Abstract
Chagas’ disease is a major public health problem affecting nearly 10 million in Latin America. Despite several experimental vaccines have shown to be immunogenic and protective in mouse models, there is not a current vaccine being licensed for humans or in clinical trial against T. cruzi infection. Towards this goal, we used the backbone of Yellow Fever (YF) 17D virus, one of the most effective and well-established human vaccines, to express an immunogenic fragment derived from T. cruzi Amastigote Surface Protein 2 (ASP-2). The cDNA sequence of an ASP-2 fragment was inserted between E and NS1 genes of YF 17D virus through the construction of a recombinant heterologous cassette. The replication ability and genetic stability of recombinant YF virus (YF17D/ENS1/Tc) was confirmed for at least six passages in Vero cells. Immunogenicity studies showed that YF17D/ENS1/Tc virus elicited neutralizing antibodies and gamma interferon (IFN-γ) producing-cells against the YF virus. Also, it was able to prime a CD8+ T cell directed against the transgenic T. cruzi epitope (TEWETGQI) which expanded significantly as measured by T cell-specific production of IFN-γ before and after T. cruzi challenge. However, most important for the purposes of vaccine development was the fact that a more efficient protective response could be seen in mice challenged after vaccination with the YF viral formulation consisting of YF17D/ENS1/Tc and a YF17D recombinant virus expressing the TEWETGQI epitope at the NS2B-3 junction. The superior protective immunity observed might be due to an earlier priming of epitope-specific IFN-γ-producing T CD8+ cells induced by vaccination with this viral formulation. Our results suggest that the use of viral formulations consisting of a mixture of recombinant YF 17D viruses may be a promising strategy to elicit protective immune responses against pathogens, in general.
Highlights
Chagas’ disease, caused by Trypanosoma cruzi is considered a neglected infectious disease, with an estimated 7 to 10 million cases in Latin America and about 10,000 to 14,000 deaths annually {Bonaldo, 2000, The yellow fever 17D vaccine virus as a vector for the expression of foreign proteins: development of new live flavivirus vaccines.}
We could observe an overall expansion of the specific TEWETGQIpeptide IFN-c-producing cells in mice immunized with Yellow Fever (YF) 17D/ NS2B3/Tc, YF 17D/ENS1/Tc, and Formulation 1, reaching 135, 234 and 223 spot forming-cells (SFC)/106 cells, respectively, as compared to the YF 17DD group which exhibited 6 SFC/106 cells (Figure 5D)
The parasitemia for each individual mouse is represented in the graphs for: (C) mice immunized with YF 17DD; (D) mice immunized with YF 17D/NS2B3/Tc; (E) mice immunized with YF 17D/ENS1/Tc; (E) immunized with Formulation 1
Summary
Chagas’ disease, caused by Trypanosoma cruzi is considered a neglected infectious disease, with an estimated 7 to 10 million cases in Latin America and about 10,000 to 14,000 deaths annually {Bonaldo, 2000, The yellow fever 17D vaccine virus as a vector for the expression of foreign proteins: development of new live flavivirus vaccines.}. The current state of globalization of Chagas’ disease due to high immigration to non-endemic countries and the high economic impact in lost productivity, has highlighted this emerging disease as a major public health challenge. This scenario has increased government efforts in trying to prevent the spread of T. cruzi and still has encouraged advances in the treatment of the disease and development of preventive and therapeutic vaccines. DNA, viral vectors and heterologous prime-boost regimens of vaccination suggest that it is feasible to control T. cruzi infection by vaccination (reviewed by ) Despite these promising results not a single candidate vaccine has been tested in humans. This is still an intense field of investigation and could bring economic benefits
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