Accepted Manuscript

Title: Current vector control challenges in the fight against

malaria

Authors: Giovanni Benelli, John C. Beier

PII: S0001-706X(17)30698-8
DOI: http://dx.doi.org/doi:10.1016/j.actatropica.2017.06.028
Reference: ACTROP 4359

To appear in: Acta Tropica

Received date: 12-6-2017

Accepted date: 30-6-2017

Please cite this article as: Benelli, Giovanni, Beier, John C., Current
vector control challenges in the fight against malaria.Acta Tropica
http://dx.doi.org/10.1016/j.actatropica.2017.06.028

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Invited Review

Current vector control challenges in the fight against malaria

Giovanni Benelli 1 * and John C. Beier 2 **

1
Department of Agriculture, Food and Environment, University of Pisa, via del

Borghetto 80, 56124 Pisa, Italy

2
Department of Public Health Sciences, University of Miami Miller School of

Medicine, Miami, FL, United States

* Correspondence:

Tel.: +390502216141. Fax: +39-0502216087. E-mail address:

benelli.giovanni@gmail.com (G. Benelli).

** E-mail address: JBeier@med.miami.edu (J. Beier).

Graphical abstarct

• Reduce malaria incidence • Effectiveness, field suitability

• Little impact on malaria prevalence • Must have epidemiological impact
• Do not protect from outdoor • Non-target effects?
transmission
• Growing levels of insecticide resistance
LLINs e.g.
• Eave tubes
• ATSB
Development • Ivermectin
of novel
IRS control
Malaria strategies

vector
control
Environmental
Monitoring changes:
programs impact on
Larvicides population
dynamics

Knowledge • Behavioral avoidance

on vector • Vector biodiversity
behavioral • Competitive and food web interactions
Not suitable for rural areas ecology • Dispersal
• Mating and sugar-feeding behavior

Highlights

 The effective control of Anopheles vectors plays a key role in any malaria

management program.

 Most National Malaria Control Programs in Africa still rely to indoor residual

spraying (IRS) and long-lasting insecticidal nets (LLINs).

 IRS and LLINs reduce malaria incidence but generally have little impact on

malaria prevalence.

 Outdoor transmission and growing levels of insecticide resistance threaten the

efficacy of LLINs and IRS.

 This review critically discussed current challenges and trends in malaria vector

control research, outlining the pro and cons of new strategies being developed.
Abstract

The effective and eco-friendly control of Anopheles vectors plays a key role in

any malaria management program. Integrated Vector Management (IVM) suggests

making use of the full range of vector control tools available. The strategies for IVM

require novel technologies to control outdoor transmission of malaria. Despite the wide

number of promising control tools tested against mosquitoes, current strategies for

malaria vector control used in most African countries are not sufficient to achieve

successful malaria control. The majority of National Malaria Control Programs in

Africa still rely on indoor residual spraying (IRS), and long-lasting insecticidal nets

(LLINs). These methods reduce malaria incidence but generally have little impact on

malaria prevalence. In addition to outdoor transmission, growing levels of insecticide

resistance in targeted vectors threaten the efficacy of LLINs and IRS. Larvicidal

treatments can be useful, but are not recommended for rural areas. The research needed

to improve the quality and delivery of mosquito vector control should focus on (i)

optimization of processes and methods for vector control delivery; (ii) monitoring of

vector populations and biting activity with reliable techniques; (iii) the development of

effective and eco-friendly tools to reduce the burden or locally eliminate malaria and

other mosquito-borne diseases; (iv) the careful evaluation of field suitability and

efficacy of new mosquito control tools to prove their epidemiological impact; (v) the

continuous monitoring of environmental changes which potentially affect malaria vector

populations; (vi) the cooperation among different disciplines, with main emphasis on

parasitology, tropical medicine, ecology, entomology, and ecotoxicology. A better

understanding of behavioral ecology of malaria vectors is required. Key ecological

obstacles that limit the effectiveness of vector control include: behavioral avoidance,

vector biodiversity, competitive and food web interactions, dispersal, mating behavior,

and environmental changes. Overall, the trans-disciplinary cooperation among

parasitologists and entomologists is crucial to ensure proper evaluation of the

epidemiological impact triggered by novel mosquito vector control strategies.

Keywords: Anopheles; malaria; epidemiological impact; insecticide treated bed nets;

pesticide resistance; Plasmodium parasites

 1. What’s new in malaria management?

Malaria (from Middle Age Italian, “mala aria” which literally translates to “bad

air”, since ancient populations believed that the disease was associated with swampy,

marshy areas where the air smelled bad) is a disease of huge public health importance

caused by Plasmodium parasites that are transmitted to humans through the bites of

infected females belonging to the mosquito genus Anopheles (Diptera: Culicidae)

(Capanna 2006; Hempelmann and Krafts 2013). The last two years registered hot news

in the field of malarial prevention and treatment. Hot news included the Nobel Prize to

the Chinese scientist Y. Tu for the discovery of artemisinin (Callaway and Cyranoski

2015). This molecule and its semi-synthetic derivatives are the drugs showing highly

rapid action against Plasmodium falciparum malaria (Tu 2011; Su and Miller 2015).

Furthermore, the first vaccine against P. falciparum malaria, RTS,S/AS01 (also known

as Mosquirix), has been developed as a result of a partnership between

GlaxoSmithKline Biologicals (GSK), the PATH Malaria Vaccine Initiative (MVI), with

support from the Bill & Melinda Gates Foundation, and from a network of African

research centers that performed the studies (RTS,S Clinical Trials Partnership 2015;

WHO 2015; Benelli and Mehlhorn 2016). However, in a large clinical trial in sub-

Saharan African children, only transient protection by RTS,S/AS01 against malaria was

found, with special reference to infants (Gosling and von Seidlein 2016).

Notably, and perhaps most importantly, in the last 5 years, malaria incidence

among populations at risk fell by 21% globally; during the same period, malaria

mortality rates among populations at risk decreased by 29%; an estimated 6.8 million

malaria deaths have been averted globally since 2001. However, in 2015, 91 countries
and areas had ongoing malaria transmission. Among them, the African Region

continues to carry a really high share of the global malaria burden. In 2015, the region

was afflicted by 90% of malaria cases and 92% of malaria deaths. Thirteen countries –

mainly in sub-Saharan Africa – account for 76% of malaria cases and 75% deaths

globally (White 2011; Bhatt et al. 2012; White 2015; WHO 2017a). Malaria, as well

other mosquito-borne diseases, has a major impact on the economic development of

developing countries, through direct medical costs and indirect costs such as loss of

productivity and tourism (Gallup and Sachs 2001; Sachs and Malaney 2002; Malaney et

al. 2004; WHO 2016a).

In this framework, the research on novel antiplasmodial drugs is crucial to face

the growing problem of Plasmodium resistance to currently employed compounds,

including chloroquine and artemisinin (Jensen and Mehlhorn 2009; WHO 2016b;

Benelli et al. 2017; Burrows et al. 2017). Two further key challenges are the reduction

of the transient effect to of RTS,S/AS01, and the development of malaria vaccines

against Plasmodium species not covered by Mosquirix (e.g. Plasmodium vivax, which is

dominant in Asian countries and the Americas). In addition, besides these tools, the

effective and environmentally sustainable control of Anopheles vectors still plays the

most important role in any malaria management program (Benelli 2015a; Hemingway et

al. 2016; Chanda et al. 2017).

2. The importance of Integrated Vector Management

Following the concept of Integrated Vector Management (IVM), it is strongly

suggested to avoid “vertical” management structures relying only on one form of

mosquito vector control (e.g. indoor spraying), as it was common in the malaria

eradication era (Nájera et al. 2011;WHO 2017b). To reduce the burden and threat of

mosquito-borne diseases that affect humans, with special reference to malaria and

dengue fever, WHO (2016a) supports the development of effective, locally adapted

sustainable vector control. To do this, the Global Vector Control Response (GVCR) key

pillars of action include (i) strengthen inter- and intra-sectoral action and collaboration,

(ii) enhance vector control surveillance and evaluation of interventions, (iii) scale up

and integrate tools and approaches, and (iv) engage and mobilize communities. The

foundation at the basis of the above-mentioned pillars of action includes enhancing

vector control capacity and capability, as well as increasing basic and applied research

and innovation (WHO 2016a).

At variance with earlier malaria vector control attempts, current IVM strongly

suggest making use of the full range of vector control tools available. This should be

flanked by regular assessments of local disease transmission dynamics, as well as

agreeing on decision-making criteria and on procedures to meet targets and thresholds

for transmission reduction (WHO 2017b). Currently, a number of tools have been

proposed to control malaria mosquito vectors (Benelli 2015a; Bourtzis et al. 2016).

However, indoor residual spraying (IRS), and long-lasting insecticidal nets (LLINs) still

represent the two most widely adopted control tools in malaria management programs

(WHO 2017a). Furthermore, in agreement with the IVM criteria, LLINs and IRS can be

effectively employed in synergy with new paradigms in mosquito control recommended

by the Vector Control Advisory Group (VCAG), including larval source management

with larvicides (e.g., Bacillus thuringiensis serovariety israelensis and Bacillus

sphaericus, Bravo et al. 2007; Lacey 2007; Boyce et al. 2013; botanical larvicides,

Pavela 2015; WHO 2017c).

Current research is focused on the development of further tools for effective

mosquito vector control. Among them, a noteworthy relevance has been achieved by

“eave tubes” and attractive toxic sugar baits (ATSB). The first method consists in a

cheap and easy-to-do modification of the ventilation gaps under house eaves. Malaria

mosquito vectors usually prefer to enter in houses exploiting the gap between the walls

and the roof, which is common in rural houses on African countries (Knols et al. 2016).

The “eave tubes” technology rely to the insertion of plastic tubes under the roofline; the

rest of the gap is then sealed. At the end of each eave tube, the mosquito will encounter

a adulticide-coated mesh. This method can be viewed as an “attract and kill” strategy,

where the human odor from each house lure mosquitoes, allowing their contact with a

contact insecticide (Sternberg et al. 2016; Waite et al. 2016). Still in the framework of

“lure and kill” control tools, the ATSB method relies on the use of sugar bait attracting

sugar-feeding malaria mosquito vectors. The ATBS can be provided in bait stations or

sprayed on plants; both male and female mosquitoes feed on them (Allan et al. 2011;

Beier et al. 2012). The ATSB are co-formulated with low-risk toxic substances, with

special reference to boric acid, which kill mosquitoes upon ingestion (Xue et al. 2006;

Xue et al. 2008; Muller et al. 2008; Muller et al. 2010; Xue et al. 2011; Stewart et al.

2013; Naranjo et al. 2016). Overall, both “eaves tubes” and ATSB methods have been

reported as highly effective, target-specific, and with minimal non-target effects and

contamination of the environment.

Further control strategies being developed for malaria vector control can include

Wolbachia endosymbiotic bacteria inducing cytoplasmic incompatibility in mosquitoes

(Wiwatanaratanabutr et al. 2010), Sterile Insect Technique (SIT) and “boosted SIT”

(Oliva et al. 2012, 2013; Bouyer and Lefrançois 2014), the use of genetically modified

mosquitoes (e.g. Release of Insects carrying a Dominant Lethal, RIDL) (Bourtzis et al.

2016), as well as more “classic” control tools, including selective microbial and plant-

borne pesticides effective against mosquito young instars (Benelli 2015a; Pavela 2016),

oviposition deterrents (Xue et al. 2001), also in nano-formulations (Benelli 2016;

Rajaganesh et al. 2016), insecticide-treated clothes and other materials for the personal

protection of risk specific groups (Banks et al. 2012), spatial repellents reducing human-

vector contact (Achee et al. (2012), and synthetic and plant-borne compounds repelling

adults from humans (see review by Pavela and Benelli 2016a).

In addition, aquatic predators (e.g. cyclopoid copepods, Toxorhynchites

mosquitoes, waterbugs, backswimmers, odonate young instars, tadpoles, and fishes)

have been used as biological control agents of mosquito young instars (Marten et al.

1994; Hwang and Strickler 2001; Bowatte et al. 2013; Murugan et al. 2015). The

efficacy of larvivorous fishes (e.g., the mosquitofish Gambusia affinis and the guppy,

Poecilia reticulata) is widely acknowledged, despite their impact on non-target aquatic

species (see Walshe et al. 2013 and Benelli et al. 2016 for recent reviews).

Lastly, another strategy showing a promising potential in malaria vector control

is the employ of the endectocide ivermectin. This molecule has been employed

extensively for more than thirty years in the framework of onchocerciasis and lymphatic

filariasis control (Ōmura and Crump 2005; Chaccour et al. 2017). Ivermectin acts as

feed-through insecticide against malaria vectors. Indeed, it has been showed that

ivermectin that remains in the human bloodstream following a standard oral dose can
kill blood-feeding Anopheles mosquitoes (Omura and Crump 2017; Chaccour and

Rabinovich 2017a, 2017b).

3. A brief research agenda for malaria vector control

Overall, the strategies for Integrated Vector Management (IVM) (WHO 2004,

2007, 2012, Beier et al. 2008) require novel technologies to effectively reduce outdoor

transmission of malaria (The malERA Consultative Group on Vector Control 2011).

Despite the promising control tools recently tested against mosquitoes, current strategies

for malaria vector control used in most African countries are not sufficient to achieve

successful malaria control and local elimination (Hemingway et al. 2016; WHO 2016a).

As outlined in the paragraphs above, the majority of the National Malaria Control

Programs in Africa rely on LLINs and IRS (WHO 2006). Notably, both methods used

exclusively inside houses reduce transmission by >90%, thus the incidence of new

infections and malaria-related morbidity and mortality (Lengeler 2004; WHO 2008;

Pluess 2010). However, beyond low transmission sites or on islands (WHO 2008;

Bhattarai et al. 2007; Kleischmidt et al. 2007; Keating et al. 2011) these methods have a

limited impact on malaria prevalence (Protopopoff et al. 2007, 2008; Beier 2008). For

example, in stable transmission areas, it has been showed that insecticide-treated bed

nets reduce malaria prevalence only 13% (Lengeler 2004).

Furthermore, malaria vector control in Africa needs to be improved because

even very low levels of malaria parasite transmission confound efforts to reduce malaria

prevalence. Indeed, it is well known that the prevalence of P. falciparum malaria is

strongly related to the number of infective bites per person per year annual, also known
as entomological inoculation rates (EIRs), which range from <1 to >500 (Beier et al.

1999). In areas of high EIRs, malaria prevalence rates are >80%. However, it has been

noted that rates from 40 to 60% occur even when annual EIRs are <5, while a

significant reduction in malaria prevalence requires that annual EIRs be reduced to

levels <1 (Beier et al. 1999). However, vector control tools in Africa have not been

shown to reduce and sustain annual EIRs to levels <1 (Shaukat et al. 2010).

Furthermore, outdoor transmission is a growing concern that affects malaria

transmission dynamics in Africa (Killeen 2014). Due to extensive indoor vector control,

transmission is shifting from the highly endophilic to more exophilic outdoor-adapted

species within the Anopheles gambiae complex (Bayoh et al. 2010; Fornadel et al.

2010; Russell et al. 2010; Derua et al. 2012; Mwangangi et al. 2013). In addition,

growing levels of insecticide resistance in targeted vectors threaten the efficacy of

LLINs and IRS (Tabashnik 1994; Hemingway and Ranson 2000; Ranson et al. 2009;

Enayati and Hemingway 2010; Ranson et al. 2011; Naqqash et al. 2016).

It should be also pointed out that classic larvicidal treatments are useful (Walker

and Lynch 2007; Fillinger et al. 2009; Afrane et al. 2016) but are not generally

recommended for rural areas (WHO 2004; see also Tesfazghi et al. 2016).

Lastly, the recent WHO Health and Environment Linkages Initiative (HELI)

(WHO 2017b), stressed the importance of basic knowledge on mosquito vector

behavior and ecology, to develop tailor-made vector management actions (Charlwood et

al. 2002; Cabrera and Jaffe 2007; Diabate et al. 2011; Dabiré et al. 2014; Oliva et al.

2014; Pitts et al. 2014; Diabate and Tripet 2015). Indeed, a better understanding of

malaria vector and transmission ecology is needed (Ferguson et al. 2010). Key

ecological obstacles that limit the effectiveness of vector control include the variation in
mosquito behavior, development of insecticide resistance, presence of behavioral

avoidance, high vector biodiversity, competitive and food web interactions, lack of

insights on mosquito dispersal and mating behavior, and the impact of environmental

changes on mosquito ecological traits. In this scenario, a more holistic approach is

required (Fish 2008; Benelli and Mehlhorn 2016).

4. Challenges and future outlooks

Overall, the development of effective and reliable mosquito vector control

programs is faced with several challenges, which can be classified as systemic,

structural, informational, environmental, human movement, political and financial ones

(WHO 2016a). First, capacity for vector surveillance and control is insufficient in most

the countries at risk from mosquito-borne diseases. Second, many countries that are

endemic for more than one major mosquito-borne disease have disease-specific

programs and strategies that do not optimally promote synergies, and sometimes

compete for resources. Third, the evidence base to sustain effective vector control is

limited for most vector-borne diseases due to lack of research support. Fourth, changes

in vector habitats such as those due to rapid urbanization or alterations in land use,

water management and farming practices are often unpredictable and hard to manage.

Also, climatic changes that extend the distribution of vectors to more temperate climates

(Becker et al. 2012; Sinka et al. 2012). Fifth, the increased global human population

movement boosts the introduction of invasive species into receptive areas and expose

non-immune populations to new diseases (Benelli and Mehlhorn 2016). Sixth, even

though financial support has been dedicated for the scale up of LLINs and IRS against
malaria vectors since 2000, the focus on other vector control interventions is still

limited, especially in the absence of either large epidemics or high mortality rates.

Investments in vector surveillance have remained minimal in general, and vector control

monitoring and evaluation is often limited (WHO 2016a).

Notably, while a basic research agenda for vector control may be determined by

the interests of particular research groups or institutions, the applied research agenda

should be defined by the national vector-borne disease control program in consultation

with national and international experts in the relevant field. The agenda should outline a

prioritized list of strategic focus areas required to inform vector control in the country,

and should serve to guide research and academic institutes to align the focus of their

work (WHO 2017b). To our mind, also in agreement with the WHO (2017b) criteria,

the research needed to improve the quality and delivery of mosquito vector control

should focus on:

(i) The assessment of the capacity, strengths and weaknesses of the involved

health systems in order to optimize processes and methods for vector control delivery.

(ii) The evaluation of mosquito vector populations with updated and reliable

techniques ensuring that results are informative for vector control; in this context, the

development of robust methods for standard assessing mosquito outdoor biting is of

particular relevance (Figure 1).

(iii) The development of effective and eco-friendly tools to reduce the burden or

eliminate malaria and other mosquito-borne diseases, in accord with recommendations

by VCAG; this is particularly important in the framework of growing resistance to

currently marketed insecticides in targeted vector populations (Hemingway and Ranson

2000; Naqqash et al. 2016). To our mind, further research should be aimed to validate
the potential synergies arising from the join employ of IRS and LLIN-based programs

with novel eco-friendly tools, such as “eave tubes technology” (Sternbert et al. 2016),

ATSB methods (Muller et al. 2010) and even the employ of the ectendocide ivermectin

(Ōmura and Crump 2017).

(iv) The careful evaluation of field suitability and efficacy of new mosquito

control tools, in order to prove their epidemiological impact through randomised

controlled trials with entomological and clinical outcomes (Figure 1); this has been

done for LLINs and IRS, but remains a major challenge for other anopheline control

strategies,

(v) The continuous monitoring of environmental changes which potentially

affect malaria vector populations; monitoring should always follow development

projects (e.g., dam construction, irrigation, growing urbanization, and emergency

situations).

(vi) Enhance and boost cooperation among different disciplines, with special

reference to parasitology, tropical medicine, ecology, entomology, ecotoxicology and

environmental science; this will help to understand the impact of novel interventions on

vectors and non-target organisms as well. Ecotoxicology will also allow to carefully

evaluate the fate of products used for mosquito control in the environment, with special

reference to aquatic ones, and the impact on human health, as well as on wildlife,

livestock and pets (Hicks et al. 2017; Silver et al. 2017) (Figure 1). The trans-

disciplinary cooperation among parasitologists and entomologists (see also Benelli and

Mehlhorn 2016) is also extremely important to ensure adequate evaluation of the

epidemiological impact triggered by novel mosquito vector control strategies.

Acknowledgements

This study was supported by the National Institute of Allergy and Infectious

Diseases of the National Institutes of Health under Award Numbers R01AI100968 and

U19AI089702. The content is solely the responsibility of the authors, and does not

necessarily represent the official views of the National Institutes of Health.

Conflict of Interest

The Author declare no competing interest.

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Figure 1. Main challenges and trends in current malaria vector control research.

• Reduce malaria incidence • Effectiveness, field suitability

• Little impact on malaria prevalence • Must have epidemiological impact
• Do not protect from outdoor • Non-target effects?
transmission
• Growing levels of insecticide resistance
LLINs e.g.
• Eave tubes
• ATSB
Development • Ivermectin
of novel
IRS control
Malaria strategies

vector
control
Environmental
Monitoring changes:
programs impact on
Larvicides population
dynamics

Knowledge • Behavioral avoidance

on vector • Vector biodiversity
behavioral • Competitive and food web interactions
Not suitable for rural areas ecology • Dispersal
• Mating and sugar-feeding behavior