Update
Research Focus
Malaria vector control: current and future strategies
Willem Takken and Bart G.J. Knols
Laboratory of Entomology, Wageningen University and Research Centre, PO Box 8031, 6700 EH Wageningen, The Netherlands
The recently announced call for malaria eradication
represents a new page in the history of this disease.
This has been triggered by remarkable reductions in
malaria resulting from combined application of effective
drugs and vector control. However, this strategy is
threatened by development of insecticide resistance.
Efforts to develop alternative tools to complement or
even replace insecticide-based vector-control strategies
must continue. Here, an overview is presented of the
novel vector-control tools expected to contribute to
malaria eradication.
Integrated approaches to malaria control
In the recent World Malaria Report [1], falls in malaria
deaths of 50% or more are reported for Eritrea, Rwanda,
and São Tomé and Principe between 2000 and 2006.
Similar results are reported from The Gambia, Kenya,
Zambia and Zanzibar. This is the first time that the
incidence of malaria has declined in highly endemic
countries since the WHO policy change of 1972, when
the global malaria-control strategy based on indoor
residual spraying (IRS) was formally abandoned. In the
countries mentioned above, the widespread use of long-
lasting insecticide-treated bednets (LLITNs) and treat-
ment of uncomplicated Plasmodium falciparum malaria
with artemisinin-based combination therapies and inter-
mittent preventive treatment for infants and pregnant
women have contributed to the reported reductions in
malaria. It is this remarkable result, stemming from the
integration of several intervention tools coupled with new
prospects of effective malaria vaccines, that has led to the
resolve of Bill and Melinda Gates to call for a new global
initiative for the eradication of malaria [2].
Recently, Brian Greenwood [3] considered the implica-
tions of this paradigm shift for malaria research and
suggested that drug-based strategies, coupled with
malaria vaccine development and vector control (mainly
based on the use of insecticides), should now receive high-
est priority to achieve this ambitious goal. Greenwood
makes valuable suggestions for research areas that need
to be addressed based on recent developments. When
considering vector control, the astounding success of insec-
ticide-treated bednets, coupled with the renewed introduc-
tion of IRS, demonstrates that vector control has a
substantial part to play in the eradication of this disease,
and it is suggested that efforts be undertaken to enhance
the development of new insecticides, in addition to altern-
atives to overcome the inevitable evolution of resistance in
vector populations [4].
Corresponding author: Takken, W. (willem.takken@wur.nl).
The historic successful eradication of malaria in various
parts of the world was achieved chiefly by vector control [5],
and this indicates that renewed efforts in this field, other
than the current insecticide-based strategies, should be
considered a central aspect of the new malaria eradication
strategy. In the Roll Back Malaria (RBM) programme of
the WHO, vector control is based mainly on the continu-
ation and upscaling of insecticide-based strategies. How-
ever, given the increasing prevalence of mosquito
resistance against the currently used chemicals, the need
for development of new insecticides has high priority, and
the Innovative Vector Control Consortium is focusing on
the development of new public health insecticides and
innovative formulations or mixed application of existing
ones [6]. This notwithstanding, it seems unlikely that a
new class of insecticides will be ready for field use soon and,
even if this happens, resistance is likely to develop within a
short time of broad-scale application, caused by the se-
lective pressure put on the vector population [7]. It, there-
fore, seems likely that the continued practice of net
impregnation with synthetic pyrethroids is endangered
and finite [4]. A recent expert consultation on vector control
recommends the urgent development of alternative tools
for vector control in view of the rapid development of
insecticide resistance (K. Aultman, personal communi-
cation). A multitude of novel malaria vector-control tools
has been developed in recent years, and several of these are
at an advanced stage, nearing broad-scale implementation
(Table 1).
Recognizing that vector control has been the only effec-
tive approach that has led to lasting malaria eradication,
we propose that new initiatives be developed to enable the
rapid implementation of the aforementioned novel vector-
control tools. Recently, successes were reported with Bacil-
lus thuringiensis israelensis (Bti) for larval control [8].
Resistance against this biological pesticide is unlikely to
develop because it consists of four endotoxins that cause
the death of mosquitoes. Because Bti is also highly se-
lective, targeting mostly a limited number of families of
blood-feeding Diptera, the prospect of wide-scale environ-
mental side-effects from the use of this biocide seems
negligible. Novel adult-control tools include entomopatho-
genic fungi, insect-pathogenic viruses, push–pull systems
based on chemical ecology, the introduction of genetically
engineered mosquitoes and the sterile insect technique
(SIT). A field study with the entomopathogenic fungus
Metarhizium anisopliae, conducted in Tanzania, has
demonstrated the strong impact of this fungus on adult
house-frequenting anophelines and indicated that this
method can be effective by scaling up the areas covered
[9]. Insect-killing viruses are another group of natural
enemies of mosquitoes that seem highly effective because
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Update Trends in Parasitology Vol.25 No.3

Table 1. Overview of vector-control tools for malaria control

Method
House improvement
Indoor residual spraying (IRS)
Long-lasting insecticide-treated
nets (LLITNs)
Entomopathogenic fungi
Entomopathogenic viruses
Removal trapping and/or
confusion techniques
Spatial repellents
Genetically engineered
mosquitoes
Sterile insect technique
Environmental modification
(e.g. larval habitat modification) development (e.g. stream clearing)
Bacillus thuringiensis
israelensis or Bacillus
sphaericus
Insect-growth regulators
Predators (fish)
a
Numbers in the last column correspond with those in the decision chart in Figure 1.
Mechanism State of development Refs Corresponding
no. in Figure 1 a
Prevention of house entry Can be used at any time [20] 1
Repellent and/or killing of adult Widespread use; recently reintroduced in Africa [21] 2
mosquitoes
Repellent and/or protection against Widespread use, part of the RBM programme [22] 3
biting; killing of adult mosquitoes
Slow killing Field testing in progress [9] 4
Killing Laboratory, needs (semi) field testing [10] 5
Reduction of mosquito abundance Odour baits and traps in development [23] 6
Prevention against biting Can be used; improvements under development [12] 7
Prevention of parasite development in Under development; no field testing done [13] 8
mosquito; reduction of longevity
Reduction or eradication of mosquito Field tests under way in Sudan [24] 9
population
Prevention of oviposition and/or larval Can be implemented in specific environments [25] 10
Killing of larvae Needs to be implemented on a large scale [8] 11
Killing of larvae Ready for implementation [26] 12
Killing of larvae Can be implemented in specific environments [27] 13

they are species specific, non-toxic to humans and easy to
distribute [10]. Studies with odour baits and repellents are
at an advanced stage of field testing, and the results
indicate that mosquitoes can be attracted to odour-baited
targets, opening the way for the development of a push–
pull system [11]. Odour baits are likely to be acceptable to
communities in disease-endemic regions because these
devices are unlikely to infringe on daily life, unlike other
vector-control tools. Spatial repellents can be exploited
effectively to reduce the number of mosquitoes entering
houses [12]. Several, albeit laboratory-based, successes in
the development of genetically modified anopheline mos-
quitoes (GMMs) have been reported in recent years. These
mosquitoes carry effector genes, the expression of which
leads to impaired development of malaria parasites, ren-
dering the mosquitoes refractory to Plasmodium [13]. If
these GMMs can be used to replace natural mosquito
populations, the ‘new’ mosquito populations would be
refractory to malaria parasites and, hence, cease to trans-
mit them. To date, no field experiments have been con-
ducted with GMMs to measure fitness and population
replacement in pilot experiments, and the technique,
therefore, might not be available soon. Finally, SIT was
developed >50 years ago to eradicate screw-worm flies
from the USA and Central America. Pilot studies with
mosquitoes are currently being undertaken in the Sudan,
with assistance from the International Atomic Energy
Agency [14]. Should this be successful, SIT can be added
to the arsenal of tools available for vector control, particu-
larly in areas that are relatively isolated and have a single
vector species.
With the exception of Bti, which is already used success-
fully in some areas, the other tools mentioned are in an
advanced state of development and, with additional fund-
ing, several could be commercialized within a short time.
To achieve this, however, several outstanding questions
need to be resolved. These include production methods,
formulation and tools for application. For example, appro-
priate, long-lasting formulations and a simple application
method of entomopathogenic fungi are needed before this
technology can be widely applied. In the same vein, odour
baits and repellents require long-lasting slow-release for-
mulations that do not interact with the environment. Many
of the new tools have not been tested in large field trials,
and their overall impact on disease transmission or con-
tribution to eradication can only be guessed or modelled at
best. Clearly, field-based trials in which the impact of these
vector-control tools on public health is properly measured
are needed before they can be adopted to complement the
malaria-control tools currently in use. These trials must
also consider operational challenges and acceptability by
the variety of stakeholders.
Two historically proven vector-control tools should also
be considered: species sanitation and house improvement.
Both methods have a well-accepted record of efficacy and
long-lasting effect. Indeed, in Indonesia, the environmen-
tal changes that led to periodic drainage of rice fields and
cleaning of fish ponds contributed to the disappearance of
malaria on Java [15]. Today, 80 years after implementa-
tion, these effects are still visible. Elsewhere, house im-
provement by screening has also led to substantial
reductions in malaria. There is renewed interest in these
methods because they are likely to be acceptable to end
users that see them as improving their quality of life.
Because it is becoming increasingly clear that malaria
control can be most effective if several tools are applied
simultaneously, complementing each other [16], we pro-
pose that for each specific malaria setting, those respon-
sible for the execution of malaria control consider a
package of tools in which the most effective ones applicable
to that setting are integrated. Indeed, the renewed atten-
tion to integrated vector management enables the integ-
ration of several of these tools to achieve an even stronger
impact [17]. Public health workers developing effective
malaria intervention tools can use a decision chart in
which the (proven) effective tools are presented, leading
to the best outcome of malaria control (Figure 1). This chart
can be viewed as a toolbox, to which new and effective

102
Update
Figure 1. Decision chart for integrated vector management (the numbers refer to the tools presented in Table 1).
components can be added. The novel tools presented in
Table 1 will, over time, become part of the decision chart.
Importantly, entomologists need to work jointly with
medical doctors, epidemiologists and sociologists in design-
ing the most effective intervention strategy.
Entomological tools aimed at the destruction of malaria
vectors will directly cause a reduction in mosquito biting
and, hence, in disease transmission. Medical tools (i.e. drugs
and vaccines) coupled with sociological approaches remain
essential for the successful road to malaria eradication and
can be implemented jointly with the proposed vector-control
tools. This is clearly illustrated by, for example, the current
widespread use of LLITNs, IRS and combination therapies
[18]. We argue that vector-control strategies, which are
historically of vital importance, should be considered to play
a more prominent part in the eradication of malaria and that
these tools be integrated with other, medicine- and/or
vaccine-based, strategies that are currently applied. After
all, the basic reproductive number of malaria seems particu-
larly sensitive to small changes in the entomological
parameters biting intensity and mosquito survival [19].
Because these parameters are directly affected by the pro-
posed control strategies, vector control should become an
integral part of the newly launched programme for the
eradication of malaria.
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Research Focus
The merozoite has landed: reticulocyte-binding-like
ligands and the specificity of erythrocyte recognition
Julian C. Rayner
Sanger Institute Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge,
CB10 1SA, UK
Plasmodium falciparum erythrocyte invasion depends
on several imperfectly understood multiprotein families.
Two recent papers have shifted our understanding of the
P. falciparum reticulocyte-binding-like family to the level
of individual amino acids by identifying an erythrocyte-
binding domain in one ligand and showing that poly-
morphisms in another can change the species specificity
of erythrocyte binding. Erythrocyte invasion might be
even more complex and harder to target than previously
thought.
So many ligands, so little time
Plasmodium falciparum merozoites are essentially eryth-
rocyte-invasion machines. As the only extracellular stage
of the asexual P. falciparum blood cycle, merozoites are
literally blown out of the host erythrocyte in which they
formed [1] and thrown into the peripheral circulation to
find a new erythrocyte to invade to start the asexual cycle
anew. The invasion process is not simple, and the invasion
of human erythrocytes by P. falciparum merozoites is
particularly complicated. Plasmodium vivax, a distant
cousin of P. falciparum, depends entirely on the interaction
between the Duffy-binding protein and its erythrocyte re-
ceptor, the Duffy-antigen receptor for chemokines (DARC),
to catalyze invasion, making Duffy-negative humans who
do not express DARC on the erythrocyte surface resistant
to P. vivax infection [2] (although a handful of Duffy-
negative individuals have been observed with what seem
to be P. vivax infections [3]). By contrast, there is no single
human genotype that is resistant to P. falciparum inva-
sion, and the P. falciparum genome contains several multi-
gene families that seem to have redundant and
overlapping functions during the invasion process
(reviewed in Refs [4,5]).
One of these families is part of the reticulocyte-binding-
like (RBL) superfamily, members of which have been found
in every Plasmodium species studied to date. The first
Corresponding author: Rayner, J.C. (jr9@sanger.ac.uk).
104
Trends in Parasitology Vol.25 No.3
26 Yapabandara, A.M. and Curtis, C.F. (2004) Control of vectors and
incidence of malaria in an irrigated settlement scheme in Sri Lanka by
using the insect growth regulator pyriproxyfen. J. Am. Mosq. Control
Assoc. 20, 395–400
27 Chandra, G. et al. (2008) Mosquito control by larvivorous fish. Indian J.
Med. Res. 127, 13–27
1471-4922/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.pt.2008.12.002 Available online 23 January 2009
RBLs cloned were the P. vivax reticulocyte-binding
proteins [6], but it was only with the cloning of a homologue
in the mouse parasite Plasmodium yoelii that it became
apparent that the RBL superfamily spanned the long
evolutionary distances between rodent and human Plas-
modium parasites [7]. The P. falciparum genome contains
multiple RBLs and, as is common for P. falciparum genes
worked on by multiple groups, these genes have accumu-
lated several different acronyms over the years. The acro-
nym that is now in the widest use is PfRH (P. falciparum
reticulocyte-binding protein homologue), and for clarity, it
is hoped that this will now become the standard term.
Many publications have investigated PfRHs in recent
years (reviewed in Ref. [5]) but, in part because of their
sheer unmanageable size (ranging from 220kDa for PfRH4
to 350kDa for PfRH2b), progress has been slow at the
protein level. Two recent papers have now shifted the
resolution of our understanding of PfRHs to the level of
individual amino acids.
Finding a binding domain in a needle
Gao and colleagues [8] used a heterologous expression
system to identify for the first time a specific domain of
PfRH1 that binds to erythrocytes. By breaking down
PfRH1 into smaller fragments and expressing each one
on the surface of COS cells, they identified a single domain
near the PfRH1 N terminus that enabled human erythro-
cytes to adhere to the surface of the transfected COS cells.
Crucially, interaction between this domain and erythro-
cytes was dependent on sialic acids on the erythrocyte
surface but was resistant to pre-treatment of the erythro-
cytes with trypsin, which is identical to what was already
known about the interaction between native PfRH1 and
human erythrocytes [9]. The same PfRH1 subdomain
bound erythrocytes when expressed and purified from
Escherichia coli, and circular dichroism spectroscopy
showed that the E. coli-expressed fragment was rich in
a-helices. This and other features of the PfRH1 sequence
around the binding domain indicate the formation of coiled
coils projecting out from the merozoite surface to interact