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Updates on Malaria

Din Syafruddin
Department of Parasitology, Faculty of Medicine, Hasanuddin University, Makassar 90245
Eijkman Institute for Molecular Biology, Jalan Diponegoro 69, Jakarta 10430, Indonesia
Presented on Annual Meeting of PDGKI, Makassar 25 April 2015

Every day is Malaria Day


April 25th marks World Malaria Day, a day to focus on the plight caused by malaria and also the efforts made to control the disease.
However, every day is malaria day for half the world, as the disease is a part of their everyday lives. Likewise, for the scientists and
organisations working to control and eliminate the disease, malaria is an everyday nemesis. The Every Day is Malaria Day series features
some of the research carried out every day around the world on malaria.

Malaria J for World Malaria Day

Introduction
Efforts against malaria has yielded dramatic progress over
the last 10-15 years. The scale up of malaria control
intervention between 2001-2012 resulted in an estimated 3.3
million lives saved (WHO, 2014).
Malaria-control and management strategies include
chemotherapy for patients, indoor residual spraying (IRS),
and long-lasting insecticide treated nets (LLINs) to reduce
mosquito populations
The spread of parasite and anopheline vector resistance and
lack of a efficacious malaria vaccine renew emphasis on
development of innovative preventive tools

Global Malaria and Endemicity


(WHO malaria report 2014)

Global Distribution of Insecticide resistance

WHO Malaria Report 2014

Life Cycle of the malarial parasite


Plasmodium spp

Pathogenic basis of malaria

Miller et al, (2002)

Parasite resistance to Anti malarial drugs

Available antimalarial drugs

cinchona alkaloids
4-aminoquinolines
amodiaquine
8-aminoquinolines
tafenoquine
4-quinoline methanols
9-phenanthrene methanols

antifolic drugs
proguanil
sulpha drugs

quinine
chloroquine,
primaquine,
mefloquine
halofantrine
pyrimethamine,
a) sulphones;

dapsone
b) sulphonamides;

sulphadoxine, sulfalene
sesquiterpene lactones

a) artemisinin,

History of antimalarial drug


resistance
Introduced

Quinine
Chloroquine
Proguanil
Sulphadoxinepyrimethamine
Mefloquine
Atovaquone
Artemisinin

First Report
of Resistance

1632
1945
1948
1967

1910
1957
1949
1967

278
12
1
0

1977
1996
2000

1982
1996
2009

5
0
9

Difference
(years)

Mechanism for the antimalarial drug


resistance (Borst and Ouellette, 1995)
a. Alteration in drug transport
Quinoline antimalarials
Artemisinin (?)

b. Alteration in binding affinity to enzyme


Antifolates, Sulpha drugs,
Coenzyme Q analogues such as atovaquone

EIJKMAN INSTITUTE

Menard et al, 2013

Menard et al, 2013

Extrachromosomal genomes
in the malarial parasites
CO I

CO III

6kb

Cytb

Predicted Secondary Structure of the putative


apocytochrome b of Plasmodium berghei
QoL144S

WLC

Q I VP

Cytoplasmic

E
W
G
T
Q
H
I
I
V
YS
G
L
Y
Y
Y
F
A
Y
R
T
Y
L
G131, N245, F264 Mucidin
T
N 250
S
FP
E
Y
V
V
A
M
L
I
I141, T142 Stigmatellin
M
V
S
W
Q
KL
Y268N
TPD
E
S
I
F123, G131, G137, Myxothiazol
T
I
A
P
G M133I G
I
Y268C
N
K
S
P
W
M133, L144, I258, F267,
W
50 Y
D
R
C
P
P V284FS
R
D
F
F
Y268, L271, K272, P275,
Q
H
K
P
R
S
L
I
F
G280, L283, V284
S
F
N
A
V
V
Y
I
QL
L I P
L V
GA
HM
C
Y I G H L F
L
L
Y
V
F G
Atovaquone
G
G
A
I
GV F
T
I
AF T
GT
R FL
V I I
L FP S I Q
LQ I
LW L
A LS
A
V
F
A
F
N27, G33, L217 Antimycin AI F
I L
I
I I L
L SLQ
AV L
Y S
F VL F
L
F
L
FA I
FF S
I C V F
T Y
L
C
F
I I LG
I14, L215 Diuron
M F
L
F
LI I
L I G
L F
GS
HL
L
W
L
I
H F I
G
F
NN
I
A
I
IS
LS
I
F
Y
W
F
L
L
G
N
E
R
P
S
V
Q
Q
L
LW
F
H
K
G
F
N
N
R
P
S
I
L
V
N
L
N
L
K
Y
L
D
H
N
KT
P
E
L
Y
L
300
S
H YD
R
Y
C
T
S
2
SYL
G
A
P
T
Y
M
L
1
S
I
T
L
Y
N
S
0
N
I
N
F
N
Y
I
S
Q
0
V
L HT K V L N I S N
P
P
Q
F KM
A
LG
I
N
2
YD T A LK I P F Y
0
0
A
L
V
G I L
L
W V N GI
Y T T S PS
S

Qi

1.
2.
3.

Qo

NH

Qi

Budimulja et al, 1997. Mol. Biochem. Parasitol, 84:137-141.


Syafruddin et al 1999. Mol Biochem. Parasitol, 104:185-194.
Siregar et al, 2008. 2008. Parasitol Int, 57:229-232.

Matrix

COO

Mosquito resistance to insecticide

Available Insecticides
I. Sodium channel modulators
1. Pyrethroids: permethrin
2. Pyrethrin: pyrethrin
3. DDT
II. GABA-gated chloride channel inhibitors
1. Cyclodione organochlorine: Chlordane, endosulfan,
gammaHCH
2. Phenylfirazole (Fiproles): Ethiprole, Fipronil
III. Acetyl choline esterase inhibitors:
1. Carbamates: Aldiocarb, bendiocarb etc
2. Triazemates
3. Organophosphate: Acephate, temephos, malathion

Target site mutations


Sodium channel (VGSC) gene mutations confer
resistance to DDT and pyrethroid.

Alleles: Wild type at codon 1014 (TTA-Leucine) (kds)


West type resistance (TTT-Phenilalanine) (kdr-w)
East type resistance (TCA-Serine) (kdr-e)

Molecular analyses of GABA Gene


Anopheline mosquitoes from Indonesia
Study Sites (Province)

North Molluca
Molluca
North Sumatera
Central Java (Purworejo)

Lampung

Bangka Belitung
East Nusa Tenggara (Sumba)

Species

An punctulatus
An punctulatus
An. farauti
An vagus
An sundaicus
An vagus
An aconitus
An barbirostris
An balabacensis
An vagus
An sundaicus
An. barbirostris
An kochi
An sundaicus
An letifer
An vagus
An sundaicus
An subpictus
An tesselatus
An minimus
An flavirostris
An indefinitus
An kochi
An maculatus

(n)
= 97

3
3
5
2
2
1
7
7
5
6
23
1
1
6
2
3
2
9
1
1
2
3
1
1

GCA
WT
3(100%)
3(100%)
4(80%)
2(100%)
2(100%)
0
5(71%)
6(86%)
5(100%)
4(67%)
22(96%)
0
0
6(100%)
2(100%)
3(100%)
2(100%)
9(100%)
1(100%)
1(100%)
2(100%)
3(100%)
1(100%)
1(100%)

(%)
(TCA)
RT
0
0
0
0
0
1(100%)
2(29%)
1(14%)
0
2(33%)
1(4%)
1(100%)
1(100%)
0
0
0
0
0
0
0
0
0
0
0

Samples collected from collaboration with Indonesia Goverment and


Sumba SPIRIT Study supported by GATES Foundation

(GGA)
RT
0
0
1(20%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

Molecular analyses of ace1 Gene


Anopheline mosquitoes from Indonesia

(%)

Study Sites

G119
wild type

119S
Resistance Type

Lampung

100

Purworejo

100

North Molluca

100

Bangka Belitung

100

Samples collected from collaboration with Indonesia Goverment and


Sumba SPIRIT Study supported by GATES Foundation

Possible innovative tools

Spatial Repellent (SR)


Spatial Repellent is one of the potential tools to explore.
Different from IRS/LLIN, SR does not require a tarsal
contact of the vector to chemically-treated surface/space.
The core mechanism of action of an SR approach is
inhibition of vector entry into a treated space by a
chemical vapor.

IRRITANCY
TOXICITY

REPELLENCY

Wainyapu

Umbungedo

All villages

Cluster 1
(W1)

Cluster 2
(W2)

Cluster 3
(U1)

Cluster 4
(U2)

Cluster
1+4

Cluster
2+3

90%
Active+
10%
placebo

10% Active+
90% placebo

10% Active+
90% placebo

90% Active+
10%placebo

Active
clusters

Placebo
clusters

Household

108

114

115

108

216

Active:placebo

(98:10)

(11:103)

(12:103)

(98:10)

(196:20)

229
(23:206)

Population

368

523

596

633

1001

1119

Samples

42

44

43

41

83

87

Malaria
incident

26

40

21

31

61

652

602

866

888

1540

1468

0.040

0.066

0.024

0.006

0.020

0.042

Incidence density
Person-week
Incidence
rate

Without clustering effect


RR (95%CI)

With clustering effect

0.484 (0.3140.746)

Wainyapu

Umbungedo

All villages

Cluster 1
(W1)

Cluster 2
(W2)

Cluster 3
(U1)

Cluster 4
(U2)

Cluster
1+4

Cluster
2+3

90%
Active+
10%
placebo

10% Active+
90% placebo

10% Active+
90% placebo

90% Active+
10%placebo

Active
clusters

Placebo
clusters

0.619

0.909

0.488

0.122

0.373

0.701

Cumulative
incidence
Proportion
of
Incidence

Without Clustering effect


RR (95%CI)

0.533 (0.390
0.727)

Un-adjusted
2

18.37 (p < 0.001)

With Clustering effect


Cluster-specific adjusted

2.356 (p = 0.124)

Cumulative attack rates of An. sundaicus pooled by


village (indoor only)
Cumulative Attack in Wainyapu (W1+W2)
Indoor Only

Cumulative Density / Person

Cumulative Attack in Umbungedo (U1+U2)


Indoor Only

70

3.5

60

50

2.5

40

Cumulative Density / Person

30
20

10

0.5

Week
Indoor - A.I

1.5

Indoor - Placebo

Wilcoxon Paired Test: Statistically different


densities between AI vs. Placebo (p=0.0342)

Week
Indoor - A.I

Indoor - Placebo

Wilcoxon Paired Test: No Significant


difference in densities between AI vs.
Placebo (p=0.1562)

CMLE Rate Ratio: 32.9% reduction in attack rate for a


person inside an active coil house (p=0.04388)
CMLE Rate Ratio: Not applicable

1. Active mosquito coil in the homes of subjects was


associated with a significant protective efficacy (52%)
against new infections by plasmodial parasites
2. Reduction in mosquito attack rate might be associated
with reduction in malaria attack rates

Spatial Repellent is potential


tool to circumvent mosquito
resistance

Malaria and Nutrition

Association between malaria and malnutrition


Is severe malnutrition protective against of malaria?
a) malaria parasites in the blood are known to increase
after a re-feeding;
b) the findings of autopsy studies; and
c) studies on trace elements and C - reactive protein in
malaria.
The data could not be proven in later study. Therefore,
the relationship is not clearly understood!
Facts:

Innovations and Recent Developments in


Malaria Prevention
Intermittent Preventive treatment in Pregnant women (IPTp)
Intermittent Preventive treatment in Children (IPTc)

Study team
1. Eijkman Institute for Molecular
Biology, Jakarta, Indonesia
Din Syafruddin*
Krisin Chand
Puji BS Asih
Christian Nixon
Christina Nixon
2. Eijkman-Oxford Clinical Research
Unit, Jakarta, Indonesia
Kevin Baird
Siti Nurlaela
3. University Hasanuddin, Makassar,
Indonesia
Din Syafruddin*
Isra Wahid
Hasanuddin
Joko Hendarto
Dian Sidik

4. Sumba Foundation, Indonesia


Claus Bogh
5. SOS Indonesia
Michael Bangs
6. Department of Preventive Medicine
and Biometrics,Uniformed Services
University of the Health Sciences,
Bethesda, MD USA
John Grieco
Nicole Achee

Thank you