pathways to treat UTI without antibiotics. Our data suggest that the innate response shapes the strength and nature of the long-term adaptive response to UTI. We test how manipulating the innate host response impacts development of UPEC-specific long-lasting immunity, focusing on three non-antibiotic based therapies approved for use in humans in other contexts.
Group: Nolwen Jouvenet
The first generation of viral vaccines relied on empiric attenuation by repeated passage in animals and/or cultured cells. A successful attenuation process eliminates virulence without losing viral immunogenicity. My group is studying live attenuated viral vaccines as models to understand key features of viral attenuation. Such studies are crucial for rational design of live attenuated viral vaccines and better understanding of virus-host interactions.
Group: Nathalie Pardigon
Attenuation of viruses achieved by inserting mutations at defined positions in the viral genome is now seen as a promising approach to vaccine design. By introducing a double mutation (M-I36F/A43G) in the coding sequence for the M protein of West Nile Flavivirus, we obtained a stable mutant virus with improper assembly but correct secretion. In vivo studies demonstrated full protection against lethal challenge in a mouse model. Targeting the M protein of Flaviviruses with such a double mutation may allow generating attenuated viruses as a source of new vaccines.
Junior Group: Jessica Quintin
The themes of our research projects are focused on the study of the modulation of innate immune responses termed “training”. Although until very recently sole the adaptive immune responses were described with memory properties, others and us established that innate monocytes can recall a first encounter with the fungal pathogen Candida albicans and its associated cell wall component b-glucan. Our efforts are directed towards understanding the in vivo physiology and mechanisms of b-glucan training which will help build new combinational therapies and vaccination strategies based on innate immunity.
Unit: Félix Rey
We are working in engineering correct immunogens to use for vaccination against dengue viruses. We have evidence that the antibodies most prone to ADE are those raised against conserved segments of the envelope protein that are not normally exposed on correctly conformed particles. In contrast, antibodies directed against quaternary epitopes have a much less negative effects and can be more protective, especially if they target the EDE epitope identified by structural studies. In parallel, we are investigating the epitopes of the most strongly neutralizing antibodies against viruses in the Bunyavirales order (hantaviruses, Rift Valley fever virus, Crimean-Congo hemorrhagic fever virus).
Unit: Olivier Schwartz
In collaboration with the laboratory humoral responses to pathogens, directed by Hugo Mouquet, the scientists study the effect of anti-HIV-1 broadly neutralizing antibodies (bNAbs) on HIV-1 spread. The unit focuses on effector functions of bNAbs, and their ability to eliminate HIV-1 infected cells through ADCC (Antibody-Dependent Cellular Cytotoxicity) and other means.