Plasmodium vivax vaccine development and antigen discovery using P. berghei malaria models.

Author(s)

Irina Dobrescu

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2019-07-26

Examining board members

Daniel Youssef Bargieri; Josué da Costa Lima Junior; Daniela Santoro Rosa; Gerhard Wunderlich

• Advisor: Daniel Youssef Bargieri

Abstract

Malaria is a preventable, diagnosable and treatable disease. Yet, the disease causes thousands of deaths every year, and millions of people are still endangered. Almost all malaria cases worldwide are due to infection with Plasmodium vivax or P. falciparum. There is an urgent need to eliminate malaria, since drug resistance is reappearing, and new strategies, like efficient vaccines, will be required. Developing a malaria vaccine is one of the greatest challenges in biomedical sciences. Vaccine development against P. vivax is even more challenging, because the parasite cannot be continuously cultured in laboratories. The lack of cultures has been an obstacle slowing pre-clinical tests of vaccine formulations against P. vivax based on known antigens and makes new antigen discovery particularly difficult. This project had two major proposals: i) use a malaria murine model, P. berghei, to construct hybrid transgenic parasites expressing a P. vivax blood stage antigen, MSP119, and use the hybrid parasite to challenge mice vaccinated with available PvMSP1 based vaccines, testing the efficacy of these formulations; ii) use P. berghei to search for Plasmodium functional homologs of the P. falciparum-specific invasion molecule PfRh5, a promising vaccine antigen candidate that has recently been shown to bind to basigin on the surface of host cells and to be essential for invasion. We found that the replacement of P. berghei MSP119 by the one of P. vivax is possible in both ANKA and NK65 strains. Mutant hybrid parasites infected hosts similarly to the respective wild type. Mice immunization with PvMSP119 vaccine formulations induced high specific IgG titers. The model of BALB/c mice immunization and NK65 hybrid challenge may be a valuable model for testing PvMSP119 vaccine formulations. The formulation FliC-PvMSP119-PADRE + poly (I:C) was the most protective in this model, showing a delay in mortality without control of parasitemia. In addition, P. berghei RIPR is essential for parasite erythrocytic replication as it is for P. falciparum, localizes at micronemes and its interactome was described. (AU)

• FAPESP's process: 14/23083-1 - Plasmodium vivax vaccine development and antigen discovery using P. berghei malaria models.
• Grantee: Irina Dobrescu
• Support Opportunities: Scholarships in Brazil - Doctorate