Did the prolonged residual efficacy of clothianidin products lead to a greater reduction in vector populations and subsequent malaria transmission compared to the shorter residual efficacy of pirimiphos-methyl?

The reduction in malaria incidence by 18% worldwide between 2010 and 2016, and by 20% in the WHO African Region [1], was the result of the intensive use of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) [2]. IRS is an important intervention that can rapidly reduce the density and longevity of disease-carrying mosquitoes when carried out properly [3]. It has had a positive impact on entomological transmission indicators (ETI) of malaria in Benin since 2008 in sprayed communes [4]. Similarly, in several other African countries, IRS has reduced malaria transmission and burden in children [5‐9]. However, despite the progress made in implementing vector control and treatment access strategies, challenges remain, and the decline in malaria morbidity and mortality has slowed in recent years [10]. Several hypotheses have attempted to explain the slowdown in progress after 2016. The lack of predictable, sustainable and solid funding at national and international level to ensure continuous surveillance, and the resistance of mosquitoes to insecticides, could be major causes of the stagnation of progress [11, 12].

To advance progress and achieve the goals of reducing global malaria mortality rates to minus 75% by 2025, reducing global malaria incidence to minus 75% by 2025, eliminating malaria from 20 countries with transmission in 2015 by 2025, and preventing the re-emergence of malaria in malaria-free countries, it is important to overcome the difficulties associated with poorly functioning health systems, in particular the use of ineffective vector control tools [12]. Indeed, the selection of an insecticide product for IRS should always be a decision made on the basis of recent local data on the susceptibility of target vectors to insecticides [13]. However, to optimize the impact of IRS and to manage potential resistance of malaria vectors to pirimiphos-methyl (after three years of IRS use), Benin's National Malaria Control Programme (NMCP) opted for the use of clothianidin 500 g/kg + deltamethrin 62.5 g/kg and clothianidin 50 WG alone in 2020 and 2021, respectively. Clothianidin 50 WG and the mixture clothianidin 500 g/kg and deltamethrin 62.5 g/kg are two new IRS formulations prequalified by the WHO in 2017 and 2018 [14]. Clothianidin is a neonicotinoid that targets nicotinic acetylcholine receptors, a representing a novel target for public health vector control interventions. In Benin, clothianidin-based insecticides have a long residual efficacy of 8 to 10 months in large-scale in community trials on mud and cement walls, in contrast to pirimiphos-methyl 300 CS, which has a residual efficacy of 4 to 5 months [15].

The aim of the present study was to show whether the prolonged residual efficacy of clothianidin-based products resulted in a greater reduction in vector populations and subsequent malaria transmission compared with the shorter residual efficacy of pirimiphos-methyl. The findings at the end of the evaluation will enable decision-makers to make a judicious choice of insecticide for indoor residual spraying, taking into account not only the cost-effectiveness of the insecticide with the best residual activity, but also the residual activity of the insecticide on walls and its impact in reducing malaria ETIs.

This study was conducted to investigate the difference in malaria transmission indicators (human bite rate, sporozoite rate, entomological inoculation rate, malaria incidence, indoor resting density, blood feeding rate and parous) after IRS with pirimiphos-methyl and clothianidin products. Fluctuations were observed in the abundance of mosquitoes collected according to genus and species per study year. Culex quinquefasciatus (59.6%) was the predominant mosquito species collected, followed by An. gambiae s.l. (37.6%). Over the 3 years of the study, Cx. quinquefasciatus was more abundant in urban, while An. gambiae s.l. was generally predominant in rural. The abundance of Cx. quinquefasciatus may be linked to its ability to lay eggs and develop in a variety of natural and artificial larval habitats [24]. Of the 8 species of Anopheles collected, An. gambiae s.l., An. funestus and An. nili were identified as malaria vectors. The An. gambiae complex was omnipresent throughout the study area, accounting for 98.6% (18,683/18,940) of all Anopheles collected. The An. funestus group was the second most abundant [1% (190/18,940)] followed by An. nili [0.03% (5/18,940)]. This predominance of An. gambiae s.l. was previously reported in northern Benin [25‐27] in Kandi, Atacora and Donga and Alibori, respectively. Molecular characterization of An. gambiae s.l. showed that An. gambiae s.s. (52.9%), An. coluzzii (46.4%) and An. arabiensis (0.8%) are the members of this complex in the two departments studied. These results are similar to those of Salako et al. [27].

The reduction in the rate of bites inside treated houses compared with control houses suggests the complementary prevention represented by IRS in endemic areas where LLINs are used as a preventive intervention. Previously, Akogbéto et al. [28], have shown high rates of An. gambiae bites on humans inside houses using only LLINs as a means of prevention.

The results of study indicate a greater reduction in human-vector contact, sporozoite rate (SR) and entomological inoculation rate (EIR) of An. gambiae both inside and outside homes sprayed with pirimiphos-methyl 300 CS in the Alibori and Donga departments. There was also a moderate reduction in all three indicators inside homes sprayed with the clothianidin 500 g/kg + deltamethrin 62.5 g/kg mixture. In the case of clothianidin 50 WG alone, both indoor and outdoor biting rates and sporozoite infections remained high after IRS. These results confirm the efficacy of pirimiphos-methyl 300 CS used in indoor residual spraying (IRS) for the elimination and control of pyrethroid-resistant malaria vectors. In northern Benin and Kenya, the findings of work by Akogbéto et al. [22], Salako et al. [21] and Abong'o et al. [23] have demonstrated the positive impact of pirimiphos-methyl 300 CS IRS in reducing entomological indicators of malaria transmission. The 10-month residual efficacy of pirimiphos-methyl 300 CS in Kenya in 2020 [29], led not only to a drastic reduction in the density of An. funestus, the main malaria vector, but also to a reduction in the number of malaria cases recorded at health facilities. The positive effect of IRS with pirimiphos-methyl 300 CS on the longevity of malaria vectors at rest and outside treated dwellings in Alibori and Donga departments results from the rapid action [30] of the insecticide. The reduction in malaria transmission with clothianidin 50 WG alone and the clothianidin 500 g/kg + deltamethrin 62.5 g/kg PID mixture against pyrethroid-resistant mosquitoes was higher indoors but the effects were not statistically significant. Clothianidin-based insecticides used in IRS have a slow lethal effect on mosquitoes.

When the Anopheles field strain comes into contact with clothianidin, it can survive for up to 120 h [15, 31, 32]. The results of studies by Hoppé et al. [34] and Lees et al. [35] diverge on the efficacy of clothianidin. Hoppé et al. [34] reported low insecticidal activity of clothianidin against Aedes aegypti, a mosquito species responsible for the transmission of diseases, such as dengue and Zika virus infection. Lees et al. [35] found clothianidin to be sufficiently effective against mosquitoes, particularly Anopheles, in tarsal contact tests. These contradictory results may be due to several factors, such as research methodologies, mosquito species studied, clothianidin application conditions, and possibly other unknown factors.

The resting density of An. gambiae inside sprayed houses is significantly lower than in unsprayed houses in 2019 with the use of pirimiphos-methyl 300 CS in IRS and in 2020 with the mixture clothianidin 500 g/kg + deltamethrin 62.5 g/kg throughout the study area. However, in 2021, the opposite situation was observed, with more An. gambiae resting in houses sprayed with clothianidin 50 WG alone compared to control houses. This result is similar to that of Agossa et al. [37] at Covè, where the exophily induced by clothianidin 50 WG alone was relatively low as clothianidin does not have excito-repulsive and irritant properties.

The high feeding rates observed in treated dwellings may be explained by the anthropophilic behaviour of An. gambiae which seeks its blood meal first before resting. These results are similar to those obtained in other studies [25, 28, 38‐41]. During the first 2 h after sunset, An. gambiae females feed on blood [33, 42] when household residents are engaged in domestic activities or watching television or radio. Also, An. gambiae may also take a blood meal at dusk [33] when household members leave their LLINs for prayer and other domestic activities such as cooking. After feeding, the females of An. gambiae go to rest on the various supports hung on the walls sprayed with insecticide to avoid contact with the insecticide.

The low rate of parity observed in homes sprayed with pirimiphos-methyl confirms the high insecticidal effect of this compound and a reduction in adult longevity. These results confirm those of Salako et al. [27]. However, no significant difference was observed with clothianidin 50 WG alone. This may be due to its slow action [33] as mosquitoes may be able to complete a full gonotrophic cycle before succumbing to the insecticide. However, the lack of difference in sporozoite rates suggests that this insecticide had minimal impact on mosquito longevity in Benin.

Despite the increasing EIR in 2020 and 2021 with the use of clothianidin 500 g/kg + deltamethrin 62.5 g/kg mixture and clothianidin 50 WG alone in IRS, malaria incidence was slightly reduced in Alibori in both years, though only in 2020 in Donga. This reduction in incidence through the decline in the number of new malaria cases recorded is probably explained by IRS and the national distribution and use of LLINs which were distributed through a mass campaign in 2020 intended to cover all households counted throughout the country [36]. This slight reduction in new malaria cases could also be attributed to the confinement measures introduced in response to COVID-19. This measure engendered fear and a change in behaviour among the population with regard to access to health services. For fear of being diagnosed positive for COVID-19 and being separated from their families, some patients would prefer to stay at home to receive treatment. For others, health centres no longer seemed to be appropriate options during this period, as they were perceived as places at risk of contamination by COVID-19.

However, it should be noted that clothianidin's poor performance in reducing entomological indicators of malaria transmission could be linked to other factors such as climate and intervention coverage [15].

Overall, indoor residual spraying with clothianidin-based insecticides did not further reduce vector populations and malaria transmission indicators, despite the longer residual efficacy compared with the shorter residual efficacy of pirimiphos-methyl-based products.