Genomic analysis of a pre-elimination Malaysian Plasmodium vivax population reveals selective pressures and changing transmission dynamics
Research into the malaria parasite Plasmodium vivax has often been overshadowed by the more deadly P. falciparum species, but accumulating reports of resistance to antimalarial drugs, and life-threatening disease complications in children and pregnant women with P. vivax infection emphasize the urgency to eliminate this species. However, prior to our study, little was known about the molecular epidemiology of P. vivax during the highly vulnerable end stages of malaria elimination.
Our study was undertaken in Malaysia, where there has been a sharp decline in P. vivax prevalence over the past decade; an impressive feat achieved against a backdrop of high levels of resistance to chloroquine, the frontline drug for treating this species in the country until 2016. In this low endemic setting, we observed striking population structure, which contrasted sharply against the two higher endemicity comparator populations from Thailand and Papua Indonesia. Whilst we acknowledge that this structure might simply reflect neutral changes as the parasite population is bottlenecked under the increasing pressure of interventions, it is interesting to note that the structure mirrors that previously observed with the emergence of artemisinin-resistant P. falciparum populations in Cambodia (https://www.ncbi.nlm.nih.gov/pubmed/23624527).
Given the high levels of chloroquine resistance in the Malaysian P. vivax population, we speculate that the population structure might partly reflect drug-related adaptations. We therefore investigated known drug resistance determinants, demonstrating a high prevalence of these variants which suggests that intense drug pressure has impacted heavily on the Malaysian vivax population. However, the molecular determinant of chloroquine resistance in P. vivax unfortunately remains elusive. We sought to identify potential new determinants using genomic approaches to identify regions under positive selection. This analysis revealed several interesting new candidate drug resistance loci including the multi-drug resistance protein 2, but we emphasize that further validation is required.
We also undertook temporal assessment of the Malaysian P. vivax population, revealing continual changes in genetic make-up, including a striking expansion, which we referred to as the K2 strain. Curiously, a significant number of K2 infections presented in students. The reason for this pattern is unclear, but a possibility is that it reflects transmission events taking place in or around school or college, highlighting occupation as a potentially important epidemiological link for reactive case detection.
Overall, the continual flux in the genetic make-up of the Malaysian vivax population, rapid expansion of new strains, and high prevalence of known resistance-associated determinants highlight the strong adaptive potential in a population on the verge of elimination. Based on these findings, we call for a stronger foundation for molecular surveillance to monitor the early emergence of adaptive parasites and guide appropriate and timely public health interventions.