Step by step one goes very far
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 :
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