Ecology of insecticide resistant vectors: consequences for the effectiveness of malaria control strategies

Insecticides impregnated into bednets is the most widespread strategy to control and eliminate malaria worldwide. Insecticides work by killing mosquitoes that can transmit malaria and have been extremely successful in reducing malaria cases throughout sub-Saharan Africa. However, mosquitos are increasingly resistant to insecticides, threatening to reduce their effectiveness. Despite the gravity of this impending threat, the extent of insecticide resistance (IR) and its consequences for public health remain poorly understood. A fundamental assumption is that resistant mosquitoes are identical to susceptible ones in all aspects other than their response to insecticides. However, there are several reasons why this may not be the case. For example, malaria transmission is known to be more sensitive to variation in the long-term survival and behaviour of mosquitoes than to their overall abundance. These features, in addition to other mosquito life-history traits such as their reproductive success, may be altered in resistant mosquitoes. Together this could result in insecticide-based control methods retaining a higher than expected degree of efficacy, even in areas where IR levels are high, which would suggest the possibility of developing control methods to mitigate the consequences of resistance i.e. "resistance busting strategies".

Thus understanding the ecology and behaviour of IR mosquitoes and how their life history is affected in the short and long-term by control measures is crucial for prediction of the consequences of resistance. Unfortunately, these parameters are difficult to directly measure under natural field conditions, and may be poorly reflected in laboratory bioassays. However, recent developments in ecological modelling have delivered breakthrough, but as yet rarely applied, methods for deriving such hidden (latent) information from the multiple types of data that are routinely collected in mosquito surveillance. I propose to use these new methods to investigate the population dynamics and ecology of malaria mosquitoes in an area of high IR, and to quantify the impacts of both traditional and novel control methods on mosquito life history under field operational conditions. I will focus on the Banfora district of Burkina Faso, a region of high IR, and will make use of mosquito surveillance data, including mosquito abundance, infectiousness, IR status and behaviour, being collected by my collaborators in the AvecNet programme. This data collection is part of a 2-year 90-villages large-scale intervention trial of two alternative malaria control methods for which laboratory assays predict will reduce mosquito populations through two different routes: 1) traditional bednets (LLIN) that are coated with the insecticide pyrethroid, which works by killing adult female mosquitos; and 2) new Olyset DUO nets that are coated with a pyrethroid to reduce adult mosquito survival but also with pyriproxifen, an insect juvenile hormone that affects fecundity and longevity. However, it is unclear how reliably these expected demographic impacts occur when applied within natural populations.

To address these issues I will apply novel analytical tools that integrate the various types of data generated from widely-used surveillance techniques with clinical incidence data, in order to reconstruct the hidden population dynamics and life history-traits of IR mosquito vectors, and use it to 1) determine how the ecology of IR mosquitoes modulates their malaria transmission potential, 2) quantify the impacts of current and novel control methods on these mosquitoes and 3) design optimal deployment of future intervention methods in areas of high IR.

Despite substantial progress with malaria control, transmission persists throughout much of Africa due to a combination of complex vector ecology, parasite and vector resistance, and poor health infrastructure. Malaria is thus an archetypal example of a complex infectious disease. Epidemiologists increasingly recognize that no single methodological approach or data type is sufficient to understand such complex disease systems and inform evidence-based policy decisions. Instead, a more holistic approach incorporating diverse data on pathogens, hosts and (where applicable) vectors will be needed. Enabling the integration of numerous sources of data remains one of the outstanding challenges for modern medical sciences but potentially game-changing advances in this area are now possible through recent innovations at the intersection of applied biology, ecology and statistics. Armed with these new modelling tools, namely a state-space model, this proposal will borrow strength from all the available types of malaria vector surveillance techniques as well as host data such as clinical incidence from a large-scale intervention trial to understand one of the most impending threats for malaria control: insecticide resistance (IR). The overall objective is to determine if the fundamental assumption that IR mosquitoes are identical to susceptible ones in all aspects other than their response to insecticides is true. We hypothesise that vector ecology may also be altered in these IR mosquitoes. In this proposal will apply these new tools to estimate the values of latent life-history traits of IR mosquitoes that could modulate the epidemiological outcome of vector control methods. Specifically, I propose to investigate the population dynamics and ecology of malaria vectors in an area of high IR (Banfora region of Burkina Faso), and to quantify the impacts of both traditional and novel control methods on mosquito life history.

The two interlinked components of this proposal: the development of methods to integrate multiple data types and reconstruct population and transmission dynamics, and their application to improve the control of vector-borne disease; will deliver meaningful impact over different time scales but the pathway to impact will be similar through:

Teaching and training researchers from both malaria endemic and scientifically engaged countries (including the UK) about how cutting-edge statistical analysis can bring novel perspectives and insights to old problems and obtain a wider range of policy-relevant insights. Dr. Heather Ferguson, one of my sponsors, and other researchers in the University of Glasgow, as well as the other collaborators in this fellowship are deeply invested and richly connected with stakeholder and policy-making communities across sub-Saharan Africa and have well established training bases in Africa (e.g. Ifakara Health Institute (IHI) in Tanzania, the Centre Suisse de Recherches Scientifiques in Cote d'Ivoire, and Centre National de Recherche et de Formation sur le Paludisme CNRFP in Burkina Faso). I will piggy-back on these connections to organize two workshops in areas where the resources and access to training is limited, but where vector surveillance data are routinely collected. Together with the various workshops I attended, my teaching experience provides the necessary skills to deliver the proposed workshops. But, as their success relies on a hands-on approach, the benefit will be mutual. I expect that through the exposure to multiple types of datasets, I will gain further insight into new challenges and open opportunities for new collaborations that will allow me to continue developing analytical tools to vector-host systems; in turn perpetuating the long-term benefit of this fellowship.

Communication and dissemination of my findings to researchers, stakeholders and policy makers will constitute an important pathway with cascading consequences for policy and public health. I intend to pursue this through presentations and meetings to stakeholder and policy forums such as those organized by the WHO Roll Back Malaria Consortium, and through meetings with representatives from the National Malaria Control Programme (NMCP) in Burkina Faso. I also intend to disseminate my findings to a wider community of researchers and disease control managers through presentations at international conferences including the American Society of Tropical Medicine and Hygiene, and Multilateral Initiative on Malaria conference. This will be coupled with publication of results in peer-reviewed journals, which combined with my planned presentations will also deliver a direct benefit to the UK public in terms of strengthening their profile at the forefront of global health research. Benefit to the UK public will also come through the teaching I can provide both through public engagement and outreach activities, informal teaching and seminars at the University of Glasgow, and at the institutions of my other UK collaborators. Other communication activities planned include participation in awareness raising campaigns such as World Malaria Day and Glasgow Science Festival.

Engagement - My findings on the ecology of insecticide resistant mosquitoes have direct relevance to how we think about controlling malaria. This impact will mainly come from engagement with my collaborators and their large collaborator network that include researchers and policy makers. For example, Dr. Ferguson and Profs. Ranson and Lindsay work closely with CNRFP that guides the implementation of the Burkina Faso national malaria control programme, including research to identify new malaria control measures and adapt existing ones to local conditions. The findings of this proposal can therefore have direct influence on the control strategy implemented, future work they may wish to carry out to control malaria and public health.