Ellie Sherrard-Smith

Background: The 8-aminoquinoline primaquine is used as a single low dose with antimalarial treatment to reduce malaria transmission. An alternative 8-aminoquinoline, tafenoquine has a substantially longer half-life and may therefore provide more sustained transmission-blocking activity, but direct comparisons with primaquine are limited. We compare the transmission-blocking activity and pharmacokinetics of these drugs in vivo. Methods: We assess primaquine dose response in Plasmodium berghei -infected mice and compare an equimolar dose of tafenoquine in a mouse-to-mosquito-to-mouse transmission model. We also assess both drugs against Plasmodium falciparum gametocytes in humanized immunodeficient mice using bioluminescence and microscopy, and measure plasma drug concentrations. Dose-response relationships are modeled using generalized linear and nonlinear regression, with appropriate statistical tests for transmission and parasite endpoints. Results: Here we show that primaquine produces stronger early transmission-blocking activity, reducing mosquito infection more effectively than tafenoquine 24 hours after treatment. In contrast, tafenoquine retains greater activity at later time points, coinciding with prolonged systemic exposure. Similar temporal differences are observed when the drugs are combined with the schizonticide sulphadiazine. In humanized mice, both drugs reduce gametocyte abundance in a dose-dependent manner, while tafenoquine shows sustained exposure for several days compared with the more rapid decline of parent primaquine. Conclusions: Primaquine and tafenoquine have distinct temporal transmission-blocking profiles in vivo. Sustained activity of tafenoquine is consistent with prolonged exposure rather than greater intrinsic potency. These findings are observed across multiple models, both in the absence or presence of a partner schizonticide and thus demonstrate a potential advantage of the utilization of tafenoquine when compared to primaquine.

Implementing vector control interventions against infectious diseases is operationally challenging, with delivery and population uptake taking considerable time within a community. Studies have suggested that the slow mass drug administration (MDA) of the endectocide, ivermectin, may have contributed to the lower epidemiological impact against malaria observed in recent cluster-randomised controlled trials, although evidence supporting this hypothesis is lacking. It is unclear whether interventions which have short but highly effective durations of entomological impact are more impactful than tools which kill the same number of mosquitoes but over a longer period. Transmission dynamics mathematical models can be used to explore the trade-offs between product profiles and investigate how different implementation periods could influence disease control. First, we use a simple vector-borne disease compartmental model to explore the epidemiological impact of killing the same number of mosquitoes over 10, 30 or 90 days. We find that for different mosquito-killing periods, the total number of cases averted is similar, although the observable impact may depend on when efficacy is assessed. Secondly, we adapted an existing malaria transmission model and simulated the fast and slow deployment of an effective endectocide MDA campaign in different seasonal settings. In perennial and seasonal settings and for a given coverage, slow MDA deployment averts more clinical cases of malaria than a fast synchronised distribution (completed in a single day, although the difference was modest). The benefits of the intervention depend on how well-timed a deployment is relative to the peak of the transmission season, with the efficacy of an ivermectin-like endectocide MDA being up to approximately 42% lower if started late. The work indicates that the time taken to complete MDA campaigns is unlikely to drive major differences in the effectiveness of short-lived endectocides and showcases how transmission dynamics models can be used to support epidemiological trial interpretation. Author summary: Mathematical models can be used to help guide the development and implementation of control interventions against infectious diseases and explore how real-world complexities can impact disease control. Previous modelling work indicated that the mass drug administration (MDA) of the mosquito-killing drug, ivermectin, could substantially reduce malaria transmission, assuming eligible individuals due to receive the drug do so on the same day. Logistical constraints mean that MDA campaigns are often slower to implement, although the epidemiological impact of this is unclear. We develop a mathematical modelling framework to explore how the speed at which an intervention is deployed, or its period of effectiveness, influences vector-borne disease dynamics. Results suggest that spreading the impact of an intervention over a longer period provides slightly greater protection. Slower MDA deployment of an ivermectin-like drug is generally more efficacious, although impact is diminished in areas with seasonal mosquito abundance if it is implemented too late in the transmission season.

Background: Gaps in unimproved house structures, especially in eaves and windows, allow mosquito entry, increasing indoor vector-borne disease transmission. Simple modifications to such houses may reduce human exposure, and insecticide treatment may kill mosquitoes, benefiting all community members. This study evaluated insecticide-treated screening (ITS) for eaves and windows, incorporated with deltamethrin and piperonyl butoxide (PBO), compared to a permethrin and PBO-treated bednet in Tanzania. Method: A randomised Latin-square design (4 × 4) was used in four experimental huts within a large netting cage to allow mosquito recapture inside and outside of huts. Four treatments were evaluated: (1) new (12-month stored) ITS; (2) 12-month naturally-aged ITS; (3) 12-month field-used pyrethroid-PBO bednet (standard of care in Tanzania), and (4) no treatment. The study was performed for 32 nights using 30 mosquitoes per strain, per hut per night. Four laboratory-reared strains were used: malaria vectors ( Anopheles arabiensis and An. funestus ), dengue vector ( Aedes aegypti ), and nuisance biting ( Culex quinquefasciatus ). Recaptured mosquitoes were assessed for mortality at 72 h, blood-feeding, and hut entry. A simulation with a modified mechanistic model tracking Plasmodium falciparum malaria was used to illustrate potential epidemiological impact from these products. Results: Against all mosquito species compared to 12-month aged pyrethroid-PBO-treated bednet, new ITS induced higher mortality [Odds Ratio:2.25(95%Confidence Interval:1.65–3.06), p < 0.0001], and aged-ITS was similar [OR:0.80(95%CI:0.59–1.08), p = 0.141]. Both new and aged ITS significantly ( p < 0.0001) reduced mosquito blood-feeding [new OR:0.02(95% CI:0.01–0.03); aged OR:0.09(95%CI:0.05–0.14)] and hut entry [new IRR:0.10(95%CI:0.08–0.13); aged IRR:0.25(95%CI:0.21–0.31)]. Transmission model estimates indicate epidemiological impacts of ITS may supersede pyrethroid-PBO-treated bednets at the population level. The model results indicate impact potency depends on assumed intervention percentage cover, durability, and mosquito bionomics. Conclusions: This study introduces a standardised semi-field bioassay to evaluate ITS, generating entomological data that, for the first time, enabled modelling of its potential impact on malaria transmission. ITS is an efficacious tool for public health as it kills substantial proportions of malaria and dengue vectors, and reduces nuisance biting. Given its simplicity, it should be considered an additional or stand-alone tool for screening unimproved houses.

In this essay, we describe efforts to curtail the spread of vector-borne infections and how these efforts are entangled in the causes and consequences of the destruction of life, and the ecosystems which support life, on our planet. Using examples from malaria and sleeping sickness, we show how current efforts to control vector-borne diseases reflect the Western logic of a highly compartmentalized, hierarchical approach, dominated by biomedicine and commoditized interventions. These have dramatically reduced morbidity and mortality yet perpetuate colonial legacies, global inequities, and environmental harm. For instance, billions of insecticide-treated nets, rapid diagnostic tests, and other single-use plastics used in health products generate waste and emissions, while reinforcing fossil-fuel dependence and Global North dominance. These approaches treat diseases as isolated problems detached from the broader socio-ecological system. They excel at suppressing symptoms but leave untouched the root causes such as poverty, ecosystem destruction, and entrenched power imbalances. Current disease research and control strategies are situated within a wider dominant culture that has led to multiple undesirable effects on our planet (including climate, ecological functions, and biosphere integrity) driven largely by wealthy minorities and a global extractive economic system. Our intention is not to promote the idea that communities should be denied commodities that protect against vector-borne disease, but to identify that a shift is urgently required to make space for alternatives. A change involving transdisciplinary, socially-just strategies, that center local leadership, and enforce full life-cycle responsibility for health commodities; all of which are essential to safeguard both human and planetary health.

The invasive urban malaria vector Anopheles stephensi threatens 126 million city dwellers in Africa. Controlling An. stephensi requires greater understanding of its origin, invasion dynamics, and insecticide resistance mechanisms. Analysis of 645 whole genomes sampled across Africa, the Middle East, and Asia supports an invasion scenario in which an initial South Asian introduction established a bridgehead population in Djibouti, which seeded distinct invasion fronts in Sudan, Ethiopia/Kenya, and Yemen. These incursions show contrasting rates and routes of spread shaped by landscape topology. Insecticide resistance is predominantly mediated by metabolic detoxification genes, with resistance haplotypes and copy-number amplifications introduced from South Asia. These findings, alongside a companion genomic resource, enable genomic surveillance of An. stephensi spread and resistance to aid control strategies.

Entomological surveillance is an important component of mosquito-borne disease control. Mosquito abundance, infection prevalence and the entomological inoculation rate are the most widely reported entomological metrics, although these data are notoriously noisy and difficult to interpret. For many infections, only older mosquitoes are infectious, which is why, in part, vector control tools that reduce mosquito life expectancy have been so successful. The age structure of wild mosquitoes has been proposed as a metric to assess the effectiveness of interventions that kill adult mosquitoes, and age grading tools are becoming increasingly advanced. Mosquito populations show seasonal dynamics with temporal fluctuations. How seasonal changes in adult mosquito emergence and vector control could affect the mosquito age distribution or other important metrics is unclear. We develop stochastic mathematical models of mosquito population dynamics to show how variability in mosquito emergence causes substantial heterogeneity in the mosquito age distribution, with low frequency, positively autocorrelated changes in emergence being the most important driver of this variability. Fitting a population model to mosquito abundance data collected in experimental hut trials indicates these dynamics are likely to exist in wild Anopheles gambiae populations. Incorporating age structuring into an established compartmental model of mosquito dynamics and vector control, indicates that the use of mosquito age as a metric to assess the efficacy of vector-control tools will require an understanding of underlying variability in mosquito ages, with the mean age and other entomological metrics affected by short-term and seasonal fluctuations in mosquito emergence.

Malaria vector control tools currently focus on insecticide treated nets (ITNs) and indoor residual spraying in malaria-endemic locations, but additional preventative strategies are needed to address protection gaps. Larval source management (LSM) includes larvicide application to aquatic habitat and an array of alternative forms of environmental efforts. An individual-based transmission model for falciparum malaria is used to demonstrate the theoretical benefit of suppressing malaria adult mosquito vector densities through LSM. The model simulates results of epidemiological trials from Western Kenya (a hilly area with papyrus swamps adjacent to human settlements and moderate to high perennial malaria transmission) and Côte d’Ivoire (an area with Sudanese climate, reducing vegetation cover and high transmission) that applied larvicide alongside ITNs, and investigates whether estimated changes in adult density can be used to project changes in human malaria. In the Western Kenya setting generalised linear models estimate 82% (90% credible intervals: 64% – 92%) and 88% (79% – 94%) reductions in the proportion of adult Anopheles funestus and Anopheles gambiae complex mosquitoes respectively as measured by CDC light traps. In Côte d’Ivoire, an 82% (56% – 93%) reduction of the dominant An. gambiae vector was estimated using standard window trap and pyrethrum spray catch. Both studies had variable village-level impacts. The transmission dynamics model predicted that these entomological impacts would result in a reduction in malaria prevalence in children of 6-months to 10-years of age of 48 – 72% in Kenya, and a 11 – 78% reduction in all-age clinical incidence across villages in Côte d’Ivoire, which are broadly consistent with the empirically observed outcomes. High heterogeneity between villages within the same study indicate that the relative or absolute reductions in mosquito adult density observed in these trials cannot be simply extrapolated to other regions. The LSM strategy adopted, unit area covered, and multiple environmental covariates all contribute to differences in indicators that could be used to assess entomological impacts and the corresponding epidemiological outcomes. This important malaria control tool was impactful across all sites examined, though further work is needed to understand how best to use this tool in the fight against malaria.

Insecticide-treated nets (ITNs) are most effective against malaria if mosquitoes attempt to bite people when they are in bed. Collecting the biting behaviour data required to quantify a key metric - the proportion of bites taken when people are in bed - is challenging. We tested the reliability of a simplified mosquito sampling method against data from a published systematic review. Using the methodology in the remote, malaria-endemic Bijagos archipelago, Guinea-Bissau, we estimate this proportion is 0.95 (95% Credible intervals, CrI: 0.84, 1.00). Transmission modelling suggests that pyrethroid-only ITNs in a Bijagos-like setting could avert 86% of Plasmodium falciparum clinical cases in under 5-year-olds (95% CrI: 77, 89%), compared to without ITNs. Due to agricultural work, some islanders sleep without ITNs in temporary outdoor shelters, potentially reducing the predicted population-level impact of ITNs by 35%. Our methodology increases the feasibility of monitoring the impact of indoor malaria control interventions in resource-limited settings.

Entomological surveillance is an important component of mosquito-borne disease control. Mosquito abundance, infection prevalence and the entomological inoculation rate are the most widely reported entomological metrics, although these data are notoriously noisy and difficult to interpret. For many infections, only older mosquitoes are infectious, which is why, in part, vector control tools that reduce mosquito life expectancy have been so successful. The age structure of wild mosquitoes has been proposed as a metric to assess the effectiveness of interventions that kill adult mosquitoes, and age grading tools are becoming increasingly advanced. Mosquito populations show seasonal dynamics with temporal fluctuations. How seasonal changes in adult mosquito emergence and vector control could affect the mosquito age distribution or other important metrics is unclear. We develop stochastic mathematical models of mosquito population dynamics to show how variability in mosquito emergence causes substantial heterogeneity in the mosquito age distribution, with low frequency, positively autocorrelated changes in emergence being the most important driver of this variability. Fitting a population model to mosquito abundance data collected in experimental hut trials indicates these dynamics are likely to exist in natural Anopheles gambiae populations. Incorporating age structuring into an established compartmental model of mosquito dynamics and vector control, indicates that the use of mosquito age as a metric to assess the efficacy of vector-control tools will require an understanding of underlying variability in mosquito ages, with estimates affected by short-term and seasonal fluctuations in mosquito emergence.

The invasion of Africa by the Asian urban malaria vector, Anopheles stephensi, endangers 126 million people across a rapidly urbanising continent where malaria is primarily a rural disease. Control of An. stephensi requires greater understanding of its origin, invasion dynamics, and mechanisms of widespread resistance to vector control insecticides. We present a genomic surveillance study of 551 An. stephensi sampled across the invasive and native ranges in Africa and Asia. Our findings support a hypothesis that an initial invasion from Asia to Djibouti seeded separate incursions to Sudan, Ethiopia, and Yemen before spreading inland, aided by favourable temperature, vegetation cover, and human transit conditions. Insecticide resistance in invasive An. stephensi is conferred by detoxification genes introduced from Asia. These findings, and a companion genomic data catalogue, will form the foundation of an evidence base for surveillance and management strategies for An. stephensi .