Connecting points and learning from the past for better future protection.

When engaging various parties across many geographical locations about the topic of control of vector mosquitoes it is quite common to hear variations of the refrain, “we should bring back ______ insecticide…it is strong!”  It is interesting to consider how there is such an association between concepts of superlatives equating to being better. Public discourse so often includes idioms such as, “bigger is better” and “might is right” and other alliterative or rhyming phrases which further conflagrate and entrench this perception of strength with success. When, however, one is talking about introducing remedies, this trigger response should be tempered back to two questions, “is this effective against the target and can this be used?”

While there is an array of substances that can kill mosquitoes, caution guides that many of them should not be used. This is why the dossiers submitted in support of registration of a product in countries tend to be quite substantial, as they contain information generated from many tests in well reputed laboratories and institutions to assess the likely effect of the ingredients on environmental, animal and human health should contact occur. If it is found that the product falls within certain limits for the various criteria when applied in the certain fashions with the appropriate Personal Protective Equipment (PPE) and equipment, the product is deemed “safe for use” provided the directions on the label are followed. It is for this reason why it is incorrect to state that one product is “safer” than another product.

Usually, the registration dossier guidelines will also call for recently generated data proving efficacy against the target pest  (usually local) when applied as described. This all makes a lot of sense and protects the public further from purchasing products that won’t work against the pests. The difficulty comes in when insecticide resistance development is introduced to the picture.

The dawn of the insecticide revolution was essentially in the early 1940’s with the development of dichloro-diphenyl-trichloroethane, which for obvious reasons was abbreviated to DDT. Finally, a solution existed for insect pests which could be mass produced in a cost-effective manner. It was with enthusiasm that this was adopted and the insecticide was spread around with a fair degree of what experience shows to be reckless abandon. Due to a combination of natural variation or mutations, as well as inappropriate application practices, sub-lethal dosages to this single type of selection pressure led to traits lending resistant properties to the product passed from one generation to the next, until there was a repeated failure of the product to achieve the expected level of control. Lessons were learned and more responsible practices suggested, some of which were adopted. Aside from restrictions on those allowed to conduct the applications, resulting in better training and application practices, introducing products with new modes of action to challenge the insect differently, and rotating between these different modes of actions. These guidelines have certainly helped slow down, and in some cases even reverse, insecticide resistance development. Unfortunately, owing in part to a very limited pool of products with different and unrelated modes of action registered for use in public health, and still to inadvertent inappropriate application in the field, it is still common to see the targets develop resistance to the new insecticides. This not only limits the life cycle of the product but places people at risk while the race to identify and develop new products is taking place.

It was with this in mind that when the Environmental Sciences department which was at the time still part of Bayer (before becoming Envu) set out to develop a new product specifically for Indoor Residual Spraying (IRS) rather than borrowing a product from the agricultural sector, the development team sat down and decided what properties they wanted in the new product. Obviously if a product can be made which can span a transmission season this would limit the expense and logistics of reapplications. Non-staining and without odour were other criteria which would probably be preferred by the human population. And to get around the insecticide resistance, an active ingredient (ai) was needed with a novel mode of action. Clothianidin was identified as this ai, but the team were also weary of this cycle of introduction and resistance development following in short order. To aid the new active ingredient, it was decided to add another active ingredient with an unrelated mode of action. Aside from a safety net notion, the active ingredient chosen would also be able to have a synergistic effect with the clothianidin. The AI chosen was deltamethrin. This became the product Fludora Fusion.

Aside from providing adequate and ample evidence to achieve Prequalification with the WHO, which answers the question of if the product can be used, many data showed that the relationship between the two active ingredients tended to result in faster mortality than the products with just those as individual active ingredients. Of the many reasons why this is a benefit, arguably the most important of them pertains to preventing the exposed female mosquito from being able to lay viable eggs following a blood meal (usually approximately 48 hours later) thereby interrupting the flow of genes from one generation to the next. This is crucial in fending off insecticide resistance development.

Further to these ordinary type of assessments, the team wanted to learn from the past to plot the future with this new active ingredient (clothianidin) in the vector control sphere. To this end a study was commissioned to examine how the combination product of clothianidin and deltamethrin would compare to the single active ingredient related products over many generations exposed to sub-optimal application doses. This mimicked inappropriate application in the field without rotation of active ingredients. Ultimately, as expected the cohort population exposed to the deltamethrin solo product had developed substantial resistance to the full dose rate, and interestingly, the cohort population exposed to the clothianidin solo product had also developed significant resistance. It was only the cohort exposed to the product composed of both the active ingredients that had not developed resistance.

This was a very seminal finding for it demonstrated that if appropriate active ingredients are combined within the same product so that mosquitoes are exposed to both ai’s simultaneously, a level of self-protection is imparted to the product. This helps bridge a gap in product stewardship, between the guidelines, advice and label instructions and the reality of field applications. Sufficient supervision in the field can be costly considering employment, and very often supervision is not as strong as would be preferable. As a result, bad spraying practices may not receive correction and become entrenched, faulty equipment not identified and maintained. This can result in incorrect application rates on the wall, and likely with an uneven distribution spray pattern. While not a failsafe, this level of self-protection demonstrated does help cover some cracks. It should, however, be noted that investing in stewardship such as using improved tools for training (and monitoring) spray operators, and ensuring nozzles and sprayers are fully functional goes a long way to ensuring the products’ life cycles are longer and the funding is well spent and able to reach as far as it is meant to. This is an even more important consideration in environments where funding options are limited.

And of course, in a sparse funding environment, one does not want to waste resources on an insecticide that doesn’t work. This is where susceptibility testing comes into play. There is no such thing as a “strong” insecticide, the only if it is effective against the target or not. It is therefore important to regularly conduct susceptibility bioassays on mosquitoes of known ages (usually F1’s) gathered from the field. This will adequately inform whether a product will likely work against a specific target insect. These last words are in bold to stress the importance of testing against what you wish to control. One can’t reliably extrapolate between mosquitoes of different genus or even species. This may seem obvious but, sadly, it happens. There are standard operating procedures (SOPs) approved by the WHO for testing the various active ingredients against the mosquitoes. It is important to use the correct assay method for the active ingredient under consideration for reliable results. The neonicotinoid active ingredients, for instance, form large crystals on paper, leading to inconsistent data. The appropriate method is bottle bioassays. The WHO SOP describes how to prepare the bottles for individual active ingredients, but it does not describe how to assess the interaction between two active ingredients, such as clothianidin and deltamethrin. Envu have developed a SOP which takes that extra step to also prepare additional bottles coated with a combination of the two active ingredients, thus helping guard against false negatives.

While it is noted that not all active ingredients will have synergistic effects when mixed with others, the benefits of adopting this mindset opens the opportunities to protect the integrity of active ingredients, the life cycle of the product, and thereby ultimately extending campaigns’ abilities to protect lives.