Malaria elimination and insecticide resistance: an interview with Professor Hilary Ranson, Liverpool School of Tropical Medicine

Interview conducted by April Cashin-Garbutt, MA (Editor)Oct 30 2013

Please can you give a brief history of malaria elimination efforts? How far have we come and how far is there still to go to achieve the goal of malaria elimination?

The first malaria elimination programme was in the 1950s and 1960s. Malaria was eliminated from many countries in Asia and the Americas, largely by indoor spraying with insecticide. But the campaign had very little impact in Africa and eventually resources were moved away from malaria control.

The outcome was a massive surge in malaria cases towards the latter half of the 20^th century. In 1998 a multilateral initiative ‘Roll Back Malaria’ was formed, with ambitious targets to halve malaria deaths by 2010.

In 2007 the bar was raised even higher with the Bill and Melinda Gates Foundation calling for malaria to be eradicated ‘in our lifetime’. Whilst admitting that this was an ambitious goal, Melinda Gates stated ‘Any goal short of eradicating malaria is accepting malaria; it's making peace with malaria; it's rich countries saying: "We don't need to eradicate malaria around the world as long as we've eliminated malaria in our own countries." That's just unacceptable’

The 21^st century witnessed a dramatic increase in financial commitment to malaria control and this has paid dividends in reducing malaria cases worldwide. Particularly encouraging is the 33 % reduction in malaria cases in Africa, the continent that still bears the worst burden of disease. But there is still a long way to go. Even today, despite this investment, over 600,000 children are killed by malaria every year.

A malaria mosquito on a bednet.

Currently, what are the main hurdles on the path to malaria elimination?

Effective malaria treatments and prevention measures do exist. If all people at risk of malaria had access to health services so that the disease could be promptly diagnosed and treated, and were able to protect their family by using insecticide treated bednets or included by an indoor residual spray campaign, malaria could be eliminated. So the major challenges to malaria elimination are lack of funds and poor health systems in countries where the risk of disease is greatest.

But there is another major threat on the horizon: resistance. Resistance to the front line drugs used to treat malaria (the artemesinins) has been detected in SE Asia and resistance to the insecticides used to treat bednets is rapidly spreading in malaria mosquitoes in Africa and elsewhere.

Why is insecticide resistance such a problem?

The only way that malaria can be transmitted is via a bite of an infectious mosquito. Hence preventing mosquito bites can be a very effective means of controlling the disease.

This is made easier in Africa by the behaviour of the major malaria mosquitoes. They tend to take their blood meal indoors, in the middle of the night and, when their belly is full of blood and flying long distances is difficult, they rest on the inside walls of houses.

So sleeping under a bednet can provide personal protection from mosquito bites and hence malaria. And if that bednet is treated with an insecticide, each time a mosquito attempts to feed, it will pick up a toxic dose of insecticide so the total number of infectious mosquitoes in a population is reduced. Similarly, if the wall the mosquito lands on is coated with insecticide, the bloodfed mosquitoes will be killed and unable to transmit malaria to the next person.

These two interventions have proven very effective at reducing malaria transmission in Africa but they are reliant on a very small number of insecticides. Only a single insecticide class, the pyrethroids, are available for treating bednets and only four classes of insecticides, including the pyrethroids are available for indoor spraying.

Worryingly, mosquitoes are rapidly evolving resistance to these insecticides. In the last 10 years, as malaria control efforts have been scaled up across Africa, reports of resistance in mosquitoes have escalated.

Looking for mosquitoes inside a house with a bednet.

What is known about the way mosquitoes develop insecticide resistance?

Mosquitoes can develop resistance in multiple ways. A single amino acid change in the target site of the insecticide can reduce the binding of the insecticide and thereby decrease its potency. Or mosquitoes can reduce the amount of insecticide that penetrates their outer coat or increase the rate at which they detoxify the insecticides. Alone, or in combination, these mechanisms can enable the mosquitoes to survive exposure to insecticide treated surfaces.

Another potential resistance mechanism that is widely discussed but poorly documented is behavioural resistance. There are concerns that the widespread use of insecticides inside the house, could drive genetic changes in the feeding and resting behaviour of mosquitoes. If, for example, mosquitoes altered their behaviour to feed and rest outside this would make controlling them much more difficult. As yet there is no clear evidence of genetic changes in malaria mosquitoes that are altering their behaviour but surveillance schemes to track such changes are poorly implemented.

How is this knowledge limited and what research still needs to be done?

Although we are now beginning to understand the mechanisms responsible for resistance, and have developed tools to monitor for resistance in malaria mosquitoes, there are still huge knowledge gaps that must be filled in order to effectively tackle resistance and prevent it compromising malaria control.

One major priority is to develop means of measuring the operational significance of resistance. With so few insecticides available for malaria control, and with some chemistries having higher costs and/or lower social acceptability, decisions to switch insecticide on the basis of reports of resistance are not taken lightly.

Control programmes and donors urgently need clear indicators of the predicted impact of resistance on malaria control. This is not easy to generate as disentangling the protection provided by the physical barrier of the net and the additional protection afforded by the insecticide is complex.

Even more urgent is the need for new tools to overcome resistance. This can take the form of evidence of the impact of resistance management strategies, such as insecticide rotation. Or new products that are able to kill insecticide resistant mosquitoes.

Mosquito larval collections.

Please can you give an overview of the work you are doing with AvecNet?

AvecNet (http://www.avecnet.eu) is a European Union funded consortium with 15 partners in Africa and Europe working to develop new tools which are effective against insecticide resistant mosquitoes.

We have two field sites in West Africa (Burkina Faso and Cote d’Ivoire) where insecticide resistance levels are already very high in malaria vectors, and a third in Tanzania, where resistance is just emerging.

The many activities of the consortium include field trials of new insecticides provided by industrial partners, developing new tools to track mosquito behaviour (and monitor for the possible emergence of behavioural resistance), evaluating lower cost, targeted use of vector control, understanding factors influencing householders use of mosquito prevention measures, and building capacity for malaria research in Africa.

We will soon embark on a clinical trial of a new dual action insecticide treated bednet which it is hoped will provide increased protection against malaria in areas with high levels of insecticide resistance.

To what extent have the major malaria vectors developed insecticide resistance and how sustainable are existing interventions?

Resistance is spreading very rapidly in malaria vectors. This is an inevitable consequence of the success of campaigns to scale up distribution of bednets and spraying campaigns. At present the evidence that this is having a negative impact on the success of malaria control activities in Africa is limited. But this is no cause for complacency.

The strength of this resistance is increasing very rapidly in some regions and without a concerted effort by the malaria community to minimise the impact of this resistance, and continued investment in new insecticides and control tools, there is a very real danger that the gains we have witness in malaria control in the past decade will be eroded.

A resistance bioassay.

What new tools for malaria control are currently in development and how promising are these?

IVCC (http://www.ivcc.com) is a product development partnership established to help stimulate investment in new products for vector control. New insecticides, and new formulations of existing insecticides are under development with two new long lasting formulations launched in the past 12 months. But novel insecticides, with new modes of action, that are effective against resistant mosquitoes in the field, will not be available until the end of the decade.

Complementary tools for malaria control are also being developed including spatial repellents, attractive sugar baits and odour baited traps, several of which are showing promise in field trials and may complement the use of insecticides inside the home. But for the next few years at least, malaria control will remain heavily dependent on the current tool and insecticides.

How important do you think vaccines will be in malaria elimination?

There is currently no vaccine available to prevent malaria. The GSK RTS/S vaccine is the most clinically advanced and has been shown to halve the number of malaria cases in some age groups although trials are on going and questions remain about the duration of the protection.

Clearly the development of a malaria vaccine, that could be administered as part of the routine EPI, and afforded long lasting protection, would be a game changer. We can only hope that the intensive efforts to develop such a vaccine bear fruit.

Where can readers find more information?

Further information on AvecNet and IVCC can be found online http://www.ivcc.com www.avecnet.eu

Information on insecticide resistance in malaria vectors, including resistance management strategies, can be found in the Global Plan for Insecticide Resistance Monitoring in Malaria Vectors, available from WHO (https://www.who.int/ )

About Professor Hilary Ranson

Professor Hilary Ranson is Head of the Department of Vector Biology at the Liverpool School of Tropical Medicine, UK, one of the largest departments of its kind, with research strengths in malaria, neglected tropical diseases and monitoring and evaluation. 

Professor Ranson’s own research focuses on the control of mosquito borne disease and, in particular, the use of insecticides in vector control. 

She is internationally renowned for her work on insecticide resistance and has contributed her technical expertise to a range of WHO scientific advisory boards and is a technical advisor to the Innovative Vector Control Consortium.  

Professor Ranson is the scientific coordinator of AvecNet (www.AvecNet.eu), a European Union ‘FP7-Call for Africa’ project involving 15 European and African partners, working together to develop new and improved tools for malaria vector control.

She is also scientific lead for the for the Liverpool Insect Testing Establishment (LITE) which provides a service to industrial partners in developing new insecticide products

She was awarded a personal chair in 2011 and is currently the holder of a Royal Society Wolfson Research Merit Award.