Background
Insecticide-treated nets (ITNs) have been the primary form of malaria vector control undertaken in sub-Saharan Africa over the past decade. An estimated 1.04 billion nets were distributed in sub-Saharan Africa between 2009 and 2016, of which 582 million long-lasting insecticidal nets (LLINs) were distributed between 2014 and 2016 [
1]. It is recognized that vector control has been the main driver in averting an estimated 663 million clinical cases of malaria in sub-Saharan Africa between 2000 and 2015, with ITNs contributing to 68% of cases averted and indoor residual spraying (IRS) to 11% [
2]. While LLINs have been the most widespread vector control tool, IRS is another proven strategy, which in 2016 protected an estimated 45 million people in sub-Saharan Africa [
1]. Despite the undoubted effectiveness of IRS in many transmission settings, the relatively high cost can be prohibitive and tends to limit implementation to relatively small target areas, often regions with the highest levels of malaria transmission [
3,
4]. The US President’s Malaria Initiative (PMI) is one of the primary donors supporting IRS in sub-Saharan Africa through the PMI VectorLink Project (and previously the Africa Indoor Residual Spraying (AIRS) Project). In 2017, more than 5 million houses were sprayed through PMI VectorLink, protecting more than 21 million people in sub-Saharan Africa [
5].
Insecticide formulations that currently have a World Health Organization (WHO) prequalification (PQ) listing for IRS belong to 4 chemical classes; namely carbamate, organophosphate, pyrethroid and neonicotinoid insecticides [
6]. The organochlorine insecticide DDT (dichloro diphenyl trichloroethane) is also utilized in several countries, such as India and Zimbabwe but there is currently no DDT product with PQ listing [
7]. This may make it seem like there are a plethora of options for insecticide rotation, however, before neonicotinoid formulations were PQ listed, there were only 2 modes of action across 4 insecticide classes, namely sodium channel modulation (pyrethroids and DDT) and acetylcholinesterase (AChE) inhibition (organophosphates and carbamates) [
8]. This lack of product diversity increases the likelihood of cross-resistance between products with the same mode of action [
9].
Many countries in sub-Saharan Africa have adopted the policies outlined in the Global Plan for Insecticide Resistance Management (GPIRM) produced by the WHO and have prepared national resistance management documents according to the WHO framework [
10,
11]. According to several national policy documents, insecticide rotation should be undertaken in areas of IRS, using insecticides with different modes of action against susceptible malaria vectors [
12‐
14]. However, resistance to DDT and pyrethroids is widespread and several countries have reported resistance to carbamates in some regions [
15]. Pirimiphos-methyl resistance is also beginning to emerge in some settings [
16]. In addition, the residual duration of IRS formulations is of key importance, with products such as the carbamate Ficam™ WP (wettable powder) showing extremely short residual duration on substrates such as mud, being unsuitable in areas with long transmission seasons [
17]. The end result is that there have been few, if any, viable options for insecticide rotation. Therefore, despite having established policies based on GPIRM, countries have generally been unable to practically implement insecticide rotation for insecticide resistance management.
It has taken 40 years for new chemical classes to be developed for malaria vector control. Until the recent WHO listing of neonicotinoid and pyrrole insecticides, the pyrethroids were the last new chemical class to be brought through to the public health market, in the 1980s, and have proved to be highly successful both for LLINs and IRS [
18,
19]. New IRS formulations, SumiShield™ 50WG (water dispersible granules) and Fludora Fusion™ WP-SB (wettable powder in a water soluble bag), became WHO prequalified vector control products in 2017 and 2018 respectively and were included to the list of products which meet Global Fund requirements for procurement [
6,
20]. The active ingredient of SumiShield™ 50WG is the neonicotinoid insecticide, clothianidin, which is applied in IRS at a target dose of 300 mg ai/m
2, while Fludora Fusion WP-SB contains a mixture of clothianidin and deltamethrin (pyrethroid) and is applied at 225 mg ai/m
2. Neonicotinoid compounds were first developed for agricultural use in the 1990s and soon became the most widely used pesticides in the world against a broad spectrum of economically important crop pests [
21]. Clothianidin (one of at least 8 registered neonicotinoid insecticides) is a metabolite of another neonicotinoid insecticide, thiamethoxam [
22]. Both thiamethoxam and clothianidin are market leading broad spectrum, systemic compounds used in agriculture, which diffuse throughout the crop, including the roots and foliage, thus providing long-lasting protection against a variety of sucking and chewing pests [
22]. While clothianidin is primarily a systemic insecticide targeting agricultural chewing pests, it can also be applied inside houses to control malaria vectors through tarsal contact. The target sites of neonicotinoids are nicotinic acetylcholine receptors (nAChR), which represent a novel mode of action for vector control, meaning that cross-resistance through existing mechanisms is unlikely [
8].
Studies conducted in experimental huts in Benin showed that SumiShield™ 50WG produced high levels of
Anopheles gambiae sensu lato (s.l.) mortality for at least 8 months [
23]. While village scale IRS in India demonstrated control of
Anopheles culicifacies for at least 5 months and was operationally accepted by spray operators and community members [
24]. Fludora Fusion™ WP-SB has also shown similar impressive residual longevity in experimental hut trials in Benin, lasting for at least 8 months on mud and cement walls [
25].
In 2017, all IRS programs funded by PMI in sub-Saharan Africa were conducted with Actellic™ 300CS (capsule suspension) in areas with pirimiphos-methyl susceptible malaria vectors. However, in many countries Actellic™ 300CS has been sprayed annually, for up to 4 consecutive years, and it is important to implement rotation strategies as soon as possible, before resistance develops. Baseline clothianidin susceptibility testing was conducted in 16 countries in sub-Saharan Africa to determine whether there was any resistance prior to rollout of SumiShield™ 50WG and Fludora Fusion™ WP-SB, as part of national rotation strategies.
Discussion
Susceptibility bioassays conducted with insectary and wild Anopheles species confirmed that clothianidin is a relatively slow-acting insecticide, at the concentration tested, unlike other neurotoxic insecticides such as pyrethroids, organophosphates, carbamates and organochlorines. Generally more than 90% of clothianidin-induced mortality occurred within 72 h of exposure, however, 7 days was often required to reach 100% mortality. While standard WHO susceptibility bioassays have a holding period of 24 h after exposure, it was necessary to record delayed mortality for up to 7 days for clothianidin susceptibility tests. This creates greater demands on field entomology teams to keep control mortality below 20% for 7 days and also increases cost, as more time is spent in the field.
Full susceptibility was recorded with all susceptible insectary strains and > 98% mortality for wild
Anopheles at all sites in 11 out of 16 countries. However, tests in at least 1 site in 5 countries produced mortality < 98%, which could potentially be a sign of existing clothianidin resistance. A more likely explanation is that the diagnostic dose protocol needs further testing and modification. Normally, the WHO diagnostic concentration is twice the lowest concentration that gives systematically 100% mortality, in order to avoid false reporting of resistance. In this case the diagnostic dose killed 100% of insectary strains but may have been too low to prevent false detection of resistance. Inbreeding over a period of several decades generally reduces the overall fitness of reference insectary strains [
29]. Therefore, slightly lower levels of mortality when testing wild
An. gambiae s.l. is expected and does not necessarily represent evidence of true resistance. Indeed, repeat testing in Ghana and Zambia, where possible resistance was detected, subsequently showed 100% mortality in 3 sites. This highlights the need to repeat bioassays to confirm resistance, particularly when insecticide-treated papers are being self-prepared and especially when resistance is being reported for the first time. It was also useful to test an insectary strain in parallel, using the same treated filter papers, as a way to determine whether self-dosing of papers was a potential issue. In Kumbungu, Ghana, parallel testing with a susceptible insectary strain produced 100% mortality, while mortality was only 89% and 96% in 2 tests with wild
An. gambiae s.l. This may be an early indication of clothianidin resistance, but should be confirmed with further bioassays.
Insecticide selection pressure from agriculture is generally regarded as an important early driver of insecticide resistance in malaria vectors [
30,
31]. According to the Insecticide Resistance Action Committee (IRAC), neonicotinoid resistance has been reported to at least 12 species of crop pest due to agricultural use in Asia, Europe and North America, with increased expression of various P450 genes implicated in several species [
32‐
34]. Neonicotinoids are undoubtedly becoming more widely utilized for agricultural pest control in Africa. While usage statistics from sub-Saharan Africa are scanty, in 2018, there were a reported 45 neonicotinoid products registered in Cameroon (covering 4 types of neonicotinoid), 133 products registered in Tanzania (including 6 types), and > 70 products in Côte d’Ivoire for use against pests of cocoa, cotton, bananas, coffee and tomatoes [
35‐
37]. Neonicotinoids are highly water soluble and can persist for months in aerobic soil, therefore making contamination of local water surfaces following agricultural use highly likely. Neonicotinoid residues were found to be a common occurrence in puddles located in maize fields with neonicotinoid seed treatment [
38]. Such contamination of water sources may represent an important source of mosquito larval selection for neonicotinoid resistance in the future and should be monitored.
SumiShield™ 50WG received WHO PQ listing in 2017 and Fludora Fusion™ WP-SB in 2018. However, before these products can be used for IRS it is essential for baseline susceptibility testing to be conducted to ensure there is no existing resistance, either from agricultural use or cross-resistance through existing mechanisms. In a time where new insecticides for rotation strategies are desperately needed, it is vitally important for the WHO to implement timely multi-center studies to determine susceptibility protocols for new active ingredients so that guidance can be issued at the same time as a formulation receives PQ listing. A lack of susceptibility protocols for new active ingredients can result in delayed uptake due to NMCP (National Malaria Control Programme) or donor reluctance to utilize products where resistance monitoring can’t be effectively conducted.
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