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Targeting the transmission stage of malaria parasites by drug - and vaccine-based approaches
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Malaria remains a public health concern worldwide, despite significant efforts to reduce its case incidence and death rate. In recent years, due to increased funding and renewed efforts to eliminate malaria in endemic regions, interest in development of transmission-blocking strategies (TBS) gained momentum. These tools aim to reduce the prevalence of infection in a population by blocking the transmission of the parasite through the mosquito, consequently reducing the spread of drug-resistant parasites while prolonging the life span of antimalarial drugs. Moreover, targeting malaria transmission has additional advantages: antigens from mosquito stages are less genetically variant than blood and liver stage antigens; circulating parasite numbers in the bloodstream are significantly reduced once inside the mosquito; and parasites are extracellular for approximately 24 h in the mosquito compared to approximately 1 min during red blood cell invasion by merozoites. Modelling studies have predicted the potential of targeting Plasmodium transmission in the context of malaria control, linking insecticide-treated nets and indoor residual spraying to the largest decrease in case prevalence in the African continent from 2000 to 2015. Hence, it seems logical to explore tools targeting the transmission of malaria parasites to complement currently available strategies, expanding the array of malaria control interventions, while addressing concerns raised by insecticide and drug resistance. The present thesis addresses two independent but complementary TBS, transmission blocking drugs (TBDs) and transmission-blocking vaccines (TBVs), unveiling the gametocidal and sporontocidal effect of avermectins beyond their known mosquitocidal effect, as well as the potential of antiretroviral (ARV) compounds and current first-line antiretroviral therapies (ARTs) to block malaria parasite transmission, and characterizing a new multistage whole organism malaria vaccine candidate expressing a transmission-blocking target antigen. Our results show that ivermectin and other avermectins target the sporogonic stages of Plasmodium whilst exerting no inhibitory activity on the parasite’s sexual stages, lending further support to mass drug administration (MDA) of ivermectin in malaria-endemic regions to control the spread of disease. Our results also demonstrated that first-line ARTs used against human immunodeficiency virus (HIV) commonly employed in the field impair the sporogonic development of Plasmodium in vitro, with the ART of zidovudine, lamivudine, lopinavir and ritonavir, the first-line treatment recommended for children under 3 years of age, reducing oocyst density in vivo. Finally, we show that a genetically modified P. berghei parasites can be engineered for expression of multiple P. falciparum (Pf) antigens, including the pre erythrocytic Pf circumsporozoite protein (PfCSP), the mosquito stage Pfs48/45 and the erythrocytic Pf reticulocyte-binding protein homolog 5 (PfRh5), thus creating a multistage malaria vaccine candidate. Our data confirm the correct expression of PfCSP and Pfs48/45 by these parasites, as well as their immunogenicity in a rodent model of infection. The continued development of new Plasmodium TBS is essential to diversify and extend our current array of malaria control interventions. Our work provides new insights into drug and vaccine-based inhibition of Plasmodium transmission, paving the way for their further exploitation as part of the antimalarial toolbox.
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Plasmodium malaria ivermectina antirretrovirais vacina transmission-blocking strategies ransmission-blocking vaccine transmission-blocking drugs