New types of insecticide-treated nets

15 January 2020 | Q&A

Questions and answers on new types of insecticide-treated nets

Until a few years ago, all WHO-recommended ITNs contained only pyrethroid insecticide as the active ingredient (AI). These nets were assessed for physical and chemical durability over an anticipated lifespan of 3 years and 20 washes based on WHO standard washing procedures; they are referred to as pyrethroid-only long-lasting insecticidal nets (LLINs). Pyrethroid-only LLINs are the current standard of care across most malaria-endemic countries. All other nets are considered ‘new types’ (see Table 1 under Q&A References).

In 2009, the first new type of ITN – PermaNet® 3.0 – received an interim recommendation from the former WHO Pesticide Evaluation Scheme (WHOPES). The net contains a pyrethroid insecticide and the synergist piperonyl butoxide (PBO). The addition of PBO is intended to enhance the killing effect of pyrethroids, particularly in mosquito populations that exhibit metabolic resistance.

The public health value of a pyrethroid-PBO net was first demonstrated by Olyset® Plus leading to a conditional policy recommendation that encompasses all WHO prequalified pyrethroid-PBO ITNs. Further studies on the public health value of this and other pyrethroid-PBO nets are underway, with the aim of generating additional evidence to support a full WHO policy recommendation (See question “Are new types of ITNs more expensive than pyrethroid-only LLINs?”). To date, five pyrethroid-PBO products have been prequalified by WHO (Olyset® Plus, PermaNet® 3.0, Veeralin®, Tsara® Boost, and Tsara® Plus).

In recent years, other types of new nets treated with 2 AIs have been developed. Interceptor® G2 is a dual AI net treated with the pyrethroid alpha-cypermethrin and the pyrrole insecticide chlorfenapyr; it was prequalified by WHO in January 2018. In March 2019, Royal Guard®, a dual AI net containing the pyrethroid alpha-cypermethrin and the insect growth regulator pyriproxyfen, was added to the list of WHO-prequalified vector control products based on an assessment of a complete product dossier. The listing of both Interceptor® G2 and Royal Guard® in the absence of a specific WHO policy recommendation was an exception made during the transition from WHOPES to the new WHO evaluation process for vector control interventions.

With the arrival of new types of nets, the term ITN was re-introduced by the Global Malaria Programme as the umbrella term for all nets treated with an insecticide, insect-growth regulator and/or synergist. The term LLIN is only being used for ITN classes for which physical and chemical durability have been comprehensively demonstrated against the WHO thresholds of 20 washes and 3 years of use in the field. In practice, this means that only nets treated with a pyrethroid insecticide alone are presently referred to as LLINs in the WHO Guidelines for malaria vector control and companion documents.

Pyrethroid-PBO ITNs differ from pyrethoid-only LLINs in that they contain the synergist piperonyl butoxide (PBO). PBO, by inhibiting certain metabolic enzymes (e.g. mixed-function oxidases, or MFOs), is intended to enhance the killing of the pyrethroid-resistant mosquito population.

Pyrethroid-PBO nets kill susceptible mosquitoes in the same way as pyrethroid-only LLINs, while also overcoming individual pyrethroid resistance. This enhanced action can be expected to diminish over time due to ongoing selection pressure on the mosquito population. In the meantime, these types of nets are a useful intervention to deploy in areas of pyrethroid resistance.

The dual active ingredient (AI) nets prequalified by WHO, namely Interceptor® G2 and Royal Guard®, contain pyrethroids and additional chemicals that kill or sterilize mosquitoes in ways that are different from pyrethroids. Both nets are intended to perform better than pyrethroid-only LLINs by killing mosquitoes that carry pyrethroid resistance genes, provided these mosquitoes are susceptible to pyrrole insecticides or to pyriproxyfen. Field studies demonstrating improved impact in reducing or preventing Plasmodium infection and/or malaria disease in humans in areas of pyrethroid resistance are presently not available for these 2 products, nor are there conclusive data on the susceptibility of the local mosquito populations in malaria endemic areas to chlorfenapyr or pyriproxyfen.

According to available entomological evidence, new types of nets may be more effective at killing or controlling pyrethroid-resistant mosquitoes. Currently, WHO evaluation criteria guide the assessments of the entomological efficacy of ITNs against relevant mosquito strains.

The WHO prequalification team for vector control sets the baseline for quality, safety, and efficacy of all products that are prequalified. WHO considers that all types of prequalified new nets will perform at least as well as pyrethroid-only nets prior to field use and degradation due to washing and other wear and tear. WHO is, however, presently not in a position to provide guidance on these products’ potentially superior entomological performance or their chemical and physical durability in the field.

With respect to improved malaria control, this has only been demonstrated, to date, for one pyrethroid-PBO net – Olyset® Plus – in one cluster randomized trial conducted in Tanzania. A second study to demonstrate impact in controlling malaria, deploying two pyrethroid-PBO products – Olyset® Plus and PermaNet® 3.0 – is currently underway in Uganda; results will likely be made available for WHO review in 2020. For Interceptor® G2 and Royal Guard®, trials designed to measure epidemiological impact began in 2019, but data to inform potential WHO policy recommendations will not be available until 2022. A trial with Olyset Duo®, a product similar to Royal Guard®, recently ended in Burkina Faso and showed modestly improved malaria control compared to pyrethroid-only nets.

In summary, current evidence indicates that pyrethroid-PBO nets are likely to provide better malaria control than pyrethroid-only LLINs in areas of pyrethroid resistance. The extent to which this effect can be achieved by all pyrethroid-PBO nets is unclear, as no comparative performance data for the different products are available. For Interceptor® G2 and Royal Guard®, it is presently unknown whether their deployment will translate into better impact against malaria than that achieved by pyrethroid-only LLINs, or how their impact compares to pyrethroid-PBO ITNs. However, these dual AI nets do provide a new mode of action, which is desirable for pyrethroid resistance management (see question "When should a country consider purchasing a new type of ITN?").

No. The products may differ in terms of their chemical and physical specifications (see Table 1 under Q&A References for overview), regeneration times, and wash resistance. Also, there are key differences in product design with respect to the location of the synergist piperonyl butoxide (PBO) on the net (i.e. all net panels or just the top panel); the PBO loading dose (concentration); and the specific pyrethroid (e.g., alphacypermethrin, deltamethrin, and its concentration). It is unknown whether or how these differences translate into potentially different entomological efficacy over time, or epidemiological impact. A study design to test similar performance of products side-by-side – known as a ‘non-inferiority’ study – is being conducted to investigate whether this method may provide a pragmatic approach to investigate these potential differences, and to provide assurance that a policy recommendation based on epidemiological data for one product is applicable to similar products that are considered to be part of the same intervention class. Non-inferiority data on currently WHO prequalified pyrethroid-PBO nets will be available by the end of 2020.

All new types of ITNs currently cost more than a pyrethroid-only LLIN. Specific costs will depend on the size of the net, quantities purchased, lead times and other variables. 

The WHO prequalification process assesses vector control products for their safety, quality and entomological efficacy against published evaluation standards. Currently prequalified new types of ITNs have demonstrated that they are safe and effective for their intended use. Questions on long-term durability remain, particularly with regards to the wash-resistance of the synergist piperonyl butoxide (PBO) and of chlorfenapyr and pyriproxyfen. The WHO prequalification team for vector control have initiated a review of these products to address these questions.

WHO policy recommendations, in turn, are developed based on the WHO guideline development process, which requires evidence on the impact of an intervention in reducing the targeted disease(s). Given that ITNs with active ingredients other than pyrethroids have been designed to provide improved disease control in areas where malaria vectors have become insecticide resistant, the development of a policy recommendation for these new products requires demonstration of their public health value by means of at least two trials with epidemiological endpoints. In 2017, WHO granted – on an exceptional basis – a conditional policy recommendation for pyrethroid-PBO ITNs. The recommendation was developed based on findings from one trial in Tanzania and will remain conditional until data from at least one more trial conducted over 2 years have confirmed the enhanced impact on malaria that was demonstrated in the first study.

Interceptor® G2 and Royal Guard® were added, on an exceptional basis, to the list of WHO-prequalified vector control products during the WHO transition from the WHO Pesticide Evaluation Scheme to the new WHO evaluation process for vector control interventions. While both nets meet WHO standards for safety, there are no available epidemiological data to indicate whether Interceptor® G2 and Royal Guard® would control malaria better than a pyrethroid-only LLIN. For lack of a better alternative, both products are considered as covered by the WHO policy recommendation for pyrethroid-only nets. As soon as data on the epidemiological impact of these two products have been generated and reviewed by WHO’s Vector Control Advisory Group (VCAG), WHO will formulate specific policy recommendations.

Meanwhile, WHO recognizes that some Member States may be interested in deploying new types of ITNs not covered by specific policy recommendations. Guidance for such countries is included in the question "When should a country consider purchasing a new type of ITN?" 

WHO released conditional recommendations on deployment of pyrethroid-PBO nets in 2017, including guidance on the characteristics of settings most likely to benefit from deployment of pyrethroid-PBO nets. Over the last 2 years, WHO has worked with partners in translating these recommendations into the practical deployment of pyrethroid-PBO nets. 

This experience has shown that data on specific contextual characteristics – particularly data on involvement of monooxygenases – are often not available at county or province level and that countries are forced to extrapolate from existing data points. To support pragmatic decision-making, WHO has developed a simplified overview of areas where deployment of pyrethroid-PBO nets may be most beneficial, based on current available evidence (See figure 10.2 of the World malaria report 2019). Given the resource constraints of national malaria programmes and supply constraints for pyrethroid-PBO nets, further prioritization will be required to target any pyrethroid-PBO nets within the country. WHO recommends that within eligible areas, those with the highest malaria burden are prioritized.

For other types of new ITNs, no deployment guidance has been developed as this would normally accompany a WHO policy recommendation. WHO recognizes that some Member States may be interested in deploying new types of ITNs not covered by specific policy recommendations, for example to start generating local cost-effectiveness evidence to inform national prioritization processes or as part of an insecticide resistance management strategy.

In the absence of such a WHO policy recommendation and associated deployment guidance, WHO Member States that wish to deploy Interceptor® G2 or Royal Guard® are advised in the meantime to ensure any deployment supports building the local evidence base, with the ultimate aim of generating cost-effectiveness estimates to inform national prioritization processes. Consideration should be given to the ability of the health system and/or national research partners to generate data on the effectiveness of the chosen products in the local context. Areas targeted should be those where pyrethroid resistance in the main malaria vector(s) has been confirmed using WHO Test procedures for insecticide resistance monitoring. In principle, the targeting of high(er) endemicity areas should be considered, with a view to achieving maximum impact. Consideration should also be given to the need to sustain access to these or similar tools if additional epidemiological impact is demonstrated in the ongoing trials.

WHO recommends that WHO Member States considering deploying Interceptor® G2 or Royal Guard® do so only as part of a wider decision-making exercise on the most effective use of available malaria control funding. WHO further advises that any such deployment should not come at the expense of reducing existing ITN coverage.

 

There is no specific resistance threshold at which pyrethroid-only LLINs are considered to fail or at which these nets should be withdrawn from targeted areas. A WHO-coordinated multi-country study comparing net users with non-users living in areas where the main malaria vectors had developed pyrethroid resistance has shown that, irrespective of pyrethroid resistance, users of nets were significantly better protected from malaria than non-users. WHO recommends that, irrespective of pyrethroid resistance, populations in malaria-endemic areas should continue to use pyrethroid-only LLINs to reduce their risk of infection. Nevertheless, the multi-country study indicated that pyrethroid-only LLINs provide only partial protection against malaria. To achieve the targets set out in the Global technical strategy for malaria 2016–2030, WHO recognizes that the integration of new interventions, including new types of nets, will be essential. Such integration should be informed by evidence of the public health value of the new interventions.

Guidance on the selection of malaria vector control interventions based on insecticide resistance data is provided in section 3.1 of the Guidelines for malaria vector control . For pyrethroid-PBO ITNs, this guidance is consistent with that provided earlier in this Q&A document and in the corresponding policy recommendation. Interceptor® G2 and Royal Guard® are currently not included in this guidance due to the absence of a specific WHO policy recommendation; guidance for countries considering deploying these products in the meantime is provided under the question "When should a country consider purchasing a new type of ITN?"

In the event that public health value cannot be demonstrated by Interceptor® G2 or Royal Guard®, no WHO policy recommendation will be issued, and therefore, the current WHO prequalification listing of these two products would be reviewed. WHO Member States that chose to deploy these new types of ITNs would then be able to phase them out during the next mass distribution campaign and through their routine systems.  With new types of ITNs being at least as effective as pyrethroid-only LLINs, no harm will have been done.

It is recommended that communication on new types of ITNs be informed by currently available evidence on their likely impact, rather than by assumptions. Managing expectations at this time – where evidence of public health value of new types of ITNs is scarce – is crucial. A framework to inform the development of a communications strategy, as developed by the Alliance for Malaria Prevention, is provided at the following link.

The project aims to increase the evidence base for new nets and reduce the cost to an affordable level to facilitate scale-up should these nets receive a WHO policy recommendation. The project includes the following components:

  • Randomized controlled trials to produce the robust epidemiological evidence needed for WHO to consider making a policy recommendation around these nets.
  • Support procurement of volumes of the new nets that allow a limited number of pilots to take place and can be used as leverage to negotiate lower prices for these new nets.
  • Support effectiveness pilots in four key eco-epidemiological settings within sub-Saharan Africa to help develop a better understanding of the relative cost-effectiveness of these tools compared to standard nets (and in some cases to PBO nets). These will be undertaken in 4 sites: Burkina Faso, Mozambique, Nigeria and Rwanda. These pilots will be conducted within an intense evaluative framework.
  • Support other ‘operational’ pilots in limited areas where the focus is on allowing early access to these new tools in areas that may particularly benefit from any additional impact, collect operational experience to inform lessons learned on conducting national campaigns with multiple types of nets, and support the procurement of the volumes required to bring the price of the product down to an affordable level by the end of the project. 

The ‘New Nets Project’ supports work on Interceptor® G2 and Royal Guard®, not on pyrethroid-PBO nets.

This Q&A is intended as a “living” document that will be updated periodically in the coming months and years, and that will inform the refinement of WHO Guidelines on malaria vector control. If any of the information presented here is unclear or if specific questions of relevance in your context have not been included, please let us know. Send us your feedback and questions at vcguidelines@who.int.

Table 1: Overview of new types of insecticide-treated nets (ITNs) prequalified by WHO (December 2019)

Product name Manufacturer Product type WHO policy recommendation
Olyset® Plus Sumitomo Chemical Co. Ltd Permethrin + PBO incorporated into polyethylene, all panels Conditional recommendation
PermaNet® 3.0 Vestergaard Frandsen Holding SA Combination of deltamethrin coated on polyester with strengthened border (side panels), and deltamethrin + PBO incorporated into polyethylene (roof) Conditional recommendation
Tsara® Boost NRS Moon Netting Deltamethrin + PBO incorporated polyethylene, all panels Conditional recommendation 
Tsara® Plus NRS Moon Netting Combination of deltamethrin coated on polyester (side panels), and deltamethrin + PBO incorporated into polyethylene (roof) Conditional recommendation 
Veeralin® V.K.A. Polymers Pvt. Ltd Alpha-cypermethrin + PBO
incorporated into polyethylene, all panels
 
Conditional recommendation
Interceptor® G2 BASF SE Alpha-cypermethrin and chlorfenapyr coated on polyester No specific recommendation. Data from epidemiological trials awaited
Royal Guard® Disease Control Technologies, LLC Alpha-cypermethrin and pyriproxyfen incorporated into polyethylene, all panels No specific recommendation. Data from epidemiological trials awaited