Nature Reviews | Disease Primers

Manuscript number NRDP_16_048 Philips 20|7|17

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Fig 1

Human host Mosquito vector

Sporozoite
30–60 Salivary
minutes gland
Prophylactic
Hepatocyte treatment

First site
of invasion
(all species)

Liver Merozoites 10–14

6–7 days||
days*
Red blood cell
Oocyst
Schizont Gut
Ookinete
Symptomatic
stage
Transmission Zygote
Symptomatic blocking
Asexual Ring treatment treatment — Female
reproductive stage prevents macrogamete
Male
stages resistance spread microgamete
4–8 days‡
Trophozoite Gametocytes
3–10
days§

Nature Reviews | Disease Primers

 Nature Reviews | Disease Primers
Manuscript number NRDP_16_048 Philips 20|7|17

Fig 2

Malaria endemicity
Countries endemic
for malaria, 2015
Countries endemic in 2000,
no longer endemic in 2015
Countries not endemic
for malaria, 2000
Not applicable
P. falciparum prevalent
P. vivax prevalent
Nature Reviews | Disease Primers

Fig 3
Merozoite
CyPPA AMA1
Coat

Dense Nucleus RON2

granule PfRipr
Rhoptry PfPh5
Basigin
Microneme
Red blood cell

PfATP4

Hb Plasmodium
Cipargamin mitochondria
SJ733
Heme
(toxic) PfDHFR
CHQ CHQ

Haemozoin PfCRT PYR

(non toxic) P218
Cycloguanil Food
DMS265 vacuole

ATO Pfcytb PfDHODH

PfPI(4)K
Golgi Current drugs
Drug candidates
Enzymatic drug
target
MMV048 Resistance marker

Nature Reviews | Disease Primers

 Nature Reviews | Disease Primers
Manuscript number NRDP_16_048 Philips 20|7|17

Fig 2

Malaria endemicity
Countries endemic
for malaria, 2015
Countries endemic in 2000,
no longer endemic in 2015
Countries not endemic
for malaria, 2000
Not applicable
P. falciparum prevalent
P. vivax prevalent
Nature Reviews | Disease Primers

Fig 3
Merozoite
CyPPA AMA1
Coat

Dense Nucleus RON2

granule PfRipr
Rhoptry PfPh5
Basigin
Microneme
Red blood cell

PfATP4

Hb Plasmodium
Cipargamin mitochondria
SJ733
Heme
(toxic) PfDHFR
CHQ CHQ

Haemozoin PfCRT PYR

(non toxic) P218
Cycloguanil Food
DMS265 vacuole

ATO Pfcytb PfDHODH

PfPI(4)K
Golgi Current drugs
Drug candidates
Enzymatic drug
target
MMV048 Resistance marker

Nature Reviews | Disease Primers

 Nature Reviews | Disease Primers
Manuscript number NRDP_16_048 Philips 20|7|17

Fig 4
Plasmodium falciparum

U
FM
ER
U

LR LT LS
ET ES

0 12 24 36 48

Development (hours)
FM

ER
LS
LR ES
U ET
LT O
U
Plasmodium vivax

10 μm
Nature Reviews | Disease Primers

Fig 5
Research Product development (WHO Pesticide Evaluation Scheme) Access

Research categories Phase I (Lab trials) Phase II (Small-scale Phase III (Large-scale Registration
(hut) trials) (field) trials)

Re-purposed crop protection development LLIRS/re-purposed LLIN Combination LLIN Interceptor G2 K-Othrine Polyzone
compounds, including fungicides (2019–2020) active ingredients from (BASF, Sumitomo) Chlorfenapyr/ (Bayer/IVCC,
crop protection (Bayer, BASF, α-cypermethrin since 2013)
Sumitomoa; 2020–2022) (BASF/IVCC)
Novel target-based discovery (Foundation
for the NIH) Non-pyrethroid insecticide- LLIN Olyset Duo:
treated durable wall lining Momfluorothrin
Pyriproxyfen/ (Sumitomo,
permethrin since 2014)
Resistance-breaking
Resistance-breaking net formulations (Sumitomo/IVCC,
net formulations
2017–2018)
VECTA001
Bivalent carbamates (U. of Florida, USA); Novel AI (Syngenta/IVCC) Chlorfenapyr IRS Actellic CS LLIRS
Indoxacarb + α-cypermethrin for LLINs "Project Venus' (BASF/IVCC; (Syngenta/IVCC,
(LSHTM, PAMVERC) Novel AI (Sumitomo/IVCC) (Akzo Nobel) since 2013) since 2012)

Re-purposed compound Novel compound Bed net formulation Bivalent carbamates

Nature Reviews | Disease Primers

 Nature Reviews | Disease Primers
Manuscript number NRDP_16_048 Philips 20|7|17

Fig 4
Plasmodium falciparum

U
FM
ER
U

LR LT LS
ET ES

0 12 24 36 48

Development (hours)
FM

ER
LS
LR ES
U ET
LT O
U
Plasmodium vivax

10 μm
Nature Reviews | Disease Primers

Fig 5
Research Product development (WHO Pesticide Evaluation Scheme) Access

Research categories Phase I (Lab trials) Phase II (Small-scale Phase III (Large-scale Registration
(hut) trials) (field) trials)

Re-purposed crop protection development LLIRS/re-purposed LLIN Combination LLIN Interceptor G2 K-Othrine Polyzone
compounds, including fungicides (2019–2020) active ingredients from (BASF, Sumitomo) Chlorfenapyr/ (Bayer/IVCC,
crop protection (Bayer, BASF, α-cypermethrin since 2013)
Sumitomoa; 2020–2022) (BASF/IVCC)
Novel target-based discovery (Foundation
for the NIH) Non-pyrethroid insecticide- LLIN Olyset Duo:
treated durable wall lining Momfluorothrin
Pyriproxyfen/ (Sumitomo,
permethrin since 2014)
Resistance-breaking
Resistance-breaking net formulations (Sumitomo/IVCC,
net formulations
2017–2018)
VECTA001
Bivalent carbamates (U. of Florida, USA); Novel AI (Syngenta/IVCC) Chlorfenapyr IRS Actellic CS LLIRS
Indoxacarb + α-cypermethrin for LLINs "Project Venus' (BASF/IVCC; (Syngenta/IVCC,
(LSHTM, PAMVERC) Novel AI (Sumitomo/IVCC) (Akzo Nobel) since 2013) since 2012)

Re-purposed compound Novel compound Bed net formulation Bivalent carbamates

Nature Reviews | Disease Primers

 Nature Reviews | Disease Primers
Manuscript number NRDP_16_048 Philips 20|7|17
Fig 6
Preclinical development Clinical development

GMZ2 (EVI‡, UKT, PfPEBS (Vac4All‡, IP,

EBA-Rh MSP3 [181-276]
RH5.1/ AS01 NMRC-M3V-Ad-Pf5 SSI, ASH, AMANET, Sentinext
(WEEBA-RhHI/ (AMANET, EVI, CHUV,
(U. Of Oxford, UK) (NMRC) NHRC, CNRFP, LSHTM, Therapeutics,
Gennova) Bamako U., IP, CNRFP)
MUK, MRCG) EVI, CHUV, NIMR)

Full-length MSP1 PfAMA1-DiCo SE36 (SERA-5) EBA 175.R2

(U. Heidelberg, D) (INSERM, F) (Osaka U. Japan) (NIAID, USA)

Novel B cell targets

(Seattle Biomed, JHU, Polyepitope DNA P27A/PFF0165c
NIAID, WRAIR, EP 1300 (NIAID) (CHUV)
NMRC, Attreca)

ChAd63/MVA
Novel T cell targets (EBA175/)Rh5 PfSPZ-CVac ME-TRAP (U. of Oxford‡, M3V.Ad.PfCA
(NIAID) (NIAID) (Sanaria, Inc.) EVI, MRCG, CNRFP, (USAMMRC)
P. falciparum

KMRI, UCAP)

DNA/ChAd63 (CS, eeRTS,S; delayed

PfCelTOS FMP012 SAPN nanoparticle RTS,S/AS01* ppRTS,S/AS01*
AMA1, or ME-TRAP) fractioning third
(WRAIR) CSP (WRAIR) (GSK‡ and PATH) (GSK‡ and PATH)
(NMRC, U. of Oxford) dose (GSK‡ and PATH)

ChAd63/MVA PfSPZ-GA1
ME-TRAP+Matrix (Sanaria, Inc.,
(U. of Oxford, UK) U. Leuden)

Pfs25-IMX313 Pfs 48/45 and CSP Pfs25-AlMV VLP PfSPZ

(U. of Oxford, UK) mAb (PATH) (FhCMB) (Sanaria, Inc.)

Pfs 48/45 Pfs25-EPA +

(Radboud U., Pfs230-EPA
NL; KCMC) (NIAID)

PAMCPH/PlacMalVac PRIMVAC
(U. of Copenhagen, (PRIMALVAC)
DK) (INSERM)
P. vivax

PvDBP3-5 VMP002/PvCSP ChAd63/MVA PvDBP

(WEHI) (WRAIR) (U. of Oxford, UK)

Blood stage Pre-erythocytic Transmission Protection of the foetus

Nature Reviews | Disease Primers

Fig 7
a b
NPC1161B
(Mississippi)
Tafenoquineb,d
P218 (GSK/MMV,
GSK030 Cipargamin GSK/US
(GSK) AN13762 (Biotec
(KAE609)b Army)
(Anacor) Thailand) MMV
GSK607 (Novartis/MMV)
KAF156b (390)048b
(GSK) DDD498 Methylene Blue/AQ (MMV/UCT)
(Novartis/
PA92 (Merck/Dundee) (Heidelberg)
MMV) DSM265b
(Drexel/ UCT943 ACT-451840 (Takeda/MMV,
UW/GNF) (UCT) (Actelion) UTSW/UW/
Monash)

MK4815 DSM421
(Merck) (Takeda,
UTSW/UW/
MMV253 Dihydroartemisinin piperaquinea Paediatric
Monash)
(Zydus Cadila) (Sigma-Tau/Pierre Fabre)
JPC3210 Ferroquine/Artefenomel (OZ439)b (Sanofi/MMV)
(Jacobus) N-tert butyl Isoquine (LSTM/Liverpool/GSK)
Artemisinin naphthoquinea (Kunming Pharma Co.)
Fosmidomycin Piperaquine (Jomaa Pharma/GmbH)
Artemether sub-lingual sprayc (MRC/Suda)
Relapse prevention Chemoprevention Co-trimoxazole (ITM Antwerp)
Asexual blood stages Asexual blood stages SJ(557)733b (St Jude/Eisai/MMV)
Transmission reduction Artemisone (UHKST)
Asexual blood stages
Transmission reduction Relapse prevention CDRI 9778 (CDRI)
Chemoprevention SAR97276 (Sanofi)
Asexual blood stages
Chemoprevention AQ13 (Immtech)

Nature Reviews | Disease Primers

 Nature Reviews | Disease Primers
Manuscript number NRDP_16_048 Philips 20|7|17
Fig 6
Preclinical development Clinical development

GMZ2 (EVI‡, UKT, PfPEBS (Vac4All‡, IP,

EBA-Rh MSP3 [181-276]
RH5.1/ AS01 NMRC-M3V-Ad-Pf5 SSI, ASH, AMANET, Sentinext
(WEEBA-RhHI/ (AMANET, EVI, CHUV,
(U. Of Oxford, UK) (NMRC) NHRC, CNRFP, LSHTM, Therapeutics,
Gennova) Bamako U., IP, CNRFP)
MUK, MRCG) EVI, CHUV, NIMR)

Full-length MSP1 PfAMA1-DiCo SE36 (SERA-5) EBA 175.R2

(U. Heidelberg, D) (INSERM, F) (Osaka U. Japan) (NIAID, USA)

Novel B cell targets

(Seattle Biomed, JHU, Polyepitope DNA P27A/PFF0165c
NIAID, WRAIR, EP 1300 (NIAID) (CHUV)
NMRC, Attreca)

ChAd63/MVA
Novel T cell targets (EBA175/)Rh5 PfSPZ-CVac ME-TRAP (U. of Oxford‡, M3V.Ad.PfCA
(NIAID) (NIAID) (Sanaria, Inc.) EVI, MRCG, CNRFP, (USAMMRC)
P. falciparum

KMRI, UCAP)

DNA/ChAd63 (CS, eeRTS,S; delayed

PfCelTOS FMP012 SAPN nanoparticle RTS,S/AS01* ppRTS,S/AS01*
AMA1, or ME-TRAP) fractioning third
(WRAIR) CSP (WRAIR) (GSK‡ and PATH) (GSK‡ and PATH)
(NMRC, U. of Oxford) dose (GSK‡ and PATH)

ChAd63/MVA PfSPZ-GA1
ME-TRAP+Matrix (Sanaria, Inc.,
(U. of Oxford, UK) U. Leuden)

Pfs25-IMX313 Pfs 48/45 and CSP Pfs25-AlMV VLP PfSPZ

(U. of Oxford, UK) mAb (PATH) (FhCMB) (Sanaria, Inc.)

Pfs 48/45 Pfs25-EPA +

(Radboud U., Pfs230-EPA
NL; KCMC) (NIAID)

PAMCPH/PlacMalVac PRIMVAC
(U. of Copenhagen, (PRIMALVAC)
DK) (INSERM)
P. vivax

PvDBP3-5 VMP002/PvCSP ChAd63/MVA PvDBP

(WEHI) (WRAIR) (U. of Oxford, UK)

Blood stage Pre-erythocytic Transmission Protection of the foetus

Nature Reviews | Disease Primers

Fig 7
a b
NPC1161B
(Mississippi)
Tafenoquineb,d
P218 (GSK/MMV,
GSK030 Cipargamin GSK/US
(GSK) AN13762 (Biotec
(KAE609)b Army)
(Anacor) Thailand) MMV
GSK607 (Novartis/MMV)
KAF156b (390)048b
(GSK) DDD498 Methylene Blue/AQ (MMV/UCT)
(Novartis/
PA92 (Merck/Dundee) (Heidelberg)
MMV) DSM265b
(Drexel/ UCT943 ACT-451840 (Takeda/MMV,
UW/GNF) (UCT) (Actelion) UTSW/UW/
Monash)

MK4815 DSM421
(Merck) (Takeda,
UTSW/UW/
MMV253 Dihydroartemisinin piperaquinea Paediatric
Monash)
(Zydus Cadila) (Sigma-Tau/Pierre Fabre)
JPC3210 Ferroquine/Artefenomel (OZ439)b (Sanofi/MMV)
(Jacobus) N-tert butyl Isoquine (LSTM/Liverpool/GSK)
Artemisinin naphthoquinea (Kunming Pharma Co.)
Fosmidomycin Piperaquine (Jomaa Pharma/GmbH)
Artemether sub-lingual sprayc (MRC/Suda)
Relapse prevention Chemoprevention Co-trimoxazole (ITM Antwerp)
Asexual blood stages Asexual blood stages SJ(557)733b (St Jude/Eisai/MMV)
Transmission reduction Artemisone (UHKST)
Asexual blood stages
Transmission reduction Relapse prevention CDRI 9778 (CDRI)
Chemoprevention SAR97276 (Sanofi)
Asexual blood stages
Chemoprevention AQ13 (Immtech)

Nature Reviews | Disease Primers

 Nature Reviews | Disease Primers
Manuscript number NRDP_16_048 Philips 20|7|17

Fig 8
Trimethoprim: part of AQ13b Ferroquineb Cipargamin (KAE609)b Fosmidomycin
Co-trimoxazole (ITM Antwerp) (Immtech) (Sanofi/MMV) (Novartis/MMV) (Jomaa Pharma/
NH2 GmbH)
HN N Cl
O HN N F HO OH
N NH N P
Fe O OH
H2N N O Cl N O
O Cl N Cl N H O N
H

MMV(390)048b Tafenoquineb,c SJ(557)733 DSM265b ACT-451840

(MMV/UCT) (GSK/MMV; GSK/US Army) (St Jude/Eisai/MMV) (Takeda/MMV, (Actelion)
UTSW/UW/Monash)
F3C N CF3 CF3 O
NH2 O
N SF5
N O
N
O HN N
O N
N O NH N
F N N
N O N N F N
HN
O S O NH2 O
N
F N

KAF156 b
Naphthoquine a Artefenomel (OZ439)b Methylene Blue
(Novartis/MMV) (Kunming Pharma Co) (Sanofi/MMV) O (Heidelberg)
O
Cl–
H2N N
N
N OH N S+ N
F O
O
N H O
N
HN O N
NH

Cl N
F

CDRI 9778 P218 SAR97276

(CDRI) (Biotec HO O (Sanofi)
O Thailand) Br–
O O
NH2 OH N S
O O OH S OH
O O
O N N

Br–
O H2N N

Nature Reviews | Disease Primers

Box 4

H
O O

O
H H
O

Nature Reviews | Disease Primers