ALADVS · Antigenic landscape analysis of dengue virus serotypes

Dengue is a mosquito-borne viral disease, which has become an important international public health problem. Dengue can be caused by any of the four closely related, yet antigenically distinct serotypes of dengue viruses (DENV-1, -2, 3 and -4) that are members of family Flaviviridae (genus flavivirus). DENV causes disease ranging from mild dengue fever, to the potentially fatal dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Antibodies elicited by DENV infection are a mixture of serotype-specific, serotype-cross-reactive, flavivirus-cross-reactive antibodies, including long-lasting neutralizing antibodies to homologous DENV serotype. Presence of non-neutralizing, mainly serotype-cross-reactive antibodies, enhance the infection of heterologous DENV serotype and primarily responsible for DHF/DSS. Accurate detection of anti-DENV antibodies in human sera is complicated due to the shared antigenic determinants between different flaviviruses. Antibodies induced during DENV infection have also been shown to cross-react with auto-antigens. Despite all these problems, which are associated with the specificities of anti-DENV antibodies, there are serious gaps in our knowledge on DENV B-cell immune epitopes. B-cell epitopes have been primarily identified for one serotype, DENV-2 and mainly in envelope and NS1 proteins. In this application, we are proposing a novel phage display based approach (approach described in the part B) to identify B-cell immune epitopes (linear and conformational) of different specificity (e.g. DENV-specific, DENV-serotype-specific) in the proteome of four DENV serotypes. Detailed immune epitope information for all the four DENV serotypes can contribute to understand the mechanisms of antibody protection and antibody-mediated pathogenesis triggered by infections. B-cell immune epitope information for each of the four DENV serotypes will be useful for the generation of epitope-based antigens of diagnostics and vaccine use.""