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| Author(s): |
Rúbens Prince dos Santos Alves
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) |
| Defense date: | 2020-10-08 |
| Examining board members: |
Luis Carlos de Souza Ferreira;
Edison Luiz Durigon;
Wagner Quintilio;
Paula Ordonhez Rigato
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| Advisor: | Luis Carlos de Souza Ferreira |
| Abstract | |
Dengue is a disease caused by one of four dengue virus serotypes (DENV 1-4), which is the main arbovirus currently affecting the health of human beings. Although the disease has been known for over 70 years, there are no effective drugs for treatment or a worldwide aceepted licensed vaccine formulation capable of providing complete protection against infection. Experimental studies and results generated after the release of the anti-DENV vaccine have shown that the induction of high titer neutralizing antibodies does not represent a unique protective correlate and, in fact, T cell-based immune responses play a relevant role in establishing a protective immune state. In this context, the present study first sought to demonstrate the central role of T lymphocyte responses against encephalitis induced by a DENV2 strain (JHA1) in immunocompetent mice. Protective responses were associated with generation of T lymphocytes that recognized epitopes of non-structural DENV proteins. In the next step, recombinant forms of the nonstructural proteins 1, 3 and 5, following delivery in a vaccine regimen, induced the production of high levels of IFNγ, which correlated with complete protection against the challenge with DENV2. Intravenous infection of C57BL/6 mice with the JHA1 strain induced partial lethality in these animals. In addition, it was found that functional T CD8+ lymphocytes are associated with protection in the model of primary and secondary DENV homotypic infection. CD4+ T-lymphocytes generated during DENV3 infection have also been found to play a protective role against DENV2. Finally, we described and validated new zika virus (ZIKV) protein epitopes that cross-react with DENV2, restricted to HLA-DBR1*0101, which were capable of inducing protective immunity against ZIKV when administered in a vaccine formulation. Thus, the present study described new experimental models relevant to the study of DENV and ZIKV, as well as the validation of these models for the evaluation of new vaccines. (AU) | |
| FAPESP's process: | 15/02352-7 - Vaccines for control of dengue: vaccine potential of the combination of the non-structural proteins in the generation of protective cell response in an experimental model |
| Grantee: | Rúbens Prince dos Santos Alves |
| Support Opportunities: | Scholarships in Brazil - Doctorate |