Humans have always suffered at the hands of insect pests, leading to discomfort, economic loss, and even death.

Since the very beginning of civilization, humans have endeavoured to improve their well-being, and this has been exemplified in their use of chemical agents in the control of insects responsible for both the transmission of disease and the destruction of crops.

Some of the methods for insect control date back many centuries. Ancient people relied almost entirely on the use of natural products and preparations derived from these. Before the 1940s, the chemicals used to control insect pests were largely inorganic, such as compounds of lead and arsenic, which are well-known poisons that we wouldn’t dream of using today. Natural chemicals of plant origin, such as nicotine, pyrethrin and rotenone were also used for pest control.

The modern era

The beginning of the modern era of synthetic pesticides (the so-called ‘pesticide revolution’) began in the 1940s with the introduction of DDT, which was commercially manufactured in 1943 and soon became the most extensively used insecticide in vector control. However, the first cases of resistance to DDT occurred only four years later in Aedes mosquitoes in 1947. Other groups of synthetic insecticides were developed and introduced for adult mosquito control, including the first organophosphate in the early 1950s and the first carbamate in the 1960s. The euphoria surrounding insecticide use for malaria control ended in 1976 when the World Health Organization started to speak in terms of ‘control’ rather than ‘eradication’ due to, among other factors, the appearance of insecticide resistance in the mosquito vectors.

The emergence of resistance to some of the organochlorine, organophosphate and carbamate insecticides, combined with their environmental persistence, highlighted the need for effective but also safe and degradable insecticides. In the 1970s, photostable analogues of the natural product pyrethrin were introduced, such as permethrin, followed by other ‘pyrethroids’, including cypermethrin, deltamethrin and lambda-cyhalothrin. Currently, pyrethroids represent the most important weapons against insect pests of public health importance. They are also extensively used in agriculture.

The use of pyrethroids on fabrics started with impregnation of tsetse traps and permethrin dipped mosquito nets in the early 1980s. The effectiveness of these insecticide-treated nets led to the further development of ‘long-lasting insecticidal nets’ (LLINs). LLINs protect the insecticide from significant loss during use and washing, allowing an effective dose to remain for their expected life. This technology enabled the scale-up of bed net use across sub-Saharan Africa. However, this also meant that for over a decade, mosquitoes were targeted with effectively a ‘pyrethroid monotherapy’, encouraging the emergence of pyrethroid resistance, which now represents a serious threat to many malaria control programmes.

With classical indoor residual spray (IRS) programmes, there appears to be a relatively direct relationship between insecticide resistance in a mosquito vector population and impact on malaria transmission.

However, for LLINs the situation is more complex. Even in areas where resistance is widespread, new intact pyrethroid nets will provide some protection. Although, as nets age, damage to the net and declining doses of insecticide reduce both the personal protective value of the net and also the impact on the overall mosquito population. There is evidence, for example, that pyrethroid-treated nets may continue to provide some personal protection (but reduced community-wide protection) even in areas of high pyrethroid resistance. However, continued exposure to declining doses of pyrethroid may further accelerate the development of resistance in these mosquito populations.

Novel insecticides for malaria vector control

Development of novel insecticides, all the way from discovery to deployment in new vector control products, is technically challenging, costly and has a high rate of failure. As a result, there are only a small number of organisations capable, and willing, to develop new public health insecticides. The first approach to address pyrethroid resistance in bed nets came in 2009 in the form of piperonyl butoxide (PBO), a synergist that enhances the effect of the insecticide in the face of metabolic resistant mosquitoes. 2016 to 2020 saw the approval of a pyrrole insecticide and a juvenile hormone mimic for use on bed nets and a neonicotinoid for use in IRS, both new insecticidal modes of action for mosquito vector control.

To continue the progress being made in eliminating malaria, we need fully effective LLINs and IRS products. The current pipeline for new insecticides is encouraging but opportunities to identify and develop novel modes of action are limited. History shows that the effectiveness of new insecticide mode of action classes can be rapidly lost to resistance. This highlights the importance of having an Insecticide Resistance Management programme already in place when they are first used.

Author: Helen Jamet

References

Hancock, P A et al. Mapping trends in insecticide resistance phenotypes in African malaria vectors. PLOS Biology. 2020. 18(6): e3000633.

IR Mapper user guide

Kleinschmidt, I et al. Implications of insecticide resistance for malaria vector control with long-lasting insecticidal nets: a WHO-coordinated, prospective, international, observational cohort study. The Lancet Infectious Diseases. 2018. 18(6): 640-649.

Moyes, C. L., et al. Evaluating insecticide resistance across African districts to aid malaria control decisions. Proceedings of the National Academy of Sciences. 2020. 117(36): 22042-22050.

WHO (2018) Global report on insecticide resistance in malaria vectors: 2010-2016