Prevention & Cures

Malaria: Future Perspectives on Our Deadliest of Foes

For the first time in many years, the WHO World Malaria Report 2017 [1] revealed a year-on-year increase in malaria cases compared to the preceding year. With an estimated 216 million cases reported worldwide in 2016 compared to 211 million cases in 2015, the reversal in progress against this disease is a reminder of the challenges faced in fighting one of mankind’s oldest and deadliest foes – malaria. To meet WHO’s target of malaria elimination by 2030, new approaches are urgently needed.

In the African continent, researchers have found evidence of malaria dating back five to ten thousand years, and even much further back [2]. While malaria was eradicated in industrialized countries many years ago, it still represents one of the biggest health threats in the developing world: Nearly half of the world’s population is still at risk of this entirely preventable disease. More than two thirds of the 445,000 malaria deaths in 2016 were children under five years. The threat is so significant that in Africa, a child dies from the disease every two minutes.

 

 
Malaria not only takes a physical toll on these populations; it is also one of the main causes of poverty in Africa. The disease is a causal factor behind massive losses in agricultural and industrial productivity. The “Roll Back Malaria Partnership” estimates that this costs developing countries over 12 billion US dollars annually [3]. Morbidity caused by the disease also prevents many children from attending school, reducing their chances of getting an education. 

 

“Malaria has long been recognized as the most significant of the tropical diseases mainly because of the mortality impact that it has. We have gone from more than a million deaths, most of which were children under five, ten to fifteen years ago, down to a point now where we are somewhere above 400,000 to 450,000 deaths a year.”

Justin McBeath, Malaria Market Segment Manager with Environmental Science at Bayer

 

The connections between malaria and everyday life in certain regions of the world are strong. In sub-Saharan Africa, for example, rural living and malaria go hand in hand, with this disease remaining a leading cause of death and major threat to the population. Malaria is predominantly a rural disease, and many of the people affected by malaria are smallholder subsistence farmers, trying to support their families. Sustaining additional costs for treatment, travel to clinics and preventive measures against malaria means that they are forced to divert spending away from other essential items such as food, housing and education. Moreover, malaria episodes cause a decrease in farming output, reducing both food on the table as well as income for the family.

 

Overall, malaria strongly impacts the production of food. “One of the biggest hurdles to the development of more productive agriculture in Africa is malaria,” explains Frédéric Baur, Global Market Manager for Vector Control with Environmental Science at Bayer. “The three elements which are key to malaria – heat, water (to support mosquitoes) and people (an infective source for the parasite) – are also needed to grow food crops. Basically, when you have the best conditions for farming, you have also the best conditions for malaria,” adds Baur. “Usually most of the family are involved in subsistence farming in Africa, and they are at highest risk of contracting severe forms of the disease. If African food production is to develop to its potential, we need to protect people from malaria,” Baur concludes.

 

 

 

Optimizing Malaria Control Interventions is Mandatory

It is well recognized that the most effective way to prevent malaria is vector control. “Vector control has been the hero of the malaria success story to date,” says Nick Hamon. He is the CEO of the Innovative Vector Control Consortium (IVCC),a not-for-profit public-private partnership that was established as a charity in 2005 with the task of developing new compounds for vector control.“Insecticide-treated bed nets and indoor sprays are the main forms of vector control, and there is a real recognition of the role that the two have played in malaria reduction.” [4]. 

In 2015, a report in Nature [5] provided a quantification of the effects of these malaria control interventions in Africa between 2000 and 2015. There, the authors indicated that the infection prevalence halved, and the incidence of clinical disease fell by 40 percent in this period. The report suggests that nearly 80 percent of the gains made in the fight against malaria was the result of investment in, and implementation of, vector control interventions such as insecticide-treated nets (ITN) and indoor residual spraying (IRS). Early treatment of clinical malaria cases with artemisin-based combination therapy (ACT) contributed to the remaining reduction. Overall, these interventions had an impact of 663 million successfully averted clinical cases over a 15-year period. 

 

Safe homes: Indoor Residual Spraying (IRS) helps to control malaria vectors inside houses. 
 

This analysis demonstrated that the current interventions have been highly effective in the fight against malaria; however, a multilevel approach from all stakeholders such as international donors, national governments and global health system policy makers is needed to define and successfully implement these strategies. In this context, the year 2000 was a milestone in the fight against malaria with global campaigns such as the “Roll Back Malaria Partnership” and the establishment of the United Nations’ Millennium Development Goal to “halt by 2015 and begin to reverse the incidence of malaria.” These targets were then restated by WHO in the “Global Malaria Action Plan 2000-2015,” aiming at reducing case incidence by 75 percent in the same time. These key initiatives led to a twenty-fold increase of international financing for malaria control and substantially contributed to the gains made on malaria in the last two decades. Almost all endemic countries met the Millennium Development Goals target. 

 

Despite these positive results, increases in case incidence and stagnation of mortality rates were observed between 2014 and 2016, underlining that much remains to be done to further reduce the incidence of malaria and save lives. The new WHO Global Technical Strategy for Malaria 2016-2030 sets some challenging objectives to be reached: a 90 percent reduction of mortality rates and case incidence, the elimination of malaria from at least 35 countries, as well as preventing re-establishment of malaria in all malaria-free states.“Progress in malaria control in Africa is crucial to the attainment of the goals of the global technical strategy,” said Dr. Pedro Alonso, Director of the Global Malaria Programme, at the 66th Session of the WHO Regional Committee for Africa in 2016. 

 

Malaria can affect anyone – adult or child. But children are most at risk from the worst effects of the disease.

 

Challenges in the Fight Against Malaria – The Need for New Approaches

There are key challenges around maintaining progress in the fight against malaria. They include sustaining future funding in the pre-elimination setting, the development of resistance to insecticides used in current vector control interventions and the need to address what is termed ‘residual transmission’ (malaria transmission which is not impacted by current vector control interventions). Finally, as disease burden comes down, commitment and interest wanes, which results in a ‘dropping of the ball’ and resurgence of the disease. In this regard, the private sector can play an important role. 

 

 

Interview: Dr. Chouaïbou Mouhamadou
Increased Risk is Lurking in the Fields

Dr. Chouaïbou Mouhamadou is a Medical Entomologist and Vector Control Specialist with 15 years of experience in insecticide resistance in malaria vectors. He serves as Senior Researcher at the Centre Suisse de Recherches Scientifiques (CSRS) in Ivory Coast. He is collaborating with Bayer in research on mosquito susceptibility to insecticides.

How are agriculture and resistance in malaria vectors linked?
Agriculture is the backbone of economy in Ivory Coast, the world’s leader in cocoa production. Cultivation requires the use of chemicals for crop protection. Malaria vectors breed in swamps or stagnant water in the fields and can come into contact with insecticide residues, which will contribute to the selection for resistance – by causing mortality of the more susceptible individual mosquitoes (meaning mortality of the ones that are not showing some level of resistance). Those individuals showing some level for reduced susceptibility will then reproduce together and pass over the traits to their progeny, spreading resistance. As most of the chemicals used in public health come from agriculture and are reformulated to be used for vector control, their efficacy against those resistant vectors could then be limited.

How can you detect resistance in malaria vectors?
There are specific tools and guidelines to help detect resistance in field populations of malaria vectors. Most of the findings in Ivory Coast show that malaria vector mosquitoes are resistant to almost all chemicals belonging to the four classes of insecticides recommended for malaria vector control. Therefore, management of resistance should not only rely on the known insecticides. In collaboration with Bayer, we have been evaluating the level of resistance to neonicotinoids, a class of chemicals which are widely used for crop protection in cocoa plantations but have never been used in the past for vector control. During our research we found mosquitoes that were resistant to neonicotinoids, so the repurposing of these compounds alone for public health might not be ideal, as the risk of resistance developing more quickly might be high. The use of combinations of different compounds with distinct modes of action could delay the development of resistance, allowing a better impact on malaria vectors.

What are the challenges vector control strategies face today?
Actions should be taken on two levels: The first one is vector control itself. Ideally, we need to develop new chemicals with different modes of action, which are exclusively for public health and not used in agriculture. Beyond that, we must completely rethink and reimagine vector control – for example, mosquito nets that kill mechanically and not only chemically and other intervention strategies beyond indoor residual spraying and nets.

Today, the neonicotinoids are being considered for use in public health as a component in Indoor Residual Spraying. Looking at agriculture, the first neonicotinoid (imidacloprid) was launched in 1991. The development of resistance to new compounds is arguably inevitable if usage is not managed properly from the outset. We desperately need new modes of action – so compounds which are used in agriculture as well as for public health clearly require some careful management and usage if we are to retain their value for malaria control programs in the future. That's another example of why I think vector control needs to be rethought and re-imagined.

Second, people from both the agricultural and the public health sectors should sit together and discuss common plans of action and strategies. The role of agriculture is undeniable, so it is also important that vector control and pest control actions are integrated and, above all, effective, not just on paper.

 

 

A Fundamental Problem: Insecticide Resistance 

One of the most pressing challenges in the fight against malaria is insecticide resistance in mosquito vector populations. The first reports of vector resistance to insecticides date back to the 1950s in Greece, Iran and Turkey. By 2016, resistance to one or more of the insecticides used in public health was present in all malaria-endemic regions. 

 

To address this increase in resistance and avoid a failure of vector control strategies, WHO issued the Global Plan for Insecticide Resistance Management in malaria vectors (GPIRM) in 2012. This plan emphasizes the need for proactive management of insecticide resistance in public health, linked with a better monitoring of resistance development. It also calls for enhanced research efforts to better explain the causes and mechanisms of insecticide resistance. 

 


 

Various factors contribute to the emergence of resistant mosquito populations – including the limited range of insecticide classes available for the primary interventions as well as exposure of mosquito populations, in some situations, to household insecticides and insecticides used in agriculture.“Insecticides don’t cause resistance per se. The genetic diversity in any population means there are biotypes which can tolerate or are resistant to compounds in their environment,” explains Justin McBeath, Malaria Market Segment Manager with Environmental Science at Bayer. “If you repeatedly expose a mosquito population to the same insecticide selection pressure over an extended period of time, then those resistant individuals will survive and start to dominate the population – leading to control failure.”

 

The introduction of new insecticide modes of action for malaria vector control is therefore critical for the management of resistance – and a key pillar in the WHO Global Plan for Insecticide Resistance Management (GPIRM) 2012 Strategy. Life Science companies such as Bayer are therefore strongly engaged in searching for new compounds relevant for malaria vector control. This commitment is shared with the IVCC and was publicly reaffirmed with the start of the initiative “ZERO by 40” at the London Summit on Malaria, which was convened alongside the Commonwealth Heads of Government Meeting in April 2018. “ZERO by 40” joins together the world’s leading crop protection companies, the IVCC and the Bill & Melinda Gates Foundation with the goal of ending malaria through vector control by 2040.  

 

Repurposing: An Alternative Approach

The compounds which will come out of the partnership with IVCC form a crucial part of the future malaria vector control landscape, but some of them are more than five years away from market availability, and other solutions are needed in the meantime.

 

Repurposing insecticides which are already used in agricultural crop protection is the historical norm (for public health insecticides used today) and is another option to bring new modes of action and bridge the gap until the approval of completely new substances. “We have been working on this topic for many years in parallel with our work with IVCC, and one of these new products is currently undergoing the final stages of WHO evaluation prior to market availability,” highlights McBeath. 

 

However, questions remain about the role that the use of insecticides in agriculture may have in the selection for resistance in malaria vectors. Since breeding sites are often close to fields, mosquitoes can be exposed to those compounds used in crop protection. This is of relevance especially in some sub-Saharan countries such as Ivory Coast and Burkina Faso, which have particularly intense agricultural production and where farming represents the primary source of food and/or income. 

 

 

The Economic Relevance of Agriculture in Ivory Coast

Located in West Africa, Ivory Coast is an area of 318,000 km² (122,780 sq. miles), with an estimated population, of 24.9 million inhabitants (2018) [6]. Agriculture is a primary sector in the economy, employing two thirds of the population. A fifth of the land is cultivated, and the country is the world's largest cocoa producer, fourth largest producer of coffee and a major producer of cotton, coconuts, palm oil, cashew nuts, bananas, sugarcane and rubber. The cocoa industry accounts for around 15 percent of Gross Domestic Product (GDP) and 25 percent of total exports. 

Cocoa, for example, is mostly grown by smallholder farmers on less than three hectares. As a result, their income is closely correlated to the international cocoa prices and to the eventual crop loss because of plant diseases. Climate change is also a concern, as temperature rises could leave many areas in West Africa unable to grow cocoa. Even with the support of an increasing number of sustainability projects, most cocoa farmers in Ivory Coast still live far below the poverty line.

 

Sarah De Souza, Marketing Analyst with Environmental Science at Bayer in Ivory Coast, West Africa, has been dedicated to this topic for the last two years. “There was limited awareness of the relevance of crop protection usage of the ‘new’ class of repurposed chemistry in West Africa, which we are developing for Malaria Vector Control,” said De Souza. “For instance, if this insecticide class was widely used in intensive agricultural production environments, did that overlap with areas where malaria mosquitoes breed?”

 

 

Sarah De Souza is a Marketing Analyst with Environmental Science at Bayer in Ivory Coast, West Africa.
 

Various papers have been published around this topic in the past, including a review of work to date by Reid and McKenzie in the Malaria Journal [7] on 2016, but there seems to be very little direct connection – most of this has been associative rather than causal. 

 

Thus, says de Souza, “I initiated a survey in 2016 across Ivory Coast to identify actual patterns of insecticide usage in different farming systems; this was followed in a second stage by sampling mosquito larvae from these same areas and, in partnership with Centre Suisse de Recherche Scientifique (CSRS) in Abidjan, testing these mosquitoes for susceptibility to the agricultural insecticides identified.” The important finding from this study was that mosquitoes showed resistance to insecticides which they would never have been exposed to before in public health, but which were clearly used by farmers in these agricultural environments. This raises important questions about the way in which repurposed agricultural compounds should therefore be introduced into public health.

 

The Combination Approach

Combinations of different modes of action are commonly used in both drug and insecticide deployment, with the principle behind the approach being that the existence of individuals or organisms which show resistance to multiple compounds is extremely rare. Combination therapy is even used in antimalarials – with a WHO resolution requesting member states to stop the use of oral artemisin monotherapy due to the concerns around resistance development.

 

In crop protection, combinations can be used to increase the spectrum of activity against a pest complex or to provide improved efficacy under conditions of multiple resistance mechanisms. This approach is, therefore, increasingly being looked at for malaria vector control, both on insecticide-treated bednets (a new combination net product achieved WHO-PQ listing in 2017) as well as new developments from Bayer in indoor residual spraying.

 

A Survey on Agricultural Insecticide Use in Ivory Coast

Objectives of the survey:

  • understand the extent of neonicotinoid use in key crops across Ivory Coast such as cocoa, cotton, rice and vegetables
  • understand if farmers and other stakeholders in the agricultural community were aware of the potential impact of agricultural insecticides on mosquito-resistance selection
  • investigate the susceptibility of mosquitoes sampled from areas where high neonicotinoid use was reported

 

The results:

  • A total of 121 farmers responded to the survey. The group was comprised of 41 cocoa farmers, and all of them reported using products containing neonicotinoids. 
  • None of those approached in the agricultural sector were aware of the potential link between insecticide usage for crop protection and resistance in mosquitoes. During the study, the recognition of the potential linkage from agricultural stakeholders increased. 
  • Preliminary results showed that mosquitoes sampled from the survey locations showed resistance to some of the neonicotinoids tested.  
  • This illustrates the importance of putting thought and care into vector control operations and choice of tools to be used in intervention strategies.

 

The Need for New Intervention Strategies – Residual Transmission 

Unfortunately, malaria is not usually transmitted by only one species of mosquito within a given region or country, and even within a mosquito species, populations may develop behavioral adaptations to avoid current vector control practices. Long-lasting nets and indoor residual spraying address the vast proportion of malaria transmission that occurs from the main malaria vectors, which bite people indoors at night during sleeping hours and then rest on indoor surfaces after taking a blood meal. However, it is becoming increasingly recognized that malaria elimination will not be reached if we rely only on these existing ‘traditional’ intervention methods. We need new tools which can effectively reduce human-vector contact with the mosquitoes that bite people outdoors or outside of the times when people sleep under a bednet; or to target mosquitoes that bite people indoors and then rest outdoors after a bloodmeal. All of these require different approaches from what we have today.

For that reason, a suite of new tools for vector control is under evaluation. In a Guidance Note [8] of 2014, the WHO recommends testing the effectiveness of the following strategies:

  • Using physical screening barriers or repellents to exclude or limit indoor entry;
  • Following entry, preventing successful indoor feeding and/or resting using exit or other barriers, repellents or insecticides with no deterrent properties;
  • Preventing successful outdoor feeding by using insecticide-treated clothing or repellents to directly protect people;
  • Reducing adult vector densities or transmission potential by outdoor attractants to lure and trap/kill mosquitoes by topical or systemic insecticides for livestock by applying insecticides to natural sugar sources or by introducing insecticidal sugar baits.

A joint effort of national institutions, private partners, researchers and WHO will be necessary to develop, validate and implement new approaches for targeting such residual transmission.

Djèkouadjois the word many people in Ivory Coast, West Africa, use to describe malaria.

 

The Role of the Private Sector in the Future of Malaria Control 

In addition to new tools and new approaches with those tools, sustaining future funding for the fight in a pre-elimination setting will play a crucial role. As disease burden comes down, commitment and interest wanes, which can result in a resurgence of the disease. “Indeed, an arsenal of potent technologies was at the ready. Insecticide-treated bednets had been shown to protect against malaria-carrying mosquitoes, which are active primarily at night. Indoor residual spraying with insecticides remained a safe and effective alternative. And a new generation of powerful drugs had been developed for the treatment of malaria. Despite this arsenal, the fight against malaria had stalled,” commented Margaret Chan, the former head of WHO in 2010 [9]. In this regard, the private sector can play an important role.


A good example for a successful public-private partnership model for malaria elimination is Sri Lanka, where a cooperation between the government and a private sector partner considerably contributed to the elimination of the disease [10]. In this situation, private support was temporarily provided to war-damaged areas of the nation in order to ensure the continuation of blood examinations and screenings for the disease. The continuation of these efforts supported Sri Lanka to become one of the most recent countries to achieve malaria elimination, as it was certified as malaria-free by WHO in 2016 [11]. There are various opportunities to engage private sector companies in small or large-scale projects. Targeted interventions such as immunization programs, distribution of long-lasting insecticidal nets (LLINs) and improved access to diagnostics and treatments can protect communities and part of populations that live in hard-to-reach areas. In-company campaigns can help raise awareness of malaria symptoms and of the importance of prevention efforts. The expertise and resources of the private sector offer unique opportunities to confront the challenge of drug and insecticide resistance.

An Optimistic Future or a Long Way to Go?

The efforts of the international community over the past 15 years have reduced malaria risk levels for many millions of people. This is suggestive that elimination targets are within our reach, with the right level of resources and commitment and with the right tools in our hands. The challenges are many, but the commitment is strong. The pipeline for new modes of action to manage resistance in malaria vectors looks promising. There is no shortage of innovative ideas for a larger toolbox to address other elements of malaria transmission. And as economic development in some endemic countries advances, this creates less reliance on international funding, opportunities for different domestic funding mechanisms and different models of private sector engagement. 

 

At Bayer, we await the results of the 2018 World Malaria Report with bated breath and remain hopeful that, this year, we will see positive progress towards malaria elimination goals.

 

Sources:

[1] World Health Organisation, 2018

[2] Clin Microbiol Rev, 2002 

[3] RBM, 2017

[4] Fight against Malaria, 2018

[5] Nature, 2015

[6] Worldometers

[7] Malar, J., 2016

[8] World Health Organisation, 2014

[9] Margaret Chan & Ray Chambers, 2010

[10] BMC, 2018

[11] World Health Organisation, 2018

Related Content
Science & Innovation
The Hunt for Long-Term Answers
Read more