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Relapses arising from dormant liver-stage Plasmodium vivax parasites (hypnozoites) are a major cause of vivax malaria. However, in endemic areas, a recurrent blood-stage infection following treatment can be hypnozoite-derived (relapse), a blood-stage treatment failure (recrudescence), or a newly acquired infection (reinfection). Each of these requires a different prevention strategy, but it was not previously possible to distinguish between them reliably. We show that individual vivax malaria recurrences can be characterised probabilistically by combined modelling of time-to-event and genetic data within a framework incorporating identity-by-descent. Analysis of pooled patient data on 1441 recurrent P. vivax infections in 1299 patients on the Thailand–Myanmar border observed over 1000 patient follow-up years shows that, without primaquine radical curative treatment, 3 in 4 patients relapse. In contrast, after supervised high-dose primaquine only 1 in 40 relapse. In this region of frequent relapsing P. vivax , failure rates after supervised high-dose primaquine are significantly lower (∼3%) than estimated previously. Relapse, reinfection and recrudescence can all cause recurrent infection after treatment of Plasmodium vivax malaria in endemic areas, but are difficult to distinguish. Here the authors show that they can be differentiated probabilistically and thereby demonstrate the high efficacy of primaquine treatment in preventing relapse.

Plasmodium vivax elimination is challenged by dormant liver stages (hypnozoites) that can reactivate months after initial infection resulting in relapses. Relapsing infections confound antimalarial clinical efficacy trials due to the inability to distinguish between recurrences arising from blood-stage treatment failure (recrudescence), reinfection or relapse. Genetic relatedness of paired parasite isolates, measured by identity-by-descent (IBD), can provide important information on whether individuals have had single or multiple mosquito inoculations, thus informing on recurrence origin. We developed a high-throughput amplicon sequencing assay comprising 93 multi-SNP (microhaplotype) markers to determine IBD between P. vivax clinical isolates. The assay was evaluated in 745 global infections, including 128 infection pairs from a randomized controlled trial (RCT) (ClinicalTrials.gov NCT01680406). Simulations demonstrate low error in pairwise IBD estimation at the panel (RMSE < 0.12) and IBD-based networks illustrate strong clustering by geography. IBD analysis in the RCT demonstrates a lower frequency of suspected relapses or recrudescence in patients treated with primaquine compared to those without primaquine; the impact is greater when paired with chloroquine than with artemether-lumefantrine. Our results demonstrate the potential to derive new information on P. vivax treatment and transmission using IBD generated by amplicon sequencing data that can be further improved with time-to-event models. Dormant liver stages of Plasmodium vivax complicate malaria elimination efforts by causing relapses that obscure the efficacy of antimalarial treatments. Here, the authors develop a high-throughput amplicon sequencing assay to reconstruct P. vivax lineages, demonstrating its capacity for geospatial infection tracking, and distinguishing recurrent malaria caused by new infections versus untreated dormant liver stages.

More than 200 million malaria clinical cases are reported each year due to Plasmodium vivax, the most widespread Plasmodium species in the world. This species has been neglected and understudied for a long time, due to its lower mortality in comparison with Plasmodium falciparum. A renewed interest has emerged in the past decade with the discovery of antimalarial drug resistance and of severe and even fatal human cases. Nonetheless, today there are still significant gaps in our understanding of the population genetics and evolutionary history of P. vivax, particularly because of a lack of genetic data from Africa. To address these gaps, we genotyped 14 microsatellite loci in 834 samples obtained from 28 locations in 20 countries from around the world. We discuss the worldwide population genetic structure and diversity and the evolutionary origin of P. vivax in the world and its introduction into the Americas. This study demonstrates the importance of conducting genome-wide analyses of P. vivax in order to unravel its complex evolutionary history.

Chloroquine is the first-line treatment for Plasmodium vivax malaria in most endemic countries, but resistance is increasing. Monitoring of antimalarial efficacy is essential, but in P vivax infections the assessment of treatment efficacy is confounded by relapse from the dormant liver stages. We systematically reviewed P vivax malaria treatment efficacy studies to establish the global extent of chloroquine resistance. We searched Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews to identify studies published in English between Jan 1, 1960, and April 30, 2014, which investigated antimalarial treatment efficacy in P vivax malaria. We excluded studies that did not include supervised schizonticidal treatment without primaquine. We determined rates of chloroquine resistance according to P vivax malaria recurrence rates by day 28 whole-blood chloroquine concentrations at the time of recurrence and study enrolment criteria. We identified 129 eligible clinical trials involving 21 694 patients at 179 study sites and 26 case reports describing 54 patients. Chloroquine resistance was present in 58 (53%) of 113 assessable study sites, spread across most countries that are endemic for P vivax. Clearance of parasitaemia assessed by microscopy in 95% of patients by day 2, or all patients by day 3, was 100% predictive of chloroquine sensitivity. Heterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P vivax, which is now present across most countries endemic for P vivax. Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions. Wellcome Trust (UK).

Immunizing human volunteers by mosquito bite with radiation-attenuated Plasmodium falciparum sporozoites (RAS) results in high-level protection against infection. Only two volunteers have been similarly immunized with P. vivax (Pv) RAS, and both were protected. A phase 2 controlled clinical trial was conducted to assess the safety and protective efficacy of PvRAS immunization. A randomized, single-blinded trial was conducted. Duffy positive (Fy+; Pv susceptible) individuals were enrolled: 14 received bites from irradiated (150 ± 10 cGy) Pv-infected Anopheles mosquitoes (RAS) and 7 from non-irradiated non-infected mosquitoes (Ctl). An additional group of seven Fy- (Pv refractory) volunteers was immunized with bites from non-irradiated Pv-infected mosquitoes. A total of seven immunizations were carried out at mean intervals of nine weeks. Eight weeks after last immunization, a controlled human malaria infection (CHMI) with non-irradiated Pv-infected mosquitoes was performed. Nineteen volunteers completed seven immunizations (12 RAS, 2 Ctl, and 5 Fy-) and received a CHMI. Five of 12 (42%) RAS volunteers were protected (receiving a median of 434 infective bites) compared with 0/2 Ctl. None of the Fy- volunteers developed infection by the seventh immunization or after CHMI. All non-protected volunteers developed symptoms 8-13 days after CHMI with a mean pre-patent period of 12.8 days. No serious adverse events related to the immunizations were observed. Specific IgG1 anti-PvCS response was associated with protection. Immunization with PvRAS was safe, immunogenic, and induced sterile immunity in 42% of the Fy+ volunteers. Moreover, Fy- volunteers were refractory to Pv malaria. Identifier: NCT01082341.

Plasmodium vivax is geographically the most widely distributed cause of malaria in people, with up to 2·5 billion people at risk and an estimated 80 million to 300 million clinical cases every year—including severe disease and death. Despite this large burden of disease, P vivax is overlooked and left in the shadow of the enormous problem caused by Plasmodium falciparum in sub-Saharan Africa. The technological advances enabling the sequencing of the P vivax genome and a recent call for worldwide malaria eradication have together placed new emphasis on the importance of addressing P vivax as a major public health problem. However, because of this parasite's biology, it is especially difficult to interrupt the transmission of P vivax, and experts agree that the available methods for preventing and treating infections with P vivax are inadequate. It is thus imperative that the development of new methods and strategies become a priority. Advancing the development of such methods needs renewed emphasis on understanding the biology, pathogenesis, and epidemiology of P vivax. This Review critically examines what is known about P vivax, focusing on identifying the crucial gaps that create obstacles to the elimination of this parasite in human populations.

Abstract Background In Southeast Asia, Plasmodium knowlesi, a parasite of long-tailed macaques (Macaca fascicularis), is an important cause of human malaria. Plasmodium cynomolgi also commonly infects these monkeys, but only one naturally acquired symptomatic human case has been reported previously. Methods Malariometric studies involving 5422 subjects (aged 6 months to 65 years) were conducted in 23 villages in Pailin and Battambang, western Cambodia. Parasite detection and genotyping was conducted on blood samples, using high-volume quantitative PCR (uPCR). Results Asymptomatic malaria parasite infections were detected in 1361 of 14732 samples (9.2%). Asymptomatic infections with nonhuman primate malaria parasites were found in 21 individuals living close to forested areas; P. cynomolgi was found in 11, P. knowlesi was found in 8, and P. vivax and P. cynomolgi were both found in 2. Only 2 subjects were female, and 14 were men aged 20–40 years. Geometric mean parasite densities were 3604 parasites/mL in P. cynomolgi infections and 52488 parasites/mL in P. knowlesi infections. All P. cynomolgi isolates had wild-type dihydrofolate reductase genes, in contrast to the very high prevalence of mutations in the human malaria parasites. Asymptomatic reappearance of P. cynomolgi occurred in 2 subjects 3 months after the first infection. Conclusions Asymptomatic naturally acquired P. cynomolgi and P. knowlesi infections can both occur in humans. Clinical Trials Registration NCT01872702. Epidemiological studies in western Cambodia identified 21 subjects with asymptomatic monkey malaria parasite infections (8 with P. knowlesi infection and 13 with P. cynomolgi infection). These parasites represented 1.9% of all identified malaria parasites.

Plasmodium vivax causes heavy burdens of disease across malarious regions worldwide. Mature P. vivax asexual and transmissive gametocyte stages occur in the blood circulation, and it is often assumed that accumulation/sequestration in tissues is not an important phase in their development. Here, we present a systematic study of P. vivax stage distributions in infected tissues of nonhuman primate (NHP) malaria models as well as in blood from human infections. In a comparative analysis of the transcriptomes of P. vivax and Plasmodium falciparum blood-stage parasites, we found a conserved cascade of stage-specific gene expression despite the greatly different gametocyte maturity times of these two species. Using this knowledge, we validated a set of conserved asexual- and gametocyte-stage markers both by quantitative real-time PCR and by antibody assays of peripheral blood samples from infected patients and NHP ( Aotus sp.). Histological analyses of P. vivax parasites in organs of 13 infected NHP ( Aotus and Saimiri species) demonstrated a major fraction of immature gametocytes in the parenchyma of the bone marrow, while asexual schizont forms were enriched to a somewhat lesser extent in this region of the bone marrow as well as in sinusoids of the liver. These findings suggest that the bone marrow is an important reservoir for gametocyte development and proliferation of malaria parasites. IMPORTANCE Plasmodium vivax malaria continues to cause major public health burdens worldwide. Yet, significant knowledge gaps in the basic biology and epidemiology of P. vivax malaria remain, largely due to limited available tools for research and diagnostics. Here, we present a systematic examination of tissue sequestration during P. vivax infection. Studies of nonhuman primates and malaria patients revealed enrichment of developing sexual stages (gametocytes) and mature replicative stages (schizonts) in the bone marrow and liver, relative to those present in peripheral blood. Identification of the bone marrow as a major P. vivax tissue reservoir has important implications for parasite diagnosis and treatment. Plasmodium vivax malaria continues to cause major public health burdens worldwide. Yet, significant knowledge gaps in the basic biology and epidemiology of P. vivax malaria remain, largely due to limited available tools for research and diagnostics. Here, we present a systematic examination of tissue sequestration during P. vivax infection. Studies of nonhuman primates and malaria patients revealed enrichment of developing sexual stages (gametocytes) and mature replicative stages (schizonts) in the bone marrow and liver, relative to those present in peripheral blood. Identification of the bone marrow as a major P. vivax tissue reservoir has important implications for parasite diagnosis and treatment.

Jane Carlton, Daniel Neafsey and colleagues report a population genomics analysis of 182 Plasmodium vivax isolates from 11 countries. They find evidence of regional adaptation and signatures of selection at genes involved in antimalarial drug resistance. Plasmodium vivax is a major public health burden, responsible for the majority of malaria infections outside Africa. We explored the impact of demographic history and selective pressures on the P. vivax genome by sequencing 182 clinical isolates sampled from 11 countries across the globe, using hybrid selection to overcome human DNA contamination. We confirmed previous reports of high genomic diversity in P. vivax relative to the more virulent Plasmodium falciparum species; regional populations of P. vivax exhibited greater diversity than the global P. falciparum population, indicating a large and/or stable population. Signals of natural selection suggest that P. vivax is evolving in response to antimalarial drugs and is adapting to regional differences in the human host and the mosquito vector. These findings underline the variable epidemiology of this parasite species and highlight the breadth of approaches that may be required to eliminate P. vivax globally.

The human malaria parasite Plasmodium vivax is responsible for 25–40% of the ∼515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P. vivax to shed light on its distinctive biological features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternative invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance investigation into this neglected species. MALARIA PARASITES: New Plasmodium sequences kick-start comparative genomics Four distinct Plasmodium species are known to regularly infect humans: Plasmodium falciparum , P. vivax , P. malariae and P. ovale . The genome sequence of P. falciparum , the cause of the most severe type of human malaria, was completed in 2002 at the same time as the mosquito vector, Anopheles gambiae . In this week's Nature , which focuses on the malaria parasite, two further malaria genome sequences are described. First that of P. vivax , which contributes significant numbers to malaria incidence in humans, though in contrast to P. falciparum , the resulting disease is usually not fatal. The genome of this rather neglected species is presented together with a comparative analysis with the genomes of other Plasmodium species. Second, we publish the genome sequence of Plasmodium knowlesi . For long regarded as a monkey malaria parasite, it is increasingly becoming recognized as the fifth human-infecting Plasmodium species. In particular, it is prevalent in South East Asia where it is often misdiagnosed as another human malaria parasite P. malariae . As a model organism P. knowlesi stands out: not only is it a primate system, useful for work on vaccines, but it can be cultured in vitro and subjected to efficient transfection and gene knockouts. In a Review Article, Elizabeth Winzeler considers the progress made towards using the genome sequence to understand basic malaria parasite biology, and in particular the work on developing rational therapeutic approaches to combat P. falciparum infections. See also the Editorial. For a comprehensive collection of resources visit Nature 's past malaria specials: Malaria killer blow ; Outlook on malaria ; Malaria web focus ; Malaria Insight ; Nature Medicine focus on malaria ; Focus on malaria