The control of mosquito populations with insecticide treated bed nets and indoor residual sprays remains the cornerstone of malaria reduction and elimination programs. In light of widespread insecticide resistance in mosquitoes, however, alternative strategies for reducing transmission by the mosquito vector are urgently needed, including the identification of safe compounds that affect vectorial capacity via mechanisms that differ from fast-acting insecticides. Here, we show that compounds targeting steroid hormone signaling disrupt multiple biological processes that are key to the ability of mosquitoes to transmit malaria. When an agonist of the steroid hormone 20-hydroxyecdysone (20E) is applied to Anopheles gambiae females, which are the dominant malaria mosquito vector in Sub Saharan Africa, it substantially shortens lifespan, prevents insemination and egg production, and significantly blocks Plasmodium falciparum development, three components that are crucial to malaria transmission. Modeling the impact of these effects on Anopheles population dynamics and Plasmodium transmission predicts that disrupting steroid hormone signaling using 20E agonists would affect malaria transmission to a similar extent as insecticides. Manipulating 20E pathways therefore provides a powerful new approach to tackle malaria transmission by the mosquito vector, particularly in areas affected by the spread of insecticide resistance.

For encapsulated bacteria such as Streptococcus pneumoniae, asymptomatic carriage is more common and longer in duration than disease, and hence is often a more convenient endpoint for clinical trials of vaccines against these bacteria. However, using a carriage endpoint entails specific challenges. Carriage is almost always measured as prevalence, whereas the vaccine may act by reducing incidence or duration. Thus, to determine sample size requirements, its impact on prevalence must first be estimated. The relationship between incidence and prevalence (or duration and prevalence) is convex, saturating at 100% prevalence. For this reason, the proportional effect of a vaccine on prevalence is typically less than its proportional effect on incidence or duration. This relationship is further complicated in the presence of multiple pathogen strains. In addition, host immunity to carriage accumulates rapidly with frequent exposures in early years of life, creating potentially complex interactions with the vaccine’s effect. We conducted a simulation study to predict the impact of an inactivated whole cell pneumococcal vaccine—believed to reduce carriage duration—on carriage prevalence in different age groups and trial settings. We used an individual-based model of pneumococcal carriage that incorporates relevant immunological processes, both vaccine-induced and naturally acquired. Our simulations showed that for a wide range of vaccine efficacies, sampling time and age at vaccination are important determinants of sample size. There is a window of favorable sampling times during which the required sample size is relatively low, and this window is prolonged with a younger age at vaccination, and in a trial setting with lower transmission intensity. These results illustrate the ability of simulation studies to inform the planning of vaccine trials with carriage endpoints, and the methods we present here can be applied to trials evaluating other pneumococcal vaccine candidates or comparing alternative dosing schedules for the existing conjugate vaccines.

12For encapsulated bacteria such as Streptococcus pneumoniae, asymptomatic carriage is 13 more common and longer in duration than disease, and hence is often a more convenient 14 endpoint for clinical trials of vaccines against these bacteria. However, using a carriage 15 endpoint entails specific challenges. Carriage is almost always measured as prevalence, 16 whereas the vaccine may act by reducing incidence or duration. Thus, to determine sample 17 size requirements, its impact on prevalence must first be estimated. The relationship between 18 incidence and prevalence (or duration and prevalence) is convex, saturating at 100% 19 prevalence. For this reason, the proportional effect of a vaccine on prevalence is typically less 20 than its proportional effect on incidence or duration. This relationship is further complicated in 21 the presence of multiple pathogen strains. In addition, host immunity to carriage accumulates 22 rapidly with frequent exposures in early years of life, creating potentially complex interactions 23 with the vaccine's effect. We conducted a simulation study to predict the impact of an 24 inactivated whole cell pneumococcal vaccine-believed to reduce carriage duration-on 25 carriage prevalence in different age groups and trial settings. We used an individual-based 26 model of pneumococcal carriage that incorporates relevant immunological processes, both 27 vaccine-induced and naturally acquired. Our simulations showed that for a wide range of 28 vaccine efficacies, sampling time and age at vaccination are important determinants of 29 sample size. There is a window of favorable sampling times during which the required sample 30 size is relatively low, and this window is prolonged with a younger age at vaccination, and in a 31 trial setting with lower transmission intensity. These results illustrate the ability of simulation 32 studies to inform the planning of vaccine trials with carriage endpoints, and the methods we 33

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The growth of the malaria parasite Plasmodium falciparum in human blood causes all the symptoms of malaria. To proliferate, non-motile parasites must have access to susceptible red blood cells, which they invade using pairs of parasite ligands and host receptors that define invasion pathways. Parasites can switch invasion pathways, and while this flexibility is thought to facilitate immune evasion, it may also reflect the heterogeneity of red blood cell surfaces within and between hosts. Host genetic background affects red blood cell structure, for example, and red blood cells also undergo dramatic changes in morphology and receptor density as they age. The in vivo consequences of both the accessibility of susceptible cells, and their heterogeneous susceptibility, remain unclear. Here, we measured invasion of laboratory strains of P. falciparum relying on distinct invasion pathways into red blood cells of different ages. We estimated invasion efficiency while accounting for red blood cell accessibility to parasites. This approach revealed different tradeoffs made by parasite strains between the fraction of cells they can invade and their invasion rate into them, and we distinguish "specialist" strains from "generalist" strains in this context. We developed a mathematical model to show that generalist strains would lead to higher peak parasitemias in vivo compared to specialist strains with similar overall proliferation rates. Thus, the ecology of red blood cells may play a key role in determining the rate of P. falciparum parasite proliferation and malaria virulence.

The growth of the malaria parasite Plasmodium falciparum in human blood causes all clinical manifestations of malaria, a process that begins with the invasion of red blood cells. Parasites enter red blood cells using distinct pairs of parasite ligands and host receptors that define particular invasion pathways. Parasite strains have the capacity to switch between invasion pathways. This flexibility is thought to facilitate immune evasion against particular parasite ligands, but may also reflect the fact that red blood cell surfaces are dynamic and composed of heterogeneous invasion targets. Different host genetic backgrounds affecting red blood cell structure have long been recognized to impact parasite growth in vivo, but even within a host, red blood cells undergo dramatic changes in morphology and receptor density as they age. The consequences of these heterogeneities for parasite growth in vivo remain unclear. Here, we measured the ability of laboratory strains of P. falciparum relying on distinct invasion pathways to enter red blood cells of different ages. We estimated invasion efficiency while accounting for the fact that even if the red blood cells display the appropriate receptors, not all are physically accessible to invading parasites. This approach revealed a tradeoff made by parasites between the fraction of susceptible cells and their invasion rate into them. We were able to distinguish between "specialist" strains exhibiting high invasion rate in fewer cells versus "generalist" strains invading less efficiently into a larger fraction of cells. We developed a mathematical model to predict that infection with a generalist strain would lead to higher peak parasitemias in vivo when compared with a specialist strain with similar overall proliferation rate. Thus, the heterogeneous ecology of red blood cells may play a key role in determining the rate of parasite proliferation between different strains of P. falciparum.

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