Displaying publications 1 - 20 of 74 in total

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  1. Ooi CH, Phang WK, Liew JWK, Atroosh WM, Lau YL
    Trop Med Int Health, 2023 Jun;28(6):486-500.
    PMID: 37042251 DOI: 10.1111/tmi.13875
    OBJECTIVES: Malaysia has achieved the status of zero indigenous human malaria cases. Nevertheless, imported human malaria has increasingly been reported in Sarawak, Malaysian Borneo. As zoonotic malaria caused by Plasmodium knowlesi remains a major public health problem in Sarawak, the threat of imported malaria must be addressed as it can cause human malaria reintroduction, sustain transmission, and lead to complications. The objectives of this study were to investigate the epidemiological characteristics of imported malaria cases reported in Sarawak and to underline the challenge posed by imported malaria towards malaria elimination efforts.

    METHODS: Imported malaria cases reported in Sarawak from 2011 to 2019 were collected from Sarawak State Health Department and analysed in this longitudinal retrospective study.

    RESULTS: A total of 2058 imported malaria cases were registered in all districts in Sarawak. Highest number of cases were reported in Kapit (n = 559; 27.16%), followed by Sibu (n = 424; 20.6%), and Miri (n = 166; 8.07%). Based on the demographic profile, most of the patients constituted of either male sex (98.49%), age group of 40-49 years (39.6%), Iban ethnic (57.92%), worked in logging industry (88.58%), Malaysian nationals (91.84%), contracted malaria in Papua New Guinea (46.11%), uncomplicated disease (77.89%), or hospitalised cases (97.86%). The most prominent Plasmodium species diagnosed were P. vivax (52.67%) and P. falciparum (35.81%).

    CONCLUSIONS: Surveillance, disease detection, and medical follow-up must be carried out thoroughly for individuals who returned from malaria-endemic countries. It is also necessary to promote pre-travel preventive education as well as chemoprophylaxis to travellers heading to endemic areas.

    Matched MeSH terms: Malaria, Vivax*
  2. Fornace KM, Topazian HM, Routledge I, Asyraf S, Jelip J, Lindblade KA, et al.
    Nat Commun, 2023 Jun 01;14(1):2945.
    PMID: 37263994 DOI: 10.1038/s41467-023-38476-8
    Reported incidence of the zoonotic malaria Plasmodium knowlesi has markedly increased across Southeast Asia and threatens malaria elimination. Nonzoonotic transmission of P. knowlesi has been experimentally demonstrated, but it remains unknown whether nonzoonotic transmission is contributing to increases in P. knowlesi cases. Here, we adapt model-based inference methods to estimate RC, individual case reproductive numbers, for P. knowlesi, P. falciparum and P. vivax human cases in Malaysia from 2012-2020 (n = 32,635). Best fitting models for P. knowlesi showed subcritical transmission (RC  1) was estimated historically for P. falciparum and P. vivax, with declines in RC estimates observed over time consistent with local elimination. Together, this suggests sustained nonzoonotic P. knowlesi transmission is highly unlikely and that new approaches are urgently needed to control spillover risks.
    Matched MeSH terms: Malaria, Vivax*
  3. Turkiewicz A, Manko E, Oresegun DR, Nolder D, Spadar A, Sutherland CJ, et al.
    Sci Rep, 2023 Feb 07;13(1):2142.
    PMID: 36750737 DOI: 10.1038/s41598-023-29368-4
    The zoonotic Plasmodium knowlesi parasite is a growing public health concern in Southeast Asia, especially in Malaysia, where elimination of P. falciparum and P. vivax malaria has been the focus of control efforts. Understanding of the genetic diversity of P. knowlesi parasites can provide insights into its evolution, population structure, diagnostics, transmission dynamics, and the emergence of drug resistance. Previous work has revealed that P. knowlesi fall into three main sub-populations distinguished by a combination of geographical location and macaque host (Macaca fascicularis and M. nemestrina). It has been shown that Malaysian Borneo groups display profound heterogeneity with long regions of high or low divergence resulting in mosaic patterns between sub-populations, with some evidence of chromosomal-segment exchanges. However, the genetic structure of non-Borneo sub-populations is less clear. By gathering one of the largest collections of P. knowlesi whole-genome sequencing data, we studied structural genomic changes across sub-populations, with the analysis revealing differences in Borneo clusters linked to mosquito-related stages of the parasite cycle, in contrast to differences in host-related stages for the Peninsular group. Our work identifies new genetic exchange events, including introgressions between Malaysian Peninsular and M. nemestrina-associated clusters on various chromosomes, including in parasite invasion genes (DBP[Formula: see text], NBPX[Formula: see text] and NBPX[Formula: see text]), and important proteins expressed in the vertebrate parasite stages. Recombination events appear to have occurred between the Peninsular and M. fascicularis-associated groups, including in the DBP[Formula: see text] and DBP[Formula: see text] invasion associated genes. Overall, our work finds that genetic exchange events have occurred among the recognised contemporary groups of P. knowlesi parasites during their evolutionary history, leading to apparent mosaicism between these sub-populations. These findings generate new hypotheses relevant to parasite evolutionary biology and P. knowlesi epidemiology, which can inform malaria control approaches to containing the impact of zoonotic malaria on human communities.
    Matched MeSH terms: Malaria, Vivax*
  4. Park JH, Kim MH, Sutanto E, Na SW, Kim MJ, Yeom JS, et al.
    PLoS Negl Trop Dis, 2022 Jun;16(6):e0010492.
    PMID: 35737709 DOI: 10.1371/journal.pntd.0010492
    Plasmodium vivax is the most widespread cause of human malaria. Recent reports of drug resistant vivax malaria and the challenge of eradicating the dormant liver forms increase the importance of vaccine development against this relapsing disease. P. vivax reticulocyte binding protein 1a (PvRBP1a) is a potential vaccine candidate, which is involved in red cell tropism, a crucial step in the merozoite invasion of host reticulocytes. As part of the initial evaluation of the PvRBP1a vaccine candidate, we investigated its genetic diversity and antigenicity using geographically diverse clinical isolates. We analysed pvrbp1a genetic polymorphisms using 202 vivax clinical isolates from six countries. Pvrbp1a was separated into six regions based on specific domain features, sequence conserved/polymorphic regions, and the reticulocyte binding like (RBL) domains. In the fragmented gene sequence analysis, PvRBP1a region II (RII) and RIII (head and tail structure homolog, 152-625 aa.) showed extensive polymorphism caused by random point mutations. The haplotype network of these polymorphic regions was classified into three clusters that converged to independent populations. Antigenicity screening was performed using recombinant proteins PvRBP1a-N (157-560 aa.) and PvRBP1a-C (606-962 aa.), which contained head and tail structure region and sequence conserved region, respectively. Sensitivity against PvRBP1a-N (46.7%) was higher than PvRBP1a-C (17.8%). PvRBP1a-N was reported as a reticulocyte binding domain and this study identified a linear epitope with moderate antigenicity, thus an attractive domain for merozoite invasion-blocking vaccine development. However, our study highlights that a global PvRBP1a-based vaccine design needs to overcome several difficulties due to three distinct genotypes and low antigenicity levels.
    Matched MeSH terms: Malaria, Vivax*
  5. Al-Mekhlafi HM, Madkhali AM, Ghailan KY, Abdulhaq AA, Ghzwani AH, Zain KA, et al.
    Malar J, 2021 Jul 13;20(1):315.
    PMID: 34256757 DOI: 10.1186/s12936-021-03846-4
    BACKGROUND: Saudi Arabia and Yemen are the only two countries in the Arabian Peninsula that are yet to achieve malaria elimination. Over the past two decades, the malaria control programme in Saudi Arabia has successfully reduced the annual number of malaria cases, with the lowest incidence rate across the country reported in 2014. This study aims to investigate the distribution of residual malaria in Jazan region and to identify potential climatic drivers of autochthonous malaria cases in the region.

    METHODS: A cross-sectional study was carried out from 1 April 2018 to 31 January 2019 in Jazan region, southwestern Saudi Arabia, which targeted febrile individuals attending hospitals and primary healthcare centres. Participants' demographic data were collected, including age, gender, nationality, and residence. Moreover, association of climatic variables with the monthly autochthonous malaria cases reported during the period of 2010-2017 was retrospectively analysed.

    RESULTS: A total of 1124 febrile subjects were found to be positive for malaria during the study period. Among them, 94.3 and 5.7% were infected with Plasmodium falciparum and Plasmodium vivax, respectively. In general, subjects aged 18-30 years and those aged over 50 years had the highest (42.7%) and lowest (5.9%) percentages of malaria cases. Similarly, the percentage of malaria-positive cases was higher among males than females (86.2 vs 13.8%), among non-Saudi compared to Saudi subjects (70.6 vs 29.4%), and among patients residing in rural rather than in urban areas (89.8 vs 10.2%). A total of 407 autochthonous malaria cases were reported in Jazan region between 2010 and 2017. Results of zero-inflated negative binomial regression analysis showed that monthly average temperature and relative humidity were the significant climatic determinants of autochthonous malaria in the region.

    CONCLUSION: Malaria remains a public health problem in most governorates of Jazan region. The identification and monitoring of malaria transmission hotspots and predictors would enable control efforts to be intensified and focused on specific areas and therefore expedite the elimination of residual malaria from the whole region.

    Matched MeSH terms: Malaria, Vivax/epidemiology*
  6. Sato S
    J Physiol Anthropol, 2021 Jan 07;40(1):1.
    PMID: 33413683 DOI: 10.1186/s40101-020-00251-9
    Malaria is one of the most devastating infectious diseases of humans. It is problematic clinically and economically as it prevails in poorer countries and regions, strongly hindering socioeconomic development. The causative agents of malaria are unicellular protozoan parasites belonging to the genus Plasmodium. These parasites infect not only humans but also other vertebrates, from reptiles and birds to mammals. To date, over 200 species of Plasmodium have been formally described, and each species infects a certain range of hosts. Plasmodium species that naturally infect humans and cause malaria in large areas of the world are limited to five-P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. The first four are specific for humans, while P. knowlesi is naturally maintained in macaque monkeys and causes zoonotic malaria widely in South East Asia. Transmission of Plasmodium species between vertebrate hosts depends on an insect vector, which is usually the mosquito. The vector is not just a carrier but the definitive host, where sexual reproduction of Plasmodium species occurs, and the parasite's development in the insect is essential for transmission to the next vertebrate host. The range of insect species that can support the critical development of Plasmodium depends on the individual parasite species, but all five Plasmodium species causing malaria in humans are transmitted exclusively by anopheline mosquitoes. Plasmodium species have remarkable genetic flexibility which lets them adapt to alterations in the environment, giving them the potential to quickly develop resistance to therapeutics such as antimalarials and to change host specificity. In this article, selected topics involving the Plasmodium species that cause malaria in humans are reviewed.
    Matched MeSH terms: Malaria, Vivax
  7. Odedra A, Webb L, Marquart L, Britton LJ, Chalon S, Moehrle JJ, et al.
    Am J Trop Med Hyg, 2020 11;103(5):1910-1917.
    PMID: 32815508 DOI: 10.4269/ajtmh.20-0491
    Liver transaminase elevations after treatment in malaria volunteer infection studies (VISs) have raised safety concerns. We investigated transaminase elevations from two human Plasmodium vivax VISs where subjects were treated with chloroquine (n = 24) or artefenomel (n = 8) and compared them with studies in Thailand (n = 41) and Malaysia (n = 76). In the VISs, alanine transaminase (ALT) increased to ≥ 2.5 × upper limit of normal (ULN) in 11/32 (34%) volunteers, peaking 5-8 days post-treatment. Transaminase elevations were asymptomatic, were not associated with elevated bilirubin, and resolved by day 42. The risk of an ALT ≥ 2.5 × ULN increased more than 4-fold (odds ratio [OR] 4.28; 95% CI: 1.26-14.59; P = 0.02) for every log10 increase in the parasite clearance burden (PCB), defined as the log-fold reduction in parasitemia 24 hours post-treatment. Although an elevated ALT ≥ 2.5 × ULN was more common after artefenomel than after chloroquine (5/8 [63%] versus 6/24 [25%]; OR 5.0; 95% CI: 0.91-27.47; P = 0.06), this risk disappeared when corrected for PCB. Peak ALT also correlated with peak C-reactive protein (R = 0.44; P = 0.012). Elevations in ALT (≥ 2.5 × ULN) were less common in malaria-endemic settings, occurring in 1/41 (2.5%) Thai patients treated with artefenomel, and in none of 76 Malaysians treated with chloroquine or artemisinin combination therapy. Post-treatment transaminase elevations are common in experimental P. vivax infection but do not appear to impact on participant safety. Although the mechanism of these changes remains uncertain, host inflammatory response to parasite clearance may be contributory.
    Matched MeSH terms: Malaria, Vivax/blood; Malaria, Vivax/drug therapy*; Malaria, Vivax/parasitology
  8. Noordin NR, Lee PY, Mohd Bukhari FD, Fong MY, Abdul Hamid MH, Jelip J, et al.
    Am J Trop Med Hyg, 2020 09;103(3):1107-1110.
    PMID: 32618263 DOI: 10.4269/ajtmh.20-0268
    Asymptomatic and/or low-density malaria infection has been acknowledged as an obstacle to achieving a malaria-free country. This study aimed to determine the prevalence of asymptomatic and/or low-density malaria infection in previously reported malarious localities using nested PCR in four states, namely, Johor, Pahang, Kelantan, and Selangor, between June 2019 and January 2020. Blood samples (n = 585) were collected and were extracted using a QIAamp blood kit. The DNA was concentrated and subjected to nested PCR. Thin and thick blood smears were examined as well. Of the 585 samples collected, 19 were positive: 10 for Plasmodium knowlesi, eight for Plasmodium vivax, and one for Plasmodium ovale. Asymptomatic and/or low-density malaria infection is a threat to malaria elimination initiatives. Eliminating countries should develop guidance policy on the importance of low-density malaria infection which includes detection and treatment policy.
    Matched MeSH terms: Malaria, Vivax/epidemiology*; Malaria, Vivax/parasitology
  9. Han JH, Cho JS, Ong JJY, Park JH, Nyunt MH, Sutanto E, et al.
    PLoS Negl Trop Dis, 2020 Jul;14(7):e0008202.
    PMID: 32645098 DOI: 10.1371/journal.pntd.0008202
    Plasmodium vivax is the most widespread and difficult to treat cause of human malaria. The development of vaccines against the blood stages of P. vivax remains a key objective for the control and elimination of vivax malaria. Erythrocyte binding-like (EBL) protein family members such as Duffy binding protein (PvDBP) are of critical importance to erythrocyte invasion and have been the major target for vivax malaria vaccine development. In this study, we focus on another member of EBL protein family, P. vivax erythrocyte binding protein (PvEBP). PvEBP was first identified in Cambodian (C127) field isolates and has subsequently been showed its preferences for binding reticulocytes which is directly inhibited by antibodies. We analysed PvEBP sequence from 316 vivax clinical isolates from eight countries including China (n = 4), Ethiopia (n = 24), Malaysia (n = 53), Myanmar (n = 10), Papua New Guinea (n = 16), Republic of Korea (n = 10), Thailand (n = 174), and Vietnam (n = 25). PvEBP gene exhibited four different phenotypic clusters based on the insertion/deletion (indels) variation. PvEBP-RII (179-479 aa.) showed highest polymorphism similar to other EBL family proteins in various Plasmodium species. Whereas even though PvEBP-RIII-V (480-690 aa.) was the most conserved domain, that showed strong neutral selection pressure for gene purifying with significant population expansion. Antigenicity of both of PvEBP-RII (16.1%) and PvEBP-RIII-V (21.5%) domains were comparatively lower than other P. vivax antigen which expected antigens associated with merozoite invasion. Total IgG recognition level of PvEBP-RII was stronger than PvEBP-RIII-V domain, whereas total IgG inducing level was stronger in PvEBP-RIII-V domain. These results suggest that PvEBP-RII is mainly recognized by natural IgG for innate protection, whereas PvEBP-RIII-V stimulates IgG production activity by B-cell for acquired immunity. Overall, the low antigenicity of both regions in patients with vivax malaria likely reflects genetic polymorphism for strong positive selection in PvEBP-RII and purifying selection in PvEBP-RIII-V domain. These observations pose challenging questions to the selection of EBP and point out the importance of immune pressure and polymorphism required for inclusion of PvEBP as a vaccine candidate.
    Matched MeSH terms: Malaria, Vivax/immunology*; Malaria, Vivax/parasitology
  10. Melo JO, Padilha MAO, Barbosa RTA, Alonso WJ, Vittor AY, Laporta GZ
    Trop Biomed, 2020 Jun;37(2):513-535.
    PMID: 33235398
    After a centenary fight against malaria, Brazil has seen an opportunity for change with the proposal of the malaria elimination policy set by the Brazilian government, in line with malaria elimination policies in other Latin American countries. Brazilian malaria experts regard eliminating malaria by 2030 to be within reach. Herein we evaluated the likelihood that malaria elimination can be accomplished in Brazil through systematic review of the literature on malaria elimination in Brazil and epidemiological analysis. Fifty-two articles referring to malaria eradication/elimination in Brazil were analyzed to identify challenges and technological breakthroughs for controlling malaria. Monthly deaths (1979-2016) and monthly severe malaria cases (1998-2018) were analyzed according to age groups, geographic region and parasite species. As a result, we observed that the declining malaria burden was mostly attributable to a decline in Plasmodium falciparum-malaria. At the same time, the proportional increase of Plasmodium vivax-malaria in comparison with P. falciparum-malaria was notable. This niche replacement mechanism was discussed in the reviewed literature. In addition, the challenges to P. vivax-malaria elimination outnumbered the available technological breakthroughs. Although accumulated and basic information exists on mosquito vector biology, the lack of specific knowledge about mosquito vector taxonomy and ecology may hamper current attempts at stopping malaria in the country. An impressive reduction in malaria hospitalizations and mortality was seen in Brazil in the past 3 decades. Eliminating malaria deaths in children less than 5 years and P. falciparum severe cases may be achievable goals under the current malaria policy until 2030. However, eliminating P. vivax malaria transmission and morbidity seems unattainable with the available tools. Therefore, complete malaria elimination in Brazil in the near future is unlikely.
    Matched MeSH terms: Malaria, Vivax/epidemiology*; Malaria, Vivax/parasitology; Malaria, Vivax/prevention & control
  11. Cheong FW, Dzul S, Fong MY, Lau YL, Ponnampalavanar S
    Acta Trop, 2020 Jun;206:105454.
    PMID: 32205132 DOI: 10.1016/j.actatropica.2020.105454
    Transmission of Plasmodium vivax still persist in Malaysia despite the government's aim to eliminate malaria in 2020. High treatment failure rate of chloroquine monotherapy was reported recently. Hence, parasite drug susceptibility should be kept under close monitoring. Mutation analysis of the drug resistance markers is useful for reconnaissance of anti-malarial drug resistance. Hitherto, information on P. vivax drug resistance marker in Malaysia are limited. This study aims to evaluate the mutations in four P. vivax drug resistance markers pvcrt-o (putative), pvmdr1 (putative), pvdhfr and pvdhps in 44 isolates from Malaysia. Finding indicates that 27.3%, 100%, 47.7%, and 27.3% of the isolates were carrying mutant allele in pvcrt-o, pvmdr1, pvdhfr and pvdhps genes, respectively. Most of the mutant isolates had multiple point mutations rather than single point mutation in pvmdr1 (41/44) and pvdhfr (19/21). One novel point mutation V111I was detected in pvdhfr. Allelic combination analysis shows significant strong association between mutations in pvcrt-o and pvmdr1 (X2 = 9.521, P < 0.05). In the present study, 65.9% of the patients are non-Malaysians, with few of them arrived in Malaysia 1-2 weeks before the onset of clinical manifestations, or had previous history of malaria infection. Besides, few Malaysian patients had travel history to vivax-endemic countries, suggesting that these patients might have acquired the infections during their travel. All these possible imported cases could have placed Malaysia in a risk to have local transmission or outbreak of malaria. Six isolates were found to have mutations in all four drug resistance markers, suggesting that the multiple-drugs resistant P. vivax strains are circulating in Malaysia.
    Matched MeSH terms: Malaria, Vivax
  12. Diez Benavente E, Campos M, Phelan J, Nolder D, Dombrowski JG, Marinho CRF, et al.
    PLoS Genet, 2020 02;16(2):e1008576.
    PMID: 32053607 DOI: 10.1371/journal.pgen.1008576
    Although Plasmodium vivax parasites are the predominant cause of malaria outside of sub-Saharan Africa, they not always prioritised by elimination programmes. P. vivax is resilient and poses challenges through its ability to re-emerge from dormancy in the human liver. With observed growing drug-resistance and the increasing reports of life-threatening infections, new tools to inform elimination efforts are needed. In order to halt transmission, we need to better understand the dynamics of transmission, the movement of parasites, and the reservoirs of infection in order to design targeted interventions. The use of molecular genetics and epidemiology for tracking and studying malaria parasite populations has been applied successfully in P. falciparum species and here we sought to develop a molecular genetic tool for P. vivax. By assembling the largest set of P. vivax whole genome sequences (n = 433) spanning 17 countries, and applying a machine learning approach, we created a 71 SNP barcode with high predictive ability to identify geographic origin (91.4%). Further, due to the inclusion of markers for within population variability, the barcode may also distinguish local transmission networks. By using P. vivax data from a low-transmission setting in Malaysia, we demonstrate the potential ability to infer outbreak events. By characterising the barcoding SNP genotypes in P. vivax DNA sourced from UK travellers (n = 132) to ten malaria endemic countries predominantly not used in the barcode construction, we correctly predicted the geographic region of infection origin. Overall, the 71 SNP barcode outperforms previously published genotyping methods and when rolled-out within new portable platforms, is likely to be an invaluable tool for informing targeted interventions towards elimination of this resilient human malaria.
    Matched MeSH terms: Malaria, Vivax/epidemiology; Malaria, Vivax/parasitology; Malaria, Vivax/transmission*
  13. Charon J, Grigg MJ, Eden JS, Piera KA, Rana H, William T, et al.
    PLoS Pathog, 2019 12;15(12):e1008216.
    PMID: 31887217 DOI: 10.1371/journal.ppat.1008216
    Eukaryotes of the genus Plasmodium cause malaria, a parasitic disease responsible for substantial morbidity and mortality in humans. Yet, the nature and abundance of any viruses carried by these divergent eukaryotic parasites is unknown. We investigated the Plasmodium virome by performing a meta-transcriptomic analysis of blood samples taken from patients suffering from malaria and infected with P. vivax, P. falciparum or P. knowlesi. This resulted in the identification of a narnavirus-like sequence, encoding an RNA polymerase and restricted to P. vivax samples, as well as an associated viral segment of unknown function. These data, confirmed by PCR, are indicative of a novel RNA virus that we term Matryoshka RNA virus 1 (MaRNAV-1) to reflect its analogy to a "Russian doll": a virus, infecting a parasite, infecting an animal. Additional screening revealed that MaRNAV-1 was abundant in geographically diverse P. vivax derived from humans and mosquitoes, strongly supporting its association with this parasite, and not in any of the other Plasmodium samples analyzed here nor Anopheles mosquitoes in the absence of Plasmodium. Notably, related bi-segmented narnavirus-like sequences (MaRNAV-2) were retrieved from Australian birds infected with a Leucocytozoon-a genus of eukaryotic parasites that group with Plasmodium in the Apicomplexa subclass hematozoa. Together, these data support the establishment of two new phylogenetically divergent and genomically distinct viral species associated with protists, including the first virus likely infecting Plasmodium parasites. As well as broadening our understanding of the diversity and evolutionary history of the eukaryotic virosphere, the restriction to P. vivax may be of importance in understanding P. vivax-specific biology in humans and mosquitoes, and how viral co-infection might alter host responses at each stage of the P. vivax life-cycle.
    Matched MeSH terms: Malaria, Vivax
  14. Oyong DA, Wilson DW, Barber BE, William T, Jiang J, Galinski MR, et al.
    J Infect Dis, 2019 11 06;220(12):1950-1961.
    PMID: 31419296 DOI: 10.1093/infdis/jiz407
    BACKGROUND: Complement-fixing antibodies are important mediators of protection against Plasmodium falciparum malaria. However, complement-fixing antibodies remain uncharacterized for Plasmodium vivax malaria. P. vivax merozoite surface protein 3α (PvMSP3α) is a target of acquired immunity and a potential vaccine candidate.

    METHODS: Plasma from children and adults with P. vivax malaria in Sabah, Malaysia, were collected during acute infection, 7 and 28 days after drug treatment. Complement-fixing antibodies and immunoglobulin M and G (IgM and IgG), targeting 3 distinctive regions of PvMSP3α, were measured by means of enzyme-linked immunosorbent assay.

    RESULTS: The seroprevalence of complement-fixing antibodies was highest against the PvMSP3α central region (77.6%). IgG1, IgG3, and IgM were significantly correlated with C1q fixation, and both purified IgG and IgM were capable of mediating C1q fixation to PvMSP3α. Complement-fixing antibody levels were similar between age groups, but IgM was predominant in children and IgG3 more prevalent in adults. Levels of functional antibodies increased after acute infection through 7 days after treatment but rapidly waned by day 28.

    CONCLUSION: Our study demonstrates that PvMSP3α antibodies acquired during P. vivax infection can mediate complement fixation and shows the important influence of age in shaping these specific antibody responses. Further studies are warranted to understand the role of these functional antibodies in protective immunity against P. vivax malaria.

    Matched MeSH terms: Malaria, Vivax/drug therapy; Malaria, Vivax/immunology*; Malaria, Vivax/parasitology*
  15. Auburn S, Getachew S, Pearson RD, Amato R, Miotto O, Trimarsanto H, et al.
    J Infect Dis, 2019 Oct 22;220(11):1738-1749.
    PMID: 30668735 DOI: 10.1093/infdis/jiz016
    The Horn of Africa harbors the largest reservoir of Plasmodium vivax in the continent. Most of sub-Saharan Africa has remained relatively vivax-free due to a high prevalence of the human Duffy-negative trait, but the emergence of strains able to invade Duffy-negative reticulocytes poses a major public health threat. We undertook the first population genomic investigation of P. vivax from the region, comparing the genomes of 24 Ethiopian isolates against data from Southeast Asia to identify important local adaptions. The prevalence of the Duffy binding protein amplification in Ethiopia was 79%, potentially reflecting adaptation to Duffy negativity. There was also evidence of selection in a region upstream of the chloroquine resistance transporter, a putative chloroquine-resistance determinant. Strong signals of selection were observed in genes involved in immune evasion and regulation of gene expression, highlighting the need for a multifaceted intervention approach to combat P. vivax in the region.
    Matched MeSH terms: Malaria, Vivax/parasitology*
  16. Commons RJ, Simpson JA, Thriemer K, Abreha T, Adam I, Anstey NM, et al.
    PLoS Med, 2019 Oct;16(10):e1002928.
    PMID: 31584960 DOI: 10.1371/journal.pmed.1002928
    BACKGROUND: Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax.

    METHODS AND FINDINGS: Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups.

    CONCLUSIONS: In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis.

    Matched MeSH terms: Malaria, Vivax/diagnosis; Malaria, Vivax/drug therapy*
  17. Barber BE, Grigg MJ, Piera K, Amante FH, William T, Boyle MJ, et al.
    J Infect Dis, 2019 09 26;220(9):1435-1443.
    PMID: 31250022 DOI: 10.1093/infdis/jiz334
    BACKGROUND: Anemia is a major complication of vivax malaria. Antiphosphatidylserine (PS) antibodies generated during falciparum malaria mediate phagocytosis of uninfected red blood cells that expose PS and have been linked to late malarial anemia. However, their role in anemia from non-falciparum Plasmodium species is not known, nor their role in early anemia from falciparum malaria.

    METHODS: We measured PS immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies in Malaysian patients with vivax, falciparum, knowlesi, and malariae malaria, and in healthy controls, and correlated antibody titres with hemoglobin. PS antibodies were also measured in volunteers experimentally infected with Plasmodium vivax and Plasmodium falciparum.

    RESULTS: PS IgM and IgG antibodies were elevated in patients with vivax, falciparum, knowlesi, and malariae malaria (P < .0001 for all comparisons with controls) and were highest in vivax malaria. In vivax and falciparum malaria, PS IgM and IgG on admission correlated inversely with admission and nadir hemoglobin, controlling for parasitemia and fever duration. PS IgM and IgG were also increased in volunteers infected with blood-stage P. vivax and P. falciparum, and were higher in P. vivax infection.

    CONCLUSIONS: PS antibodies are higher in vivax than falciparum malaria, correlate inversely with hemoglobin, and may contribute to the early loss of uninfected red blood cells found in malarial anemia from both species.

    Matched MeSH terms: Malaria, Vivax/complications*
  18. Oyong DA, Loughland JR, SheelaNair A, Andrew D, Rivera FDL, Piera KA, et al.
    Malar J, 2019 Sep 18;18(1):312.
    PMID: 31533836 DOI: 10.1186/s12936-019-2962-0
    BACKGROUND: Anaemia is a major consequence of malaria, caused by the removal of both infected and uninfected red blood cells (RBCs) from the circulation. Complement activation and reduced expression of complement regulatory proteins (CRPs) on RBCs are an important pathogenic mechanism in severe malarial anaemia in both Plasmodium falciparum and Plasmodium vivax infection. However, little is known about loss of CRPs on RBCs during mild malarial anaemia and in low-density infection.

    METHODS: The expression of CRP CR1, CD55, CD59, and the phagocytic regulator CD47, on uninfected normocytes and reticulocytes were assessed in individuals from two study populations: (1) P. falciparum and P. vivax-infected patients from a low transmission setting in Sabah, Malaysia; and, (2) malaria-naïve volunteers undergoing P. falciparum induced blood-stage malaria (IBSM). For clinical infections, individuals were categorized into anaemia severity categories based on haemoglobin levels. For IBSM, associations between CRPs and haemoglobin level were investigated.

    RESULTS: CRP expression on RBC was lower in Malaysian individuals with P. falciparum and P. vivax mild malarial anaemia compared to healthy controls. CRP expression was also reduced on RBCs from volunteers during IBSM. Reduction occurred on normocytes and reticulocytes. However, there was no significant association between reduced CRPs and haemoglobin during IBSM.

    CONCLUSIONS: Removal of CRPs occurs on both RBCs and reticulocytes during Plasmodium infection even in mild malarial anaemia and at low levels of parasitaemia.

    Matched MeSH terms: Malaria, Vivax/complications*; Malaria, Vivax/parasitology
  19. Commons RJ, Simpson JA, Thriemer K, Chu CS, Douglas NM, Abreha T, et al.
    BMC Med, 2019 08 01;17(1):151.
    PMID: 31366382 DOI: 10.1186/s12916-019-1386-6
    BACKGROUND: Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax.

    METHODS: A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model.

    RESULTS: In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p  25% to  5 g/dL.

    CONCLUSIONS: Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals.

    TRIAL REGISTRATION: This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016.

    Matched MeSH terms: Malaria, Vivax/complications*; Malaria, Vivax/drug therapy*
  20. Mussa A, Talib M, Mohamed Z, Hajissa K
    BMC Res Notes, 2019 Jun 11;12(1):334.
    PMID: 31186056 DOI: 10.1186/s13104-019-4361-6
    OBJECTIVE: Rapid diagnostic tests (RDTs) play a crucial role in the management and control of malaria infection. The histidine-rich protein 2 (PfHRP-2) based RDTs are the most commonly used RDTs for malaria diagnosis in Sudan. Deletion of pfhrp2 in Plasmodium falciparum genome affect the accuracy of PfHRP-2 based RDT kits. This study aimed to identify molecular variation of pfhrp2 among suspected malaria patients from different clinics in Omdurman, Sudan.

    RESULTS: A noticeable variation between the RDT (Alltest Biotech, China) and nPCR results was observed, for RDT 78% (46/59) were P. falciparum positive, 6.8% (4/59) were co-infected with both P. falciparum and Plasmodium vivax, 15.3% (9/59) were negative by the RDT. However, when the nPCR was applied only 44.1% (26/59) and 55.9% (33/59) was P. falciparum positive and negative respectively. The pfhrp2 was further amplified form all nPCR positive samples. Only 17 DNA samples were positive from the 26 positive P. falciparum, interestingly, variation in band sizes was observed and further confirmed by DNA sequencing, and sequencing analysis revealed a high-level of genetic diversity of the pfhrp2 gene in the parasite population from the study area. However, despite extreme sequence variation, diversity of PfHRP2 does not appear to affect RDT performance.

    Matched MeSH terms: Malaria, Vivax/diagnosis; Malaria, Vivax/parasitology
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