Combination interventions for controlling malaria transmitted by pyrethroid resistant mosquitoes: A novel bed net with synergist and IRS formulation.

The massive scale-up of vector control measures has led to a major reduction in malaria burden (up to 50%) in many sub-Saharan African countries. This is giving grounds for optimism that malaria will one day cease to be a major public health problem in Africa. The main malaria prevention and vector control tools are long lasting insecticidal nets (LLINs) and indoor residual spraying (IRS). Both rely on pyrethroid insecticides either to provide a repellent barrier between humans and mosquitoes or to kill mosquitoes before they can transmit malaria. With the huge efforts being taken to provide universal coverage of LLINs to those at risk there is, unfortunately, enormous selection pressure on mosquitoes to develop resistance to pyrethroids. Resistance is now occurring in many places and some forms appear to be so strong that vector mosquitoes survive contact and continue to transmit malaria. WHO and manufacturing industry are responding by developing new types of LLIN that, in some cases, incorporate a chemical synergist that knocks out the resistance mechanism so the LLIN continues to protect. Other manufacturers are responding by producing long-lasting non-pyrethroid insecticides that can be sprayed on walls and provide control for almost a year. By combining the two tools it is hoped that malaria shall continue to be controlled to ever decreasing levels, pyrethroid resistant mosquitoes shall continue to be killed, and further selection of pyrethroid resistance shall be prevented. Both products have undergone Phase II trials and both are approved by WHO for human use. There is great urgency to deploy this new generation of tools before pyrethroid resistance grows much worse, sets back control, or undermines our confidence to eliminate malaria, but first the tools need to be properly trialled. LSHTM together with its African partner institutions, KCMC and NIMR, have a long history of conducting mosquito vector and malaria control trials in Tanzania and have recently undertaken a cluster randomised trial in the Great Lakes border region (between Uganda and Rwanda) which showed that pyrethroid resistance is now commonplace and malaria transmission remains high despite several years of attempted control with pyrethroid IRS. We therefore propose to conduct a four-arm CRT in 48 villages in the Lakes region comparing a) current practice of universal coverage of LLINs, b) full coverage of the novel LLIN plus synergist, c) the long lasting IRS, d) the novel LLIN plus the long lasting IRS. The trial will provide epidemiological, entomological, economic and social evidence of impact, as we shall be measuring the reductions in malaria prevalence and malaria transmission rates EIR, and changes in the frequency of resistance, mosquito species ratios and economic cost effectiveness. The proposed trial will demonstrate whether the novel LLIN and long lasting IRS formulation will be more effective for controlling An.gambiae s.s. and reducing malaria prevalence than current practice with the conventional LLIN. There is great interest in conducting this trial. Alternative vector control products are limited and most new insecticides are not suitable for use on LLINs or as IRS. The main international funders of malaria control, the Global Fund and President's Malaria Initiative, are both supporting malaria control in the region. Both recognise the need to introduce new and better tools but neither has the mandate nor expertise to conduct malaria control trials. Both agencies would use the findings of this trial to make operational decisions on future strategy. Because epidemiological effectiveness and cost effectiveness of the two interventions will be evaluated alone and together this will facilitate future allocation of malaria control resources according to situation. It would not tie us down to using these two interventions in the future; rather the trial would act as a stimulus for other manufacturers to produce new types of LLIN and IRS.

The epidemic prone district of Muleba in NW Tanzania has been subject to campaigns of indoor residual spraying IRS for the last 5 years. A high frequency of pyrethoid resistance has evolved in Anopheles gambiae based on metabolic and site insensitivity mechanisms. In 2012 the prevalence of malaria parasitaemia in children under 14 years of age stood at 20%.

A community randomised trial will address the questions: 'Can two innovative vector control tools - a long lasting insecticidal net which incorporates a synergist, and a long lasting indoor residual spray formulation - overcome insecticide resistance and prove more effective at controlling malaria than current practice? Will the combination prove more effective at controlling malaria and delaying further selection of resistance than either product individually? Will the new LLIN provide better individual protection to users than the standard LLIN?

48 clusters shall be subject to restricted randomisation into 4 arms:
a) Standard pyrethroid LLIN
b) Mixture LLIN (pyrethroid and synergist)
c) Standard LLIN plus IRS with long-lasting organophosphate
d) Mixture LLIN plus IRS with long-lasting organophosphate

The objective is to determine whether malaria transmitted by pyrethroid resistant mosquitoes can be controlled using these innovative LLIN and IRS products either alone or in combination and to define future strategy for the region.

Intervention impact shall be determined by: the prevalence of malaria parasitaemia, entomological inoculation rate, prevalence of anaemia, force of infection (serological conversion rate), selection of insecticide resistance genes.

The trial shall generate the evidence to enable funding agencies and national programmes to decide whether the new generation of tools will control malaria in places showing increasing levels of insecticide resistance, and continue the reduction of malaria burden to a point where it is no longer a major public health problem.

1. Beneficiaries within the commercial private sector.

The research will stimulate the private sector and provide local employment. Sumitomo and Syngenta, the manufacturers of Olyset Plus and P-methyl CS, need trial evidence to start producing to scale. Both companies operate 'corporate social responsibility'. They do not expect profit from their investment. Sumitomo has invested in a factory in Arusha, Tanzania, to produce these nets, and this factory employs a significant number of Tanzanians. Syngenta has made significant investment into P-methyl CS - in collaboration with the IVCC and Gates Foundation - but the company need trial data before it can start producing to scale and making a return on its investment.
This trial aims to develop a new strategy for malaria control. Other companies (like BASF and Bayer) would follow suit and develop their own long lasting IRS and LLINs produces once proof of concept is demonstrated.

2. Beneficiaries in the international, government and NGO sector.

The Global Fund and President's Malaria Initiative, the two major donors in malaria control are looking to improve their strategy, and get bigger returns in terms of impact or cases averted per unit cost invested. They, like all government or international agencies, are limited to what is commercially available or approved by WHO Pesticide Evaluation Scheme (WHOPES). If new products were shown to be an improvement, and if we were able to demonstrate where and when to these should be deployed, they would switch product or revise their strategies.
The implementers of malaria control - the National Malaria Control Programmes, NGO implementers like the Malaria Consortium, Mentor, Merlin, MSF - would all benefit and deploy these new tools into their programmes. The NMCP of Tanzania would gain insight on how to maintain control around the Lakes and develop a new strategy for the interior to prevent resistance spreading to other parts of the country.
UN organisations would benefit. WHO and the Global Malaria Partnership would have evidence to support advocacy on resistance management. WHOPES provide advice to member states on product safety and efficacy. WHOPES is not a research organisation but needs our research output to justify their support for new tools like Olyset Plus and P-methyl CS and to take these into general use.
The UN implementing organisations such as UNICEF and UNHCR (Commissioner for Refugees) would have new tools to protect the vulnerable groups that they have specific responsibility for.

3. Potential for impacts

If through this trial we are able to define an improved strategy for malaria control, a strategy that can slow down the selection of resistance, one that can achieve greater personal protection and sustain transmission control in pyrethroid resistant endemic areas, then it would get a high return for the investment being asked of DFID/MRC/WTrust. This is more than a trial of one intervention over another. It seeks a new approach, one that recognises that malaria control is becoming more complex, that it is no longer a case of one size fits all. This heralds a strategy that brings in a new generation of tools to keep resistance at bay and maintain the momentum towards sustained reductions in malaria burden in the most difficult of circumstances.

The problem of resistance identified on NW Tanzanian border extends to neighbouring Uganda, Rwanda, Burundi and Kenya. The trial will provide the evidence to enable neighbouring countries to refine their national malaria control strategy. The research would surely contribute to Tanzania's and neighbours' health and wealth.

The trial will continue the policy to provide capacity development opportunities for Tanzanian scientists. Local Postdoctoral scientists and PhD students under the Wellcome Trust MCDC research training scheme would be recruited into the project.