“These strains and their close relatives have been in this region for a decade or more, spreading over hundreds of kilometres, and often circulating in low numbers until the right opportunity for their expansion presents itself. Routine genetic surveillance, which is relatively straightforward and affordable, can be a powerful tool for analysing the causes and dynamics of outbreaks – and an important activity for supporting malaria elimination and preventing rebounds,” said University of Oxford Prof Olivo Miotto, Head of the Genetic Surveillance Group at the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok.
Applying genomic epidemiology analyses, researchers found that a 2020–21 malaria outbreak in Attapeu Province, Laos was triggered by the rapid expansion of a latent parasite mutant population, likely as a result of changes of frontline antimalarial drug combinations in neighbouring countries, in response to the spread of a different resistant strain.
“Public health policy changes have a massive effect on multidrug-resistant strains. Drug-resistant populations that are successful against a particular drug regime may lose their edge when that regime is changed. In this case we observed that, as one strain wanes, other resistant strains readily take its place, causing a resurgence of the disease,” said Prof Miotto.
To conduct their analyses, researchers from the GenRe-Mekong project used genomic data from 2164 blood samples from patients in southern Laos that were confirmed positive for the malaria parasite Plasmodium falciparum – including 249 from the 2021-2021 outbreak in Attapeu. In addition, whole-genome sequencing data from additional historical samples were analysed to reconstruct the ancestry of outbreak strains.
Researchers found that the outbreak was primarily caused by the rapid clonal expansion of a multidrug-resistant strain (LAA1) carrying the kelch13 R539T mutation, which confers resistance to artemisinin, the key component of the most widely used antimalarial drug combinations. LAA1 was shown to have inherited 58·8% of its genome, including the R539T mutation, from a strain circulating in Cambodia in 2008. The study results suggest that the Laos outbreak was driven by a selective sweep, possibly associated with the multidrug-resistant phenotypes of the outbreak strains, and show that routine genetic surveillance can be a valuable tool for public health officials to respond to unexpected outbreaks.
“As we approach the last mile towards elimination, public health authorities faced with rapidly changing scenarios will need quality information to help them decide on the most effective response. This study shows that genomic surveillance can support them with valuable insights from novel analytical approaches,” said Dr Varanya Wasakul of MORU, the lead author of this study.
Plasmodium falciparum causes the deadliest form of malaria, one that results in hundreds of thousands of deaths every year, the majority of which are children in sub-Saharan Africa. Over the past two decades, mortality has been greatly reduced thanks to highly efficacious artemisinin-based combination therapies (ACTs), which combine artemisinin derivatives, fast-acting parasiticidals, with a longer-lasting partner drug that clears surviving parasites.
In the past decade, however, strains with reduced sensitivity to artemisinin have emerged and spread in the Greater Mekong Subregion, where transmission is low to moderate, and mortality is low. Some of these strains are also resistant to partner drugs (mefloquine and piperaquine), reducing ACT efficacy and forcing public health authorities to change front-line therapies.
To protect ACT efficacy globally, and particularly in Africa, intense efforts have been undertaken to contain the spread of resistant strains and to eliminate P falciparum from the Greater Mekong Subregion within the next decade. Although these efforts have led to a reduction of malaria cases across the region, the resulting increased drug pressure has caused the emergence of new resistant forms, which present new public health challenges. It has become essential for Greater Mekong Subregion public health authorities to monitor epidemiological changes, such as localised malaria outbreaks, and respond appropriately to combat any resurgence of P falciparum.
Bill & Melinda Gates Foundation; The Global Fund to Fight AIDS, Tuberculosis and Malaria; and Wellcome Trust.
Malaria outbreak in Laos driven by a selective sweep for Plasmodium falciparum kelch13 R539T mutants: a genetic epidemiology analysis. Wasakul V, Disratthakit A, Mayxay M, Chindavongsa K, Sengsavath V, Thuy-Nhien N, Pearson RD, Phalivong S, Xayvanghang S, Maude RJ, Gonçalves S, Day NP, Newton PN, Ashley EA, Kwiatkowski DP, Dondorp AM, Miotto O. THELANCETID-D-22-01791R1