Effectiveness of bi-treated long lasting insecticidal nets and deployment strategy for control of malaria transmitted by pyrethroid resistant vectors

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Infectious and Tropical Diseases

Abstract

The massive scale up of long-lasting insecticidal nets (LN) from 2% in 2000 to 55% in 2015 has made the major contribution to the decline of malaria in Africa. LN effectiveness is entirely dependent on the pyrethroids, and with high LN coverage resistance has increased in distribution and strength. Leading LN brands are giving less protection than before and in North West Tanzania are failing to control malaria despite high coverage and usage rates.

This problem was anticipated, and WHO has long encouraged industry to develop new types of 'combination' LN treated with new chemical compounds to overcome resistance and restore effectiveness. The strongest resistance is mediated by cytochrome P450s, enzymes that metabolise the pyrethroid to inactive compounds. One solution is the synergist PBO which inhibits the P450 system in insects. LN products combining pyrethroid and PBO are available but due to limited evidence of additional impact against malaria these nets have not been widely deployed. This situation is changing as we showed in a randomised controlled trial in Tanzania that LN with PBO (Olyset Plus) was able to control malaria transmission where standard LN failed due to resistance. Presently there are two types of PBO-LN available that differ in distribution of PBO on the net and it is not clear how they would compare making it difficult for malaria control agencies to make an informed choice. 'Mosaic LN' restrict the PBO to the roof panel where mosquitoes may first contact the net due to convection of CO2 from the sleeper inside. Others like Olyset Plus have all panels treated with PBO.

Bi-treated nets incorporating new types of insecticide have also become available. A leading product mixes pyrethroid with an insect growth regulator pyriproxifen (PPF) that sterilises mosquitoes that contact the net. Another type mixes pyrethroid with the pyrrole chlorfenapyr (CFP), whose unique mode of action is unlikely to confer cross resistance with other public health insecticides. LSHTM has helped develop both types of mixture LN and has evaluated them entomologically in laboratory and experimental huts. With its in depth knowledge LSHTM is in a unique position to continue evaluation at community level for malaria control. Earlier experience provides insight on how to measure the characteristics of these unusual compounds on nets when used by communities. It is important to monitor effectiveness over 3 years lifespan because effectiveness is likely to change over time.

It is important to decide how, where and when the main categories of bi-treated LN should be deployed to maximize effectiveness and resistance management potential. Insecticide combinations, as with drug combinations in the example of antimalarial therapy, are considered the best way to reduce selection pressure for resistance but the LN may differ in this capability.

To address these issues we propose a four-arm randomized non-inferiority trial in 56 villages comparing the two PBO-LN types 1/ reference PBO-LN (Olyset Plus) and 2/ mosaic PBO-LN (PermaNet 3.0), and the two mixture-LN 3/ PPF-LN (Olyset Duo) and 4/ CFP-LN (Interceptor G2).

The trial will demonstrate whether the mixture PPF-LN and CFP-LN provide similar or greater protection against malaria transmission than the reference PBO-LN. It will show whether mosaic PBO-LN provides equivalent protection to the reference PBO-LN. It will show whether bi-treated LN will reduce or prevent the selection of resistance. Health economic analysis will define which interventions are cost effective. The trial findings will guide national malaria control and international agencies (Global Fund, President's Malaria Initiative, WHO) on malaria control strategy, effectiveness of different types of bi-treated LN, cost effectiveness and deployment options to maximize impact against resistance.

Technical Summary

We propose a cluster randomised trial which compares four vector control interventions to prevent malaria in areas where vector mosquitoes are resistant to pyrethroids and the standard long-lasting insecticide treated nets (LN) are unable to control malaria adequately. These interventions are based on novel bi-treated LNs incorporating mixtures of insecticides or insecticide synergists to improve efficacy.
The proposed trial will be a four-arm, single blinded, non-inferiority cluster-randomized trial with the following arms:
1. Control arm: Olyset Plus LN (Sumitomo Chemicals) is a LN combining a synergist PBO and pyrethroid permethrin incorporated in the polyethylene fibres on all 5 panels.
2. Intervention arm 1: Permanet 3.0 (Vestergaard) is a mosaic LN consisting of polyester on the 4 side panels coated with pyrethroid deltamethrin. PBO is restricted to the top panel made of polyethylene fibres and incorporating also deltamethrin.
3. Intervention arm 2: Olyset Duo is a bi-treated polyethylene LN incorporating permethrin and an insect growth regulator pyriproxifen (PPF) that sterilises mosquitoes that contact the net.
4. Intervention arm 3: Interceptor G2 is a mixture LN made of polyester and coated with a wash-resistant formulation of chlorfenapyr (CFP) and alpha-cypermethrin pyrethroid.
The proposal will address the following questions: 1/ Do new generation of LN that include a pyrethroid and a novel insecticide (PPF or CFP) provide similar or better protection to the PBO-synergist LN against malaria transmitted by pyrethroid resistant vectors? 2/ Does mosaic PBO-LN and PBO-LN on all panels provide the same protection? 3/ Which LN (CFP, PBO or PPF) is more effective at preventing malaria and managing resistance?
Evaluation of the effectiveness of each LN will be based 1/ on malaria prevalence in children under 15 years, 2/ malaria incidence and transmission and 3/ selection of insecticide resistance. Cost effectiveness of each LN will also be compared.

Planned Impact

This project will have impacts on malaria control policy and practice, both national and international, benefiting public sector, private sector manufacturers, and community recipients.

The strategy of the Tanzania Malaria Control Program (NMCP) is flexible and evidence-based and incorporates new tools of proven impact. With the reduction in malaria burden achieved in recent years but the spread of resistance, the NMCP accepts a more tailored approach than blanket distribution of standard LN. Together we demonstrated that standard LN were no longer effective in the northwest and that PBO-LN would provide improved protection. During the preparation of this proposal, we selected with NMCP and other stakeholders the most promising types of bi-treated LN to be evaluated. Each of these bi-treated LN could make a difference in the control of resistant vectors but they need to be tested comparatively in large scale trial. This should widen the arsenal of LN products and help NMCPs to take programmatic decisions on how to deploy each LN to best effect. The trial findings have regional implications. Any data or strategy emerging will be relevant to NMCPs of neighbouring Kenya, Uganda, Burundi, DRC and Malawi, all of which have a growing resistance problem.

The trial will have beneficial impact on the private sector. The aim is not to make any bi-treated LN redundant but to establish how well each would control transmission caused by a given species (funestus, gambiae, or arabiensis) and individual capacity to prevent resistance selection. Each may differ with respect to species, selection of resistance, and environment. Each may have a useful niche. It is more important to keep the innovatory manufacturers in business than create a winner-takes-all situation. The present reality is market domination from generic LN. This has enabled universal coverage. But the future need is for LN that control resistant mosquitoes. Capacity to innovate requires depth in chemistry, in formulation technology, in polymer technology. Generic companies lack that capacity. The stimulus to innovate from IVCC and LSHTM has led to several promising products but this is not enough. To take the most promising to market requires demonstration in formal RCT of how well each product can control malaria. A more diverse and equitable market will follow, keep the innovators innovating, and help us to keep us ahead of resistance. The first step in that process is demonstration of impact.

The innovatory companies are willing to provide their LN at cost-of-goods. But a free donation is a big ask when their market share is so small. In the final analysis, this trial will shift the market to addressing the new public health need, broaden the range of players and products.

The project has representatives of PMI/CDC, WHO and Global Fund on the TSC who will keep their agencies abreast of the findings. If shown to be an improvement the agencies would switch product or revise strategy.

WHO calls for the development and evaluation of non-pyrethroid LLINs including PBO-LN. The WHO Evidence Review Group states that PBO-LN appear to have an increased efficacy in certain settings, the evidence is too limited to justify a complete switch, neither is there evidence to assume greater utility in a resistance management strategy. These new types of bi-treated LN have more complex mode of action and their full effectiveness can only be assessed by large scale CRT with epidemiological endpoints. The proposed trial would therefore help WHO to meet its recommendation.

This research will first and foremost benefit the community. Standard LN are no longer providing adequate protection in certain areas of Tanzania. The same phenomenon is being observed in neighbouring countries. It is time to switch to more effective LN and the present study will demonstrate which types of bi-treated LN are appropriate.
 
Description A formal working group and dialogue - presented results of a multi-centre study on determination of insecticide resistance in mosquitoes - WHO consultation WHO/HQ, Geneva Virtual meetings on 15-18 December 2020 and 21 January 2021
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Presented research from our research to a WHO consultation which had led to change in policy for determination and monitoring of resistance in mosquitoes - Report of a WHO consultation WHO/HQ
 
Description Evidence for efficacy of Dual AI LLINs during the 3rd years RCT post intervention and entomological surrogates established to aid the policy and PQ process
Amount $2,810,604 (USD)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 07/2018 
End 12/2022
 
Title Constrution of experimental hut (NIMR Mwanza), animal house (NIMR Mwanza) and testing and insectory facilities (NIMR Mwanza and KCMUCO Moshi) 
Description We have been constructing and improving existing facilities in both partners Institutions (National Institute of Medical Research, Mwanza and Kilimanjaro Christian Medical College, Moshi). This include 1/Construction of 6 experimental hut and a field laboratory facilities in Magu, (NIMR Mwanza, 2/ Construction of an animal house in NIMR Mwanza regional office (NIMR Mwanza) 3/ construction of a new testing and insectary facilities in Mwanza (NIMR Mwanza) and Harusini (KCMUCO, Moshi). 
Type Of Material Improvements to research infrastructure 
Year Produced 2019 
Provided To Others? No  
Impact Attract new funding's and collaboration for partner Institution. Improvement of animal welfare. 
 
Title Set up the qRT-PCR multiplexed TaqMan Assays to measure Gene expression 
Description As part of the present project, this activity aim to monitor the genetic mechanisms of insecticide resistance in Misungwi District, following the distribution of LLINs. We want to measure levels of gene expression of some P450 involved in pyrethroid resistance. Data collected during the monitoring years will be compared to the baseline, between study years and between intervention arms to investigate the impact of the different LLINs on selection of resistance mechanisms. 
Type Of Material Technology assay or reagent 
Year Produced 2020 
Provided To Others? No  
Impact Reinforcement of the institutional capacities. 
 
Description Ifakara Health Institute: Assessment of the efficacy of next generation of LLIN on Ifakara ambient Chamber 
Organisation Ifakara Health Institute
Country Tanzania, United Republic of 
Sector Charity/Non Profit 
PI Contribution The project is providing mosquito nets sampled in the field at 12, 24 and 36 months to Ifakara.
Collaborator Contribution Ifakara is conducting test using their newly developped Ambient chamber to assess the efficacy of the nets.
Impact No output/ outcomes yet as it just started.
Start Year 2020
 
Description University of Ottawa: Access to Research Networks Program 2016 - 2020, 
Organisation University of Ottawa
Country Canada 
Sector Academic/University 
PI Contribution Our research team provides leadership on management and technical support of the different activities, implementation of the different research activities (epidemiology, entomology, insecticide resistance) and data management. We provide access to the facilities and staff as well as logistics support.
Collaborator Contribution UOttawa provided a unique expertise in geospatial surveillance and analysis and will support the study design and epidemiological analysis. There is a satistician and an epidemiologist supporting the project. A PhD student from U-Ottawa will work on the geospatial analysis of the data collected as part of the RCT.
Impact The detailed analysi plan was developped as part of the partnership. No other outcomes /outputs are available yet as the data collection is ongoing.
Start Year 2018
 
Description 11th European Congress of Tropical Medicine and International Health "Evaluation of next generation of insecticide treated nets: The Tanzanian experiences presentation" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The presentation was part of a symposium on the benefits and issues of getting next generation nets into the market. Dr Jackline Mosha shared the experiences of our research team to conduct large randomised controlled trial on new vector control product and strategies in Tanzania. Representative of academia, policy makers, industries and funding agencies were presents.
Year(s) Of Engagement Activity 2019
URL https://academic.oup.com/trstmh/issue/113/Supplement_1
 
Description Community engagement and sensitiziation 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Sensitisation and engagement of the community in the study area to explain study, net distributed, informed about the different research activities. The aim is to improve adherence to net use and also acceptance of the study team.
Year(s) Of Engagement Activity 2018,2019,2020
 
Description Meeting with the vector control advisory group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The protocol was presented to VCAG for review. It was attended by a panel of 15 members.
Year(s) Of Engagement Activity 2018
 
Description Reporting of project findings from the 3rd year of the trial to WHO to advise on malaria control policy on PBO-pyrethroid nets up to 3 years of use 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact In November 2018, Protopopoff and Rowland presented the results of the 3rd year of the trial to WHO Vector Control Advisory Group to further advise of PBO-LLIN policy globally. The report of the recommendation are found in the report of VCAG. The 3rd year results are not yet the public domain. WHO were satisified with the progress of the trial and saw no reason to change policy and advocy of PBO LLIN in areas of pyrethroid resistance. They urged NP and MR to continue the research on the durability of PBO LLIN over the entire 3 years of the trial.
Year(s) Of Engagement Activity 2018
URL https://www.who.int/vector-control/vcag/nov2018/en/.
 
Description Results of the multi-centre study on determination of insecticide discriminating concentrations for monitoring of resistance in mosquitoes - Report of a WHO consultation WHO/HQ, Geneva Virtual meetings on 15-18 December 2020 and 21 January 2021 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact This was virtual meeting to arrive at a consensus on the development of techniques to measure resistance to novel insecticides used in the Dual AI LLIN products that we are testing in the MRC/WT/DFID GHT. Our CRT is evaluating the effectiveness of the Active Ingredients (PBO synergist, pyrethroid, pyriproxyfen, chlorfenapyr) on the nets against malaria. In the event that resistance to these products will evolve in mosquitoes, we (and national malaria control programmes) will need to detect resistant mosquitoes in order to take remedial action to reduce the severity of the problem they will create for the effectiveness of the nets. The gathering of academics, international control agencies, national malaria control programmes met at WHO to assess the evidence and arrive at agreement of on an accurate diagnostic concentration which would accurately detect resistant variants and the strength of the resistance.
Year(s) Of Engagement Activity 2020
 
Description Update on RCT progress to the WHO Vector Control Advisory Group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Update on the activities undertaken as part of the RCT. A report was produced by WHO-VCAG and available in the WHO website.
Year(s) Of Engagement Activity 2020
URL https://www.who.int/publications/i/item/9789240009707
 
Description Vector Control Technical Working Group, two days meeting every quarter either face to face or virtual 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact The Tanzanian National Malaria Control Program planned a Vector control Working group with different stakeholders (Research Institutions, Public Institutions, Funders etc..) involved in malaria vector control in Tanzania to get an to updates and discuss various vector control activities planned.
Our research team presented research activities.
Year(s) Of Engagement Activity 2019,2020,2021
 
Description WHO Roll Back Malaria Vector Control Working Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact A protocol was presented to WHO/RBM Vector Control Working Group on how to evaluate the bio-efficacy and durability of partner AI in next generation LLIN (like IG2 chlorfenapyr LLIN, pyriproxifen LLIN and PBO LLIN in plenary session, and discussion session. The aim was to share expertise with other Institutions like WHO, Global Fund and PMI and to aid the WHO prequalification process of new vector control product. We should emphasise this knowledge was largely obtained during phase 1 and 2 product development, and experience in practice during cluster randomised trial is still limited, and will be modified further with further experience.

The research team also attended a panel discussion about "Improving the physical durability of Long Lasting Insecticidal Nets in the field -A Coordinated Initiative". The main focus of this coordinated action is to review evidence, identify gaps, support the development stronger and more durable (fabric) LLIN and change some of the WHO specification to includes norms for stronger nets to be integrated into large-scale procurement by major institutional buyers.
Year(s) Of Engagement Activity 2020
URL https://endmalaria.org/events/5th-meeting-llin-priorities-work-stream
 
Description WHO Working Group on malaria control in humanitarian emergencies, Egypt, Sharm El-Sheik, 13-17 March 2019 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Working group meeting with representatives of UN agencies, NGOs and National and International malaria control agencies met to discuss (among other things) the WHO policy recommendation for PBO-pyrethroid long-lasting insecticide treated nets in areas of pyrethroid resistance and extend their use in different phases of humanitarian emergies during acute and chronic phases. New tools where PBO-pyrethroid intervention would be useful is the acute phase of humanitarian emergencies where blankets, shelter and food are routinely distributed. Permethrin treated blankets are sometimes distributed in acute emergencies. A new trial of PBO-pyrethroid blankets emerging from the PBO-pyrethoid LLIN recommendation was described for a refugee camp and Tanzania, discussed and considered to have potential.
Year(s) Of Engagement Activity 2019