PBO is not enough: why concentration and controlled release matter

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Bednets containing piperonyl butoxide are an important tool in the fight against malaria – if they provide long-lasting protection

A successful large-scale deployment of piperonyl butoxide long-lasting insecticidal nets (PBO LLINs) to prevent malaria in regions with high resistance is a matter of saving lives. Specifically designed to protect against pyrethroid resistant mosquitoes, the nets continue to be a simple and yet effective tool to do so. PBO LLINs already hold a cornerstone position in the young history of the High Burden High Impact strategy. However, not all PBO nets are the same, as they vary in the amount of PBO contained and in their formulation. Assessing the long-term efficacy of the various products in real-life conditions of use is required if we are to reap the full benefits of this new technology and accelerate progress to end malaria as an endemic disease.

Long-lasting protection is a cost-effective investment

Despite ongoing efforts to tackle the deadly disease, malaria claimed more than 400,000 lives worldwide in 20191. It is widely known that malaria can be prevented – the most effective way of prevention is the use of LLINs which has proven to be associated with a sharp decrease in disease incidence2. The increased access to these nets is a major factor behind the 60% reduction in malaria deaths since 2000 and has saved approximately 6.2 million lives since 20013,4. However, fast-spreading resistance to pyrethroids has required continuous innovation and led to the initial development of PBO nets by Vestergaard. PBO LLINs are being prioritised in areas with insecticide resistance and their large-scale deployment is underway as part of the High Burden High Impact approach endorsed by the World Health Organization and the RBM Partnership to End Malaria6,7.

As the deployment of PBO nets is expanding, it is crucial that their performance in real-life conditions is closely monitored. Manufacturers have taken different approaches to incorporate PBO synergist into net materials leading to a variety of initial PBO concentration in the different nets. There are currently no long-term field studies confirming the insecticidal activity of low amount PBO nets. While nets with a lower concentration of PBO might come at a lower purchase cost, the cost-effectiveness of a net is assessed based on its effectiveness throughout its intended lifetime, and not only its purchase price. With financial resources under strain – even more so with the COVID-19 pandemic impeding malaria programs and threatening to redirect funding away – investing in long-lasting protection is not only the right thing to do from a human, but also from a resource-management perspective.

Why post market surveillance is required for PBO LLINs

In product development, semi-field experimental hut studies test LLINs using 20 standard washes as a proxy for nets used for three-years. However, unlike pyrethroid insecticides, washing is not the main factor for how PBO is lost from the net. Instead, evaporation and daily usage affect PBO concentration much more significantly than washing over time. Therefore, there may be limitations in projecting the lifespan of PBO nets based on such hut studies using the 20 standard wash proxy. The ability to release and retain PBO in the product despite the various factors of loss is key in ensuring effective protection throughout the lifetime of the net – this was the ambition when PermaNet® 3.0 was developed.

Following early deployments for PermaNet 3.0, Vestergaard embarked on post-market surveillance to monitor the longevity of insecticidal activity. Long term evaluations have also since been conducted according to WHO guidelines in Ghana (Dadzie et al. 20198), India (Raghavendra et al.20189), and Kenya (Gimnig et al. 201910). PermaNet® 3.0 starts with a PBO concentration of 25g/kg ± 25% and retains and continues to release PBO to the end of the expected product life, with a concentration of PBO in the range of 5-10 g/kg at the end of three years (Figure 1).

Figure 1. Deltamethrin and PBO concentrations in PermaNet® 3.0 roof at 12, 24, and 36 months in long term studies conducted in Ghana, India, and Kenya.

 

PBO controlled release is key – The Vestergaard Blue Roof Technology

PermaNet® 3.0 is the result of a long R&D process. Vestergaard designed PermaNet® 3.0 with a conscious intention to formulate an LLIN that has sustained bioavailability of both PBO and insecticide throughout the product lifetime and also has effective PBO concentration even after 3 years of use: the net has a higher concentration of PBO to begin with and relies on a unique blue roof technology to improve migration and retention control of PBO.

This patented slow-release formulation, which uses the specific characteristics of a blue pigment, ensures that the migration of PBO and deltamethrin within the polymer is fast enough for the replenishment of insecticide that is lost from the surface through use, but also slow enough to ensure the presence of PBO for the expected lifetime of the LLIN.

Malaria can and must be stopped

Despite being treatable and preventable, malaria poses a serious mortality and financial burden (at least $12 billion per year). James Snowden of GiveWell has rightly indicated, “treating malaria is very expensive, preventing malaria is very cheap.” Vestergaard is committed to doing its part to eradicate this deadly disease by developing, manufacturing, and distributing innovative and high-quality LLINs that offer effective protection from malaria for the intended product lifetime.

 

Caroline Desrousseaux
Director of Sales Public Health

References

  1. World Health Organization. Fact sheets: Malaria. Available from: https://www.who.int/news-room/fact-sheets/detail/malaria [Accessed 08 February 2021].
  2. Centers for Disease Control and Prevention. Insecticide-treated bed nets. Available from: https://www.cdc.gov/malaria/malaria_worldwide/reduction/itn.html [Accessed 31 January 2021].
  3. WHO Global Malaria Programme. World Malaria Report 2015. World Health Organization, Geneva. Available from: https://www.who.int/malaria/publications/world-malaria-report-2015/report/en/.
  4. World Health Organization. New report signals country progress in path to malaria elimination. Available from: https://www.who.int/news/item/09-12-2015-new-report-signals-country-progress-in-the-path-to-malaria-elimination [Accessed 07 February 2021].
  5. Staedke SG, Gonahasa S, Dorsey G, Kamya MR, Maiteki-Sebuguzi C, Lynd A, et al. Effects of long-lasting insecticidal nets with and without piperonyl butoxide on malaria indicators in Uganda (LLINEUP): a pragmatic, cluster-randomised trial embedded in a national LLIN distribution campaign. The Lancet. 2020;395(10232): P1292-1303. Available from: doi: 1016/S0140-6736(20)30214-2.
  6. WHO Global Malaria Programme. World Malaria Report 2019: Briefing Kit. World Health Organization, Geneva. Available from https://www.who.int/malaria/publications/world-malaria-report-2019/World-Malaria-Report-2019-briefing-kit-eng.pdf
  7. RBM Partnership to End Malaria. High Burden High Impact. [Presentation] 11 December 2020. Available from: https://www.who.int/docs/default-source/malaria/mpac-documentation/mpac-december2020-hbhi3-update-session2-presentation.pdf?sfvrsn=76427f02_7
  8. Dadzie et al. 2019, report submitted to WHO Prequalification
  9. Raghavendra et a. 2018, report submitted to WHO Prequalification
  10. Gimnig et al. 2019, report submitted to WHO Prequalification