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Project #13204
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#13204 : Early transcriptional signature of T-cell memory after dengue vaccination
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Name of Applicant : Claude Roth
Date of application : 19-04-2019
Unit : Functional Genetics of Infectious Diseases
Location : F. Jacob, 5th Floor, room 26-05-11A
Phone : 01 45 68 89 62
@ Mail : claude.roth@pasteur.fr
@ PI-Mail : anavaj.sakuntabhai@pasteur.fr

Project context and summary :

Dengue virus (DENV) induces strong T and B cell responses upon infection. However, there is currently neither vaccine nor specific treatment against DENV, which is spreading worldwide causing 400 million new infections every year, of which 100 million cases are symptomatic, ranging from a self-limiting febrile illness named dengue fever (DF) to more severe life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). One of the major obstacles of dengue vaccine development is the cross-reactivity among antibodies against the different DENV serotypes (designed as DENV1-4) that are 67-75% identical at the amino acid level. Indeed, while a primary infection by one DENV serotype can induce a lifelong immunity against re-infection by the same serotype, subsequent infections by heterologous serotypes increase the risk of developing severe dengue, a phenomenon due to non-neutralizing or sub-neutralizing antibodies and called antibody-dependent enhancement (ADE). To avoid the induction of such enhancing antibodies, and given the identification of CD4+ and CD8+ T cell epitopes from previously dengue virus (DENV)-infected donors, we have designed a minimal DENV antigen (called DENV1-NS, patent EP14305984.8 filled on June 23 2014), which is enriched in conserved and highly antigenic epitopes. Using this minimal DENV1-NS antigen, we have first established in vivo its immunogenicity in transgenic mice expressing HLA class II and class I alleles (with the activation of DENV-specific CD4 and CD8 T cells). We have also shown that a prime-boost DNA immunization of these HLA transgenic mice induces a strong T cell immunity, with a significant protection against DENV1 infection, in the absence of neutralizing or sub-neutralizing anti-DENV antibodies (Roth et al., accepted for publication). Our proposal aims, therefore, to identify early transcriptional signatures correlated with the development of memory CD4 and CD8 T cells in vaccinated animals, which promote enhanced anti-dengue immunity.


Related team publications :
C. Roth, T. Cantaert, Colas, M. Prot, I. Casadémont, L. Levillayer, J. Thalmensi, P. Langlade-Demoyen, C. Gerke, K. Bahl, G. Ciaramella, E. Simon-Loriere and A. Sakuntabhai: A modified mRNA vaccine targeting immunodominant NS epitopes protects against dengue virus infection in HLA class I transgenic mice. (Frontiers in Immunol., accepted for publication).
F. G. Delgado, K. I. Torres, J. E. Castellanos, C. Romero-Sanchez, E. Simon-Loriere, A. Sakuntabhai and C. Roth: Improved Immune Responses Against Zika Virus After Sequential Dengue and Zika Virus Infection in Humans. Viruses, 10(9) (2018) doi:10.3390/v10090480
E. Simon-Loriere, V. Duong, A. Tawfik, S. Ung, S. Ly, I. Casademont, M. Prot, N. Courtejoie, K. Bleakley, P. Buchy, A. Tarantola, P. Dussart, T. Cantaert and A. Sakuntabhai: Increased adaptive immune responses and proper feedback regulation protect against clinical dengue. Sci Transl Med, 9(405) (2017) doi:10.1126/scitranslmed.aal5088
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Project Manager : emeline.perthame@pasteur.fr
Project Type : Short
Status : Pending


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