Insecticide resistance in the West African malaria vector Anopheles gambiae and investigation of alternative tools for its delay

There is a current policy to eliminate malaria in the African continent. Pyrethroid-incorporated Long Lasting Insecticidal Nets (LLINs) and/or Indoor Residual Spraying (IRS) are the chemical weapons being deployed to achieve that goal. Rather worryingly, resistance to pyrethroids is well documented in the major vectors of malaria in Africa, and could decimate the contribution that vector control can make to any successful elimination agenda over the next decade. DDT (Dichlorodiphenyltrichloroethane) for IRS is cost effective but undesirable because of its environmental impact. There is a need to identify pyrethroid resistance mechanisms in the areas being scaled up, evaluate their direct impact on the efficacy of these tools and identify novel tools that might have potential as alternatives to pyrethroids and DDT for net or indoor residual treatments. This thesis reports that pyrethroid, organophosphate (Ops) & carbamate resistance is present in the Mopti (M) and Savanah (S) molecular forms of the major vector of malaria, Anopheles gambiae, in two West African countries, Benin and Ivory Coast where LLINs are currently being deployed,. Mechanisms for pyrethroids include elevated oxidase activities and the knock down resistance (kdr) gene at high frequency (>80%) whereas an insensitive acetylcholinesterase conferred Ops and carbamate resistance. Experimental hut tests in Southern Benin showed that the efficacy of Insecticide Treated Net (ITN) and IRS with the pyrethroid lambdacyalothrin was seriously compromised by pyrethroid resistance in the M form of An. gambiae, as opposed to the North where there is no record of pyrethroid resistance. This type of pyrethroid resistance, now spreading through West African populations of the M molecular form of An. gambiae, appears to have major operational significance in other areas such as Bioko, Niger and Burkina Faso. The alternative candidate insecticides, indoxacarb (an oxadiazine), chlorfenapy (a pyrrole) and chlorpyrifos methyl (an organophosphate) were evaluated, in the laboratory and/or in the field. In the laboratory, indoxacarb and chlorfenapyr on netting were more toxic than permethrin over the same dosage range (100-500mg/m2). Toxic activity was rather slow and bloodfeeding of mosquitoes was uninhibited in the presence of either insecticide. The experimental hut tests conducted in Southern Benin indicated that chlorfenapyr has high potential for IRS, killing 82.9% of pyrethroid resistant An. gambiae and 69% of Culex quinquefasciatus. Likewise, IRS with chlorpyrifos methyl CS (Capsule Suspension) was very efficacious at the same site in Benin. It killed 95.5% of pyrethroid resistant An. gambiae that entered a hut and showed activity on walls that lasted for more than 9 months without significant decay. If applied at high coverage, chlorpyrifos methyl CS should show higher, more-sustained levels of malaria transmission control than that achievable with DDT or pyrethroids. The feasibility of applying synthetic insect repellents on bednets (RTNs) to control insecticide resistant mosquitoes was explored in the second country, Ivory Coast. The results of tests done in experimental huts showed that formulations of volatile DEET (N,N-diethyl-3-methylbenzamide) and ethyl butylacetylaminopropionate (IR3535) on nets reduced bloodfeeding and the entry rate of mosquitoes into huts. An unexpected result was the 69-76% mortality of An. gambiae and 51-61% mortality of Cx. quinquefasciatus in huts containing RTNs. The DEET-based product provided better efficacy but was short-lived. Further treatment of netting with a formulation of DEET in which the repellent is gradually released from a capsule that binds the repellent strongly, showed that the formulation repels, inhibits blood-feeding and kills mosquitoes for a period of at least 6 months under laboratory conditions. Application of repellents to nets warrants further investigation as well as their development as alternatives to pyrethroids. Because it will not be possible to go for malaria elimination with the current tools, based on pyrethroids only, the results obtained with chlorfenapyr, indoxacarb and chlorpyrifos methyl should encourage further studies aiming at supplementing pyrethroids for vector control in areas where malaria mosquitoes are resistant to pyrethroids.