Population replacement gene drive characteristics for malaria elimination in a range of seasonal transmission settings: a modeling study

Genetically engineering mosquitoes is a promising new vector control strategy to reinvigorate the fight against malaria in Sub-Saharan Africa. Using an agent-based model of malaria transmission with vector genetics, we examine the impacts of releasing population-replacement gene drive mosquitoes on malaria transmission and quantify the gene drive system parameters required to achieve local elimination within a spatially-resolved, seasonal Sahelian setting. We evaluate the performance of two different gene drive systems: "classic" and "integral". Various transmission regimes (low, moderate, and high - corresponding to annual entomological inoculation rates of 10, 30, and 80 infectious bites per person) and other simultaneous interventions, including deployment of insecticide-treated nets (ITNs) and passive healthcare seeking, are also simulated. Local elimination probabilities decreased with pre-existing population target site resistance frequency, increased with transmission-blocking effectiveness of the introduced antiparasitic gene and drive efficiency, and were context dependent with respect to fitness costs associated with the introduced gene. Of the four parameters, transmission-blocking effectiveness may be the most important to focus on for improvements to future gene drive strains because a single release of classic gene drive mosquitoes is likely to locally eliminate malaria in low to moderate transmission settings only when transmission-blocking effectiveness is very high (above approximately 80-90‰). However, simultaneously deploying ITNs and releasing integral rather than classic gene drive mosquitoes significantly boosts elimination probabilities, such that elimination remains highly likely in low to moderate transmission regimes down to transmission-blocking effectiveness values as low as approximately 50‰ and in high transmission regimes with transmission-blocking effectiveness values above approximately 80-90‰. Thus, a single release of currently achievable population replacement gene drive mosquitoes, in combination with traditional forms of vector control, can likely locally eliminate malaria in low to moderate transmission regimes within the Sahel. In a high transmission regime, higher levels of transmission-blocking effectiveness than are currently available may be required.

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Increasing role of pyrethroid-resistant Anopheles funestus in malaria transmission in the Lake Zone, Tanzania: implications for the evaluation of novel vector control products

10.1101/2021.04.01.438043 ◽

2021 ◽

Author(s):

Nancy S. Matowo ◽

Jackline Martin ◽

Manisha A. Kulkarni ◽

Jacklin F. Mosha ◽

Eliud Lukole ◽

...

Keyword(s):

Vector Control ◽

Malaria Transmission ◽

Anopheles Funestus ◽

Sub Saharan Africa ◽

North West ◽

Vector Population ◽

Lake Zone ◽

Sub Saharan ◽

Study District

AbstractAnopheles funestus is playing an increasing role in malaria transmission in parts of sub-Saharan Africa, where An. gambiae s.s. has been effectively controlled by long-lasting insecticidal nets. We investigated vector population bionomics, insecticide resistance and malaria transmission dynamics in 86 study clusters in North-West Tanzania. An. funestus s.l. represented 94.5% (4740/5016) of all vectors and was responsible for the majority of malaria transmission (96.5%), with a sporozoite rate of 3.4% and average monthly entomological inoculation rate (EIR) of 4.57 per house. Micro-geographical heterogeneity in species composition, abundance and transmission was observed across the study district in relation to key ecological differences between northern and southern clusters, with significantly higher densities, proportions and EIR of An. funestus s.l. collected from the south. An. gambiae s.l. (5.5%) density, principally An. arabiensis (81.1%) and An. gambiae s.s. (18.9%), was much lower and closely correlated with seasonal rainfall. Both An. funestus s.l. and An. gambiae s.l. were similarly resistant to alpha-cypermethrin and permethrin. Overexpression of CYP9K1, CYP6P3, CYP6P4 and CYP6M2 and high L1014F-kdr mutation frequency were detected in An. gambiae s.s. populations. Study findings highlight the urgent need for novel vector control tools to tackle persistent malaria transmission in the Lake Region of Tanzania.

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Gene drive to reduce malaria transmission in sub-Saharan Africa

Journal of Responsible Innovation ◽

10.1080/23299460.2017.1419410 ◽

2018 ◽

Vol 5 (sup1) ◽

pp. S66-S80 ◽

Cited By ~ 19

Author(s):

Austin Burt ◽

Mamadou Coulibaly ◽

Andrea Crisanti ◽

Abdoulaye Diabate ◽

Jonathan K. Kayondo

Keyword(s):

Malaria Transmission ◽

Sub Saharan Africa ◽

Gene Drive ◽

Sub Saharan

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The dominant malaria vector, Anopheles funestus from rural south-eastern Tanzania, is more strongly resistant to insecticides than Anopheles arabiensis

10.21203/rs.3.rs-19762/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Polius Gerazi Pinda ◽

Claudia Eichenberger ◽

Halfan S Ngowo ◽

Dickson S Msaky ◽

Said Abbasi ◽

...

Keyword(s):

Malaria Transmission ◽

Pyrethroid Resistance ◽

Mosquito Species ◽

Anopheles Funestus ◽

Indoor Residual Spraying ◽

Sub Saharan Africa ◽

Malaria Vectors ◽

Insecticide Treated Nets ◽

South Eastern ◽

Sub Saharan

Abstract Background: Long-lasting insecticide-treated nets (LLINs) and indoor residual spraying (IRS) have greatly reduced malaria transmission in sub-Saharan Africa, but are threatened by insecticide resistance in dominant malaria vectors. In south-eastern Tanzania, pyrethroid-resistant Anopheles funestus now transmit more than 80% of malaria infections even in villages where the species occurs at far lower densities than other vectors such as Anopheles arabiensis.Methods: To better understand the dominance of An. funestus in these settings and improve options for its control, this study compared intensities of resistance between females of this species and those of An. arabiensis , using WHO assays with 1×, 5× and 10× insecticide doses. Additional tests were done to assess the reversibility of such resistance using synergists. The mosquitoes were collected from villages across two districts in south-eastern Tanzania.Findings: Both species were resistant to the two pyrethroids (permethrin and deltamethrin) and the organochloride (DDT) but susceptible to the organophosphate (pirimiphos-methyl) at standard baseline doses (1×). However, An. funestus as opposed to An. arabiensis was also resistant to the carbamate (bendiocarb) at standard doses (1×). An. funestus showed strong resistance to pyrethroids, surviving the 5× doses and 10× doses except in one village. Pre-exposure to the synergist, piperonyl butoxide (PBO), reversed the pyrethroid-resistance in both An. arabiensis and An. funestus achieving mortalities >98%, except for An. funestus from two villages for which permethrin-associated mortalities exceeded 90% but not 98%.Conclusions : In these communities where An. funestus now dominates malaria transmission, the species also displays much stronger resistance to pyrethroids than its counterpart, An. arabiensis, and can readily survive more classes of insecticides, including carbamates. The resistance to pyrethroids in both mosquito species appears to be mostly metabolic and can be reversed significantly using synergists such as PBO. These findings may explain the continued persistence and dominance of An. funestus despite widespread use of pyrethroid-treated LLINs, and will also inform future choices of interventions to tackle malaria transmission in this area and other similar settings. Such interventions may include PBO-based LLINs or improved IRS with compounds such as organophosphates against which the vectors are still susceptible.

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Systematic review of the entomological impact of insecticide-treated nets evaluated using experimental hut trials in Africa

10.1101/2021.04.07.21254306 ◽

2021 ◽

Author(s):

Rebecca K Nash ◽

Ben C Lambert ◽

Raphael N'Guessan ◽

Corine Ngufor ◽

Mark Rowland ◽

...

Keyword(s):

Systematic Review ◽

Vector Control ◽

Pyrethroid Resistance ◽

Sub Saharan Africa ◽

Insecticide Treated Nets ◽

Experimental Hut ◽

Factors Influencing ◽

Sub Saharan ◽

The Impact ◽

The Relationship

Background: Resistance of anopheline mosquitoes to pyrethroid insecticides is spreading rapidly across sub-Saharan Africa, diminishing the efficacy of insecticide-treated nets (ITNs) - the primary tool for preventing malaria. The entomological efficacy of indoor vector control interventions can be measured in experimental hut trials (EHTs), which are specially designed to quantify the protection provided under controlled conditions. Experimental hut structures resemble local housing but allow collection of surviving exiting mosquitoes as well as dead or dying mosquitoes. There is a need to understand how the spread of resistance changes ITN efficacy and to elucidate factors influencing EHT results, including differences in experimental hut construction and design features, to support the development of novel vector control tools. Methods: A comprehensive database of EHTs was compiled and summarised following a systematic review to identify all known trials investigating ITNs or indoor residual spraying (IRS) across sub-Saharan Africa. This analysis focuses on EHTs investigating ITNs and uses Bayesian statistical models to characterise the complex interaction between ITNs and mosquitoes, the variability between studies, and the impact of pyrethroid resistance. Results: As resistance rises, the entomological efficacy of ITNs declines. They induce less mortality and are less likely to deter mosquitoes from entering huts. Despite this, ITNs continue to offer considerable personal protection by reducing mosquito feeding until resistance reaches high levels. There are clear associations between the different entomological impacts of ITNs, though there is still substantial variability between studies, some of which can be accounted for by hut design. The relationship between EHT outcomes and the level of resistance (as measured by discriminating dose bioassays) is highly uncertain. Conclusions: The meta-analyses show that EHTs are an important reproducible assay for capturing the complex entomological efficacy of ITNs on blood-feeding mosquitoes. The impact of pyrethroid resistance on these measures appears broadly consistent across a wide geographical area once hut design is accounted for, suggesting results can be extrapolated beyond the sites where the trials were conducted. Further work is needed to understand factors influencing EHT outcomes and how the relationship between outcomes and resistance varies when different methods are used to assess the level of resistance in wild mosquito populations. This will allow more precise estimates of the efficacy of these important vector control tools.

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An increasing role of pyrethroid-resistant Anopheles funestus in malaria transmission in the Lake Zone, Tanzania

Scientific Reports ◽

10.1038/s41598-021-92741-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nancy S. Matowo ◽

Jackline Martin ◽

Manisha A. Kulkarni ◽

Jacklin F. Mosha ◽

Eliud Lukole ◽

...

Keyword(s):

Malaria Transmission ◽

Anopheles Funestus ◽

Sub Saharan Africa ◽

North West ◽

Vector Population ◽

Lake Zone ◽

Sub Saharan ◽

Long Lasting Insecticidal Nets ◽

Study District

AbstractAnopheles funestus is playing an increasing role in malaria transmission in parts of sub-Saharan Africa, where An. gambiae s.s. has been effectively controlled by long-lasting insecticidal nets. We investigated vector population bionomics, insecticide resistance and malaria transmission dynamics in 86 study clusters in North-West Tanzania. An. funestus s.l. represented 94.5% (4740/5016) of all vectors and was responsible for the majority of malaria transmission (96.5%), with a sporozoite rate of 3.4% and average monthly entomological inoculation rate (EIR) of 4.57 per house. Micro-geographical heterogeneity in species composition, abundance and transmission was observed across the study district in relation to key ecological differences between northern and southern clusters, with significantly higher densities, proportions and EIR of An. funestus s.l. collected from the South. An. gambiae s.l. (5.5%) density, principally An. arabiensis (81.1%) and An. gambiae s.s. (18.9%), was much lower and closely correlated with seasonal rainfall. Both An. funestus s.l. and An. gambiae s.l. were similarly resistant to alpha-cypermethrin and permethrin. Overexpression of CYP9K1, CYP6P3, CYP6P4 and CYP6M2 and high L1014S-kdr mutation frequency were detected in An. gambiae s.s. populations. Study findings highlight the urgent need for novel vector control tools to tackle persistent malaria transmission in the Lake Region of Tanzania.

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Bacterial larvicides used for malaria vector control in sub-Saharan Africa: review of their effectiveness and operational feasibility

Parasites & Vectors ◽

10.1186/s13071-019-3683-5 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 9

Author(s):

Yahya A. Derua ◽

Eliningaya J. Kweka ◽

William N. Kisinza ◽

Andrew K. Githeko ◽

Franklin W. Mosha

Keyword(s):

Vector Control ◽

Malaria Vector ◽

Sub Saharan Africa ◽

Malaria Vector Control ◽

Sub Saharan

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Anopheles metabolic proteins in malaria transmission, prevention and control: a review

Parasites & Vectors ◽

10.1186/s13071-020-04342-5 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Eunice Oluwatobiloba Adedeji ◽

Olubanke Olujoke Ogunlana ◽

Segun Fatumo ◽

Thomas Beder ◽

Yvonne Ajamma ◽

...

Keyword(s):

Insecticide Resistance ◽

Vector Control ◽

Malaria Transmission ◽

Control Strategies ◽

Parasite Development ◽

Potential Contribution ◽

Population Replacement ◽

Blood Digestion ◽

Significant Toxicity ◽

And Control

Abstract The increasing resistance to currently available insecticides in the malaria vector, Anopheles mosquitoes, hampers their use as an effective vector control strategy for the prevention of malaria transmission. Therefore, there is need for new insecticides and/or alternative vector control strategies, the development of which relies on the identification of possible targets in Anopheles. Some known and promising targets for the prevention or control of malaria transmission exist among Anopheles metabolic proteins. This review aims to elucidate the current and potential contribution of Anopheles metabolic proteins to malaria transmission and control. Highlighted are the roles of metabolic proteins as insecticide targets, in blood digestion and immune response as well as their contribution to insecticide resistance and Plasmodium parasite development. Furthermore, strategies by which these metabolic proteins can be utilized for vector control are described. Inhibitors of Anopheles metabolic proteins that are designed based on target specificity can yield insecticides with no significant toxicity to non-target species. These metabolic modulators combined with each other or with synergists, sterilants, and transmission-blocking agents in a single product, can yield potent malaria intervention strategies. These combinations can provide multiple means of controlling the vector. Also, they can help to slow down the development of insecticide resistance. Moreover, some metabolic proteins can be modulated for mosquito population replacement or suppression strategies, which will significantly help to curb malaria transmission.

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