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Evidence of a hard selective sweep for artemisinin resistant

Plasmodium falciparum
Published Online Artemisinin combination therapies (ACTs) remain haplotype was present at frequencies exceeding 73%
February 1, 2017
the gold standard for the treatment of uncomplicated in northeastern Thailand, southern Laos, and western
S1473-3099(17)30056-7 Plasmodium falciparum malaria, 1 although artemisinin Cambodia. Further, the authors found evidence of
See Articles page 491 resistant P falciparum has been detected in five countries Pfplasmepsin2 amplification only in conjunction with the
in the Greater Mekong subregion (GMS).2 Artemisinin C580Y mutation in western Cambodia and northeastern
resistance is problematic, in that the associated slow Thailand, where Pfplasmepsin2 amplification was
parasite clearance leads to selection for partner drug present in 71% and 100% of isolates, respectively. The
resistance.3 Malaria treatment failure to ACTs containing finding of a dominant artemisinin resistant haplotype
the partner drugs mefloquine and piperaquine has that is associated with partner drug resistance has
already reached alarming levels in areas of the GMS.4 implications for malaria control and ACT resistance
The emergence of ACT resistant P falciparum in the containment strategies.
GMS severely threatens worldwide malaria control. Although the emergence of artemisinin and partner
This threat is underscored by the previous spread of drug resistance in the GMS is well established,4 that a
chloroquine and sulfadoxine-pyramethamine resistant common dominant artemisinin resistant P falciparum
P falciparum lineages from their origins in southeast Asia lineage is spreading should give pause, even if it was
to India and sub-Saharan Africa.5 to be expected. This observed pattern of ACT evolution
Previous evidence suggested that multiple lineages in southeast Asia resembles that of both chloroquine
of artemisinin resistant P falciparum were circulating,4,5 and sulfadoxine-pyrimethamine resistance in the
which led to a focus shift away from a containment past, before the dominant resistant lineage spreading
or firewall approach to elimination only.6 However, as to India and Africa. ACT resistance spread would be
was the case with the emergence of chloroquine and especially devastating in sub-Saharan African which has
sulfadoxine-pyrimethamine drug resistance in the past, approximately 90% of the global malaria burden.2 The
a single parasite lineage probably ultimately dominated findings of Imwong and colleagues’ study suggest that a
in the GMS, before spreading to India and Africa.7 firewall approach of increased malaria control measures
In The Lancet Infectious Diseases, Mallika Imwong and surrounding areas of antimalarial drug resistance should
colleagues8 report the results of testing the hypothesis be reconsidered and could be effective at delaying the
that a single dominant lineage of artemisinin resistant spread of artemisinin resistance. The GMS has been a
falciparum malaria parasites has spread through the persistent source of globally dominant antimalarial
GMS.8 434 P falciparum isolates were collected from resistant P falciparum lineages. We think that these
Myanmar, northeastern Thailand, southern Laos, and findings underscore the importance of containing
western Cambodia in 2008–15. Artemisinin resistance and eliminating malaria in this region. Furthermore,
was examined through PfKelch13 mutations9 and the spread of this presumably selected artemisinin
microsatellite loci flanking PfKelch13.10,11 Resistance to resistant lineage emphasises the urgency of finding a
the partner drug piperaquine was also evaluated by new antimalarial drug, or implementing alternative
amplification of Pfplasmepsin2 gene, a marker recently treatment regimens of the available antimalarial drugs.3
identified.12 Lastly, we recommend careful monitoring for the
Imwong and colleagues provide evidence of a hard PfKelch13 C580Y haplotype in neighbouring countries,
selective sweep of the PfKelch13 C580Y mutation, which as well as India and west and east Africa to identify
has spread from western Cambodia to northeastern further spread of artemisinin resistance should it occur.
Thailand and southern Laos. This evidence of a shared In conclusion, this study fills an important knowledge
origin of C580Y is supported by microsatellite data gap about the evolution of ACT resistance in the GMS.
that revealed a common long haplotype flanking Although the observed evolutionary pattern should
PfKelch13 in C580Y parasite isolates. The long C580Y not be surprising, we anticipate the findings to be

462 Vol 17 May 2017


highly impactful to malaria control policy. Imwong and 5 Miotto O, Amato R, Ashley EA, et al. Genetic architecture of
artemisinin–resistant Plasmodium falciparum. Nat Genet 2015; 47: 226–34.
colleagues provide substantial evidence that history 6 World Health Organization. Strategy for malaria elimination in the Greater
is repeating itself with regard to antimalarial drug Mekong Subregion: 2015–2030. Geneva: WHO; 2016.
7 Mita T, Tanabe K, Kita K. Spread and evolution of Plasmodium falciparum
resistance in the case of ACT resistance. drug resistance. Parasitol Int 2009; 58: 201–09.
8 Imwong M, Suwannasin K, Kunasol C, et al. A molecular epidemiology
observational study of the recent transnational spread of artemisinin
*Elizabeth Hemming-Schroeder, Eugenia Lo resistant P falciparum in the Greater Mekong Subregion. Lancet Infect Dis
University of California at Irvine, Irvine, CA 92697, USA 2017; published online Feb 1.
9 Ariey F, Witkowski B, Amaratunga C, et al. A molecular marker of
We declare no competing interests. artemisinin–resistant Plasmodium falciparum malaria. Nature 2014;
505: 50–55.
Copyright © The Author(s). Published by Elsevier Ltd. This is an Open Access
10 Talundzic E, Okoth SA, Congpuong K, et al. Selection and spread of
article under the CC BY license.
artemisinin–resistant alleles in Thailand prior to the global artemisinin
1 WHO. Guidelines for the Treatment of Malaria. 3rd ed. resistance containment campaign. PLoS Pathog 2015; 11: e1004789.
Geneva: World Health Organization, 2015. 11 Cheeseman IH, Miller BA, Nair S, et al. A major genome region underlying
2 WHO. World malaria report 2016. Geneva: World Health Organization, artemisinin resistance in malaria. Science 2012; 336: 79–82.
2016. 12 Witkowski B, Duru V, Khim N, et al. A surrogate marker of
3 White NJ. Can new treatment developments combat resistance in malaria? piperaquine–resistant Plasmodium falciparum malaria: a
Expert Opin Pharmocother 2016; 17: 1303–07. phenotype-genotype association study. Lancet Infect Dis 2017; 17: 174–83.
4 Takala–Harrison S, Jacob CG, Arze C, et al. Independent emergence of
artemisinin resistance mutations among Plasmodium falciparum in
Southeast Asia. J Infect Dis 2015; 211: 670–79.

Progress with the PfSPZ Vaccine for malaria

Substantial progress has been made in the control of which induces an immune response, but dies before

Dennis Kunkel Microscopy/Science Photo Library

malaria during the past decade, but it is estimated that rupturing into the bloodstream and releasing the
in 2015 there were still 429 000 deaths (uncertainty blood-stage parasites that cause the symptoms of
interval 235 000–639 000) from malaria, mainly in malaria. Development of a vaccine based on irradiated
children in Africa,1 and current gains are threatened sporozoites was for many years considered to be
by the emergence of resistance to artemisinin and impractical because of the need for delivery by mosquito
insecticides. New tools, including malaria vaccines, bite and to store the vaccine at a very low temperature.
are needed. The malaria vaccine RTS,S/AS01 has so However, the team behind the PfSPZ Vaccine have
far attracted the most attention because it is the overcome these challenges by developing novel Published Online
February 15, 2017
first malaria vaccine to obtain positive approval methods for the production of purified sporozoite and
from a regulatory authority2 after a long period of for storing and distributing them with a system based S1473-3099(17)30105-6

development and evaluation.3 However, during on liquid nitrogen. Many trials of PfSPZ have now been See Articles page 498

this time, substantial progress has been made with done in non-immune volunteers to define an optimum
the development of several other malaria vaccines, dose and route of administration. During a recent trial in
including the Plasmodium falciparum sporozoite (PfSPZ) the USA,6 seven of ten volunteers who were immunised
Vaccine. intravenously five times with 2·7 × 10⁵ sporozites
In an Article in The Lancet Infectious Diseases, were protected 6 months after vaccination against
Mahamadou Sissoko, Sara Healy, and colleagues report challenge with a strain of parasite homologous to that
the results of one of the first trials to investigate the used in making the vaccine. However, only one of ten
efficacy of this vaccine in a malaria-endemic country.4 volunteers challenged with a heterologous strain—the
The development of PfSPZ Vaccine has been based on kind of challenge likely to occur in malaria-endemic
the observation made in the 1970s that immunisation populations—was protected.6
with irradiated sporozoites, delivered through the bites In the study by Sissoko, Healy, and colleagues in healthy
of more than 1000 infected mosquitoes, provided adults in Mali,4 46 people in the vaccine group were
protection against challenge from a mosquito infected vaccinated intravenously with five doses of 2·7 × 10⁵
with viable sporozoites.5 Irradiated sporozoites under­ irradiated sporozoites and 47 people in the control
go partial development in liver cells to form a schizont, group received a saline placebo. The vaccine was safe Vol 17 May 2017 463