Transmission-blocking drugs for malaria elimination

Adapt or Die: Targeting Unique Transmission-Stage Biology for Malaria Elimination

“…Interventions that will inhibit the formation of gametocytes, and thereby transmission, are required to contribute to malaria elimination strategies ( Leroy et al., 2014 ; Birkholtz et al., 2016 ; Sinden, 2017 ; Delves et al., 2018a ; Birkholtz et al., 2022 ). There are multiple reasons why human to mosquito transmission of Plasmodium is an attractive target for intervention.…”

“…Gametocytes represent a targetable population bottleneck ( Sinden, 2017 ); they are present in the pharmacologically accessible blood compartment; mature, stage V gametocytes can persist for days and mature sexual parasites are extracellular for ~24 h in the mosquito, creating a significant window during which to target the parasite for therapeutic/immune destruction. Transmission-blocking antimalarials would drastically reduce the parasite reservoir (even in high-transmission settings), could target the significant proportion of asymptomatic parasite carriers and, possibly the most enticing, could protect the lifespan of antimalarials that kill asexual blood stages (ABS) if used in combination, by preventing the spread of resistant parasites against the ABS active antimalarial ( Delves et al., 2018a ; Birkholtz et al., 2022 ).…”

“…This has revealed novel chemotypes associated with targetable biology in these stages. In principle, our broader understanding of the unique biology of gametocytes and gametes ( Delves, 2012 ; Meibalan and Marti, 2017 ; Josling et al., 2018 ; Ngotho et al., 2019 ; Schneider and Reece, 2021 ; Usui and Williamson, 2021 ) therefore present a major, unexplored avenue to discover new antimalarials, and with the toolkit associated with transmission-blocking screens now well established ( Delves et al., 2018a ; Birkholtz et al., 2022 ), these should be exploited with renewed effort ( Sinden et al., 2012 ; Leroy et al., 2014 ; Nilsson et al., 2015 ; Delves et al., 2018a ). Open areas worth investigating include the commitment phase, early differentiation processes during immature gametocytogenesis, maturation of stage V gametocytes and gametogenesis itself, although the latter will rely on irreversibly compromising (sterilizing) mature stage V gametocytes, as these will be the target of intervention in humans.…”

“…These include using tools to target the parasite pool as causative agent for disease, with innovations including vaccines such as RTS,S recently approved by the WHO for use in children under five ( Laurens, 2020 ), and using antimalarial agents for additional applications aside from their continued chemotherapeutical use. This importantly also includes transmission-blocking capabilities, although the majority of clinically used antimalarials do not have this ability mostly due to differences associated with the variant biology of the different life cycle forms of malaria parasites ( Burrows et al., 2017 ; Birkholtz et al., 2022 ). This therefore motivates strategies towards the discovery of transmission-blocking antimalarial agents, focused on targeting unique transmission-associated biology; both as the focus of this review.…”

3, 2, 1, go! Cryptosporidium counts down to sex

“…parvum has relevance for developing improved control methods. Significant research on sexual development and gametocyte formation in, for example, Plasmodium falciparum , a causative agent of malaria, is an important aspect of planned strategies to block parasite transmission [ 11 ]. This stage is essential for the parasite’s survival and a key target to reduce transmission.…”