Image and improvement of immunological protection against malaria parasites

About half the world’s population is at risk of contracting malaria, the most deadly human parasitic disease, responsible for> 200 million clinical cases and ~ 700,000 deaths per year. The absence of an effective malaria vaccine is a major obstacle to the control and elimination of this devastating disease. However, the development of a malaria vaccine is encouraged by the possibility of protecting human beings, known since the 1970s, through vaccination with multiple and high doses of live attenuated sporozoites, which constitute the mobile and infectious parasitic stage transmitted by mosquitoes. Unfortunately, this method is not suitable for use in mass vaccination protocols due to major operational and economic impediments related to the production, storage and delivery of a large number of live attenuated parasites in tropical countries. Conversely, subunit pre-erythrocytic (PE) vaccines, which target sporozoites and liver stages, are more suitable for use in mass vaccination; but they protect humans only moderately as seen for RTS, S, the most prominent PE candidate vaccine based on the circumsporozoite protein (CSP), the main surface protein of sporozoites.

In this model, vaccines containing CSP are not able to induce complete protection against a rigorous challenge with sporozoites, as observed in humans. Using this model, a preliminary protocol was developed in which anti-CSP antibodies completely protected animals challenged with a dose of 5000 sporozoites. This research initially proposed to elucidate the mechanisms of this sterilizing antibody-mediated protection using in vivo imaging techniques and a library of anti-CSP monoclonal antibodies to determine when, where, how and what type of antibody is eliminating the parasite in the skin and liver of animals protected. Then, the proposal sets to improve this protective humoral protocol by adding a strong response from CD8 + T cells induced by directing the CDP epitope from CSP to dendritic cells using hybrid monoclonal antibodies anti-DEC205 / DCIR and lentiviral vectors. The third level of protection will be added by incorporating new protective PE antigens from functional screening using lentiviral vectors, where the hundred most abundant genes from the PE stages are being screened based on their protective activity. In summary, using this approach the intention to: i) characterize sterilizing effector activities at a clonal level using innovative in vivo imaging methods, ii) optimize the response of CD8 + T cells by targeting antigens to dendritic cells, and iii) test the formulations multi-antigenic agents to increase the protective responses against the parasite. Therefore, the research proposes a functional dissection of protective effectors, a first step to rationalize the development of better vaccines, and a step-by-step strategy to improve humoral and cellular protection centered on CSP, using the protein alone or in combination with new protective PE antigens.

Project details

Immunology
Vaccines

Apr 2016 — Mar 2019

Brazil