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    Malaria transmission structure in the Peruvian Amazon through antibody signatures to Plasmodium vivax.
    Rosado, J ; Carrasco-Escobar, G ; Nolasco, O ; Garro, K ; Rodriguez-Ferruci, H ; Guzman-Guzman, M ; Llanos-Cuentas, A ; Vinetz, JM ; Nekkab, N ; White, MT ; Mueller, I ; Gamboa, D ; Kamel, MG (Public Library of Science (PLoS), 2022-05)
    BACKGROUND: The landscape of malaria transmission in the Peruvian Amazon is temporally and spatially heterogeneous, presenting different micro-geographies with particular epidemiologies. Most cases are asymptomatic and escape routine malaria surveillance based on light microscopy (LM). Following the implementation of control programs in this region, new approaches to stratify transmission and direct efforts at an individual and community level are needed. Antibody responses to serological exposure markers (SEM) to Plasmodium vivax have proven diagnostic performance to identify people exposed in the previous 9 months. METHODOLOGY: We measured antibody responses against 8 SEM to identify recently exposed people and determine the transmission dynamics of P. vivax in peri-urban (Iquitos) and riverine (Mazán) communities of Loreto, communities that have seen significant recent reductions in malaria transmission. Socio-demographic, geo-reference, LM and qPCR diagnosis data were collected from two cross-sectional surveys. Spatial and multilevel analyses were implemented to describe the distribution of seropositive cases and the risk factors associated with exposure to P. vivax. PRINCIPAL FINDINGS: Low local transmission was detected by qPCR in both Iquitos (5.3%) and Mazán (2.7%); however, seroprevalence indicated a higher level of (past) exposure to P. vivax in Mazán (56.5%) than Iquitos (38.2%). Age and being male were factors associated with high odds of being seropositive in both sites. Higher antibody levels were found in individuals >15 years old. The persistence of long-lived antibodies in these individuals could overestimate the detection of recent exposure. Antibody levels in younger populations (<15 years old) could be a better indicator of recent exposure to P. vivax. CONCLUSIONS: The large number of current and past infections detected by SEMs allows for detailed local epidemiological analyses, in contrast to data from qPCR prevalence surveys which did not produce statistically significant associations. Serological surveillance will be increasingly important in the Peruvian Amazon as malaria transmission is reduced by continued control and elimination efforts.
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    Serology for Plasmodium vivax surveillance: A novel approach to accelerate towards elimination
    Tayipto, Y ; Liu, Z ; Mueller, I ; Longley, RJ (ELSEVIER IRELAND LTD, 2021-11-09)
    Plasmodium vivax is the most widespread causative agent of human malaria in the world. Despite the ongoing implementation of malaria control programs, the rate of case reduction has declined over the last 5 years. Hence, surveillance of malaria transmission should be in place to identify and monitor areas that require intensified malaria control interventions. Serological tools may offer additional insights into transmission intensity over parasite and entomological measures, especially as transmission levels decline. Antibodies can be detected in the host system for months to even years after parasite infections have been cleared from the blood, enabling malaria exposure history to be captured. Because the Plasmodium parasite expresses more than 5000 proteins, it is important to a) understand antibody longevity following infection and b) measure antibodies to more than one antigen in order to accurately inform on the exposure and/or immune status of populations. This review summarises current practices for surveillance of P. vivax malaria, the current state of research into serological exposure markers and their potential role for accelerating malaria elimination, and discusses further studies that need to be undertaken to see such technology implemented in malaria-endemic areas.
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    An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples.
    MalariaGEN, ; Ahouidi, A ; Ali, M ; Almagro-Garcia, J ; Amambua-Ngwa, A ; Amaratunga, C ; Amato, R ; Amenga-Etego, L ; Andagalu, B ; Anderson, TJC ; Andrianaranjaka, V ; Apinjoh, T ; Ariani, C ; Ashley, EA ; Auburn, S ; Awandare, GA ; Ba, H ; Baraka, V ; Barry, AE ; Bejon, P ; Bertin, GI ; Boni, MF ; Borrmann, S ; Bousema, T ; Branch, O ; Bull, PC ; Busby, GBJ ; Chookajorn, T ; Chotivanich, K ; Claessens, A ; Conway, D ; Craig, A ; D'Alessandro, U ; Dama, S ; Day, NP ; Denis, B ; Diakite, M ; Djimdé, A ; Dolecek, C ; Dondorp, AM ; Drakeley, C ; Drury, E ; Duffy, P ; Echeverry, DF ; Egwang, TG ; Erko, B ; Fairhurst, RM ; Faiz, A ; Fanello, CA ; Fukuda, MM ; Gamboa, D ; Ghansah, A ; Golassa, L ; Goncalves, S ; Hamilton, WL ; Harrison, GLA ; Hart, L ; Henrichs, C ; Hien, TT ; Hill, CA ; Hodgson, A ; Hubbart, C ; Imwong, M ; Ishengoma, DS ; Jackson, SA ; Jacob, CG ; Jeffery, B ; Jeffreys, AE ; Johnson, KJ ; Jyothi, D ; Kamaliddin, C ; Kamau, E ; Kekre, M ; Kluczynski, K ; Kochakarn, T ; Konaté, A ; Kwiatkowski, DP ; Kyaw, MP ; Lim, P ; Lon, C ; Loua, KM ; Maïga-Ascofaré, O ; Malangone, C ; Manske, M ; Marfurt, J ; Marsh, K ; Mayxay, M ; Miles, A ; Miotto, O ; Mobegi, V ; Mokuolu, OA ; Montgomery, J ; Mueller, I ; Newton, PN ; Nguyen, T ; Nguyen, T-N ; Noedl, H ; Nosten, F ; Noviyanti, R ; Nzila, A ; Ochola-Oyier, LI ; Ocholla, H ; Oduro, A ; Omedo, I ; Onyamboko, MA ; Ouedraogo, J-B ; Oyebola, K ; Pearson, RD ; Peshu, N ; Phyo, AP ; Plowe, CV ; Price, RN ; Pukrittayakamee, S ; Randrianarivelojosia, M ; Rayner, JC ; Ringwald, P ; Rockett, KA ; Rowlands, K ; Ruiz, L ; Saunders, D ; Shayo, A ; Siba, P ; Simpson, VJ ; Stalker, J ; Su, X-Z ; Sutherland, C ; Takala-Harrison, S ; Tavul, L ; Thathy, V ; Tshefu, A ; Verra, F ; Vinetz, J ; Wellems, TE ; Wendler, J ; White, NJ ; Wright, I ; Yavo, W ; Ye, H (F1000 Research Ltd, 2021)
    MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed.  Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
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    Global Population Genomics of Two Subspecies of Cryptosporidium hominis during 500 Years of Evolution
    Tichkule, S ; Caccio, SM ; Robinson, G ; Chalmers, RM ; Mueller, I ; Emery-Corbin, SJ ; Eibach, D ; Tyler, KM ; van Oosterhout, C ; Jex, AR ; Leitner, T (OXFORD UNIV PRESS, 2022-04-10)
    Cryptosporidiosis is a major global health problem and a primary cause of diarrhea, particularly in young children in low- and middle-income countries (LMICs). The zoonotic Cryptosporidium parvum and anthroponotic Cryptosporidium hominis cause most human infections. Here, we present a comprehensive whole-genome study of C. hominis, comprising 114 isolates from 16 countries within five continents. We detect two lineages with distinct biology and demography, which diverged circa 500 years ago. We consider these lineages two subspecies and propose the names C. hominis hominis and C. hominis aquapotentis (gp60 subtype IbA10G2). In our study, C. h. hominis is almost exclusively represented by isolates from LMICs in Africa and Asia and appears to have undergone recent population contraction. In contrast, C. h. aquapotentis was found in high-income countries, mainly in Europe, North America, and Oceania, and appears to be expanding. Notably, C. h. aquapotentis is associated with high rates of direct human-to-human transmission, which may explain its success in countries with well-developed environmental sanitation infrastructure. Intriguingly, we detected genomic regions of introgression following secondary contact between the subspecies. This resulted in high diversity and divergence in genomic islands of putative virulence genes, including muc5 (CHUDEA2_430) and a hypothetical protein (CHUDEA6_5270). This diversity is maintained by balancing selection, suggesting a co-evolutionary arms race with the host. Finally, we find that recent gene flow from C. h. aquapotentis to C. h. hominis, likely associated with increased human migration, maybe driving the evolution of more virulent C. hominis variants.
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    Developing sero-diagnostic tests to facilitate Plasmodium vivax Serological Test-and-Treat approaches: modeling the balance between public health impact and overtreatment.
    Obadia, T ; Nekkab, N ; Robinson, LJ ; Drakeley, C ; Mueller, I ; White, MT (Springer Science and Business Media LLC, 2022-03-18)
    BACKGROUND: Eliminating Plasmodium vivax will require targeting the hidden liver-stage reservoir of hypnozoites. This necessitates new interventions balancing the benefit of reducing vivax transmission against the risk of over-treating some individuals with drugs which may induce haemolysis. By measuring antibodies to a panel of vivax antigens, a strategy of serological-testing-and-treatment (PvSeroTAT) can identify individuals with recent blood-stage infections who are likely to carry hypnozoites and target them for radical cure. This provides a potential solution to selectively treat the vivax reservoir with 8-aminoquinolines. METHODS: PvSeroTAT can identify likely hypnozoite carriers with ~80% sensitivity and specificity. Diagnostic test sensitivities and specificities ranging 50-100% were incorporated into a mathematical model of vivax transmission to explore how they affect the risks and benefits of different PvSeroTAT strategies involving hypnozoiticidal regimens. Risk was measured as the rate of overtreatment and benefit as reduction of community-level vivax transmission. RESULTS: Across a wide range of combinations of diagnostic sensitivity and specificity, PvSeroTAT was substantially more effective than bloodstage mass screen and treat strategies and only marginally less effective than mass drug administration. The key test characteristic determining of the benefit of PvSeroTAT strategies is diagnostic sensitivity, with higher values leading to more hypnozoite carriers effectively treated and greater reductions in vivax transmission. The key determinant of risk is diagnostic specificity: higher specificity ensures that a lower proportion of uninfected individuals are unnecessarily treated with primaquine. These relationships are maintained in both moderate and low transmission settings (qPCR prevalence 10% and 2%). Increased treatment efficacy and adherence can partially compensate for lower test performance. Multiple rounds of PvSeroTAT with a lower performing test may lead to similar or higher reductions in vivax transmission than fewer rounds with a higher performing test, albeit with higher rate of overtreatment. CONCLUSIONS: At current performance, PvSeroTAT is predicted to be a safe and efficacious option for targeting the hypnozoite reservoir towards vivax elimination. P. vivax sero-diagnostic tests should aim for both high performance and ease of use in the field. The target product profiles informing such development should thus reflect the trade-offs between impact, overtreatment, and ease of programmatic implementation.
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    Naturally acquired antibody kinetics against Plasmodium vivax antigens in people from a low malaria transmission region in western Thailand
    Liu, ZS-J ; Sattabongkot, J ; White, M ; Chotirat, S ; Kumpitak, C ; Takashima, E ; Harbers, M ; Tham, W-H ; Healer, J ; Chitnis, CE ; Tsuboi, T ; Mueller, I ; Longley, RJ (BMC, 2022-03-09)
    BACKGROUND: Plasmodium vivax (P. vivax) is the dominant Plasmodium spp. causing the disease malaria in low-transmission regions outside of Africa. These regions often feature high proportions of asymptomatic patients with sub-microscopic parasitaemia and relapses. Naturally acquired antibody responses are induced after Plasmodium infection, providing partial protection against high parasitaemia and clinical episodes. However, previous work has failed to address the presence and maintenance of such antibody responses to P. vivax particularly in low-transmission regions. METHODS: We followed 34 patients in western Thailand after symptomatic P. vivax infections to monitor antibody kinetics over 9 months, during which no recurrent infections occurred. We assessed total IgG, IgG subclass and IgM levels to up to 52 P. vivax proteins every 2-4 weeks using a multiplexed Luminex® assay and identified protein-specific variation in antibody longevity. Mathematical modelling was used to generate the estimated half-life of antibodies, long-, and short-lived antibody-secreting cells. RESULTS: Generally, an increase in antibody level was observed within 1-week post symptomatic infection, followed by an exponential decay of different rates. We observed mostly IgG1 dominance and IgG3 sub-dominance in this population. IgM responses followed similar kinetic patterns to IgG, with some proteins unexpectedly inducing long-lived IgM responses. We also monitored antibody responses against 27 IgG-immunogenic antigens in 30 asymptomatic individuals from a similar region. Our results demonstrate that most antigens induced robust and long-lived total IgG responses following asymptomatic infections in the absence of (detected) boosting infections. CONCLUSIONS: Our work provides new insights into the development and maintenance of naturally acquired immunity to P. vivax and will guide the potential use of serology to indicate immune status and/or identify populations at risk.
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    Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens.
    Naung, MT ; Martin, E ; Munro, J ; Mehra, S ; Guy, AJ ; Laman, M ; Harrison, GLA ; Tavul, L ; Hetzel, M ; Kwiatkowski, D ; Mueller, I ; Bahlo, M ; Barry, AE ; Wallqvist, A (Public Library of Science (PLoS), 2022-02)
    Investigation of the diversity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies of vaccine candidates of the most virulent human malaria parasite, Plasmodium falciparum, have focused on a handful of well-known antigens, while several others have never been studied. Here we examine the global diversity and population structure of leading vaccine candidate antigens of P. falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. A stringent variant calling pipeline was used to extract high quality antigen gene 'haplotypes' from the global dataset and a new R-package named VaxPack was used to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp, trap, eba175, ama1, rh5, and CelTOS. Our analysis shows that current malaria vaccine formulations are based on rare haplotypes and thus may have limited efficacy against natural parasite populations. High levels of diversity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptation to different human host or mosquito vector populations. This study provides an essential framework for the diversity of P. falciparum antigens to be considered in the design of the next generation of malaria vaccines.
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    Infectivity of Symptomatic Malaria Patients to Anopheles farauti Colony Mosquitoes in Papua New Guinea
    Timinao, L ; Vinit, R ; Katusele, M ; Koleala, T ; Nate, E ; Czeher, C ; Burkot, TR ; Schofield, L ; Felger, I ; Mueller, I ; Laman, M ; Robinson, LJ ; Karl, S (FRONTIERS MEDIA SA, 2021-12-22)
    Plasmodium transmission from humans to mosquitoes is an understudied bottleneck in the transmission of malaria. Direct membrane feeding assays (DMFA) allow detailed malaria transmission studies from humans to mosquitoes. Especially for Plasmodium vivax, which cannot be cultured long-term under laboratory conditions, implementation of DMFAs requires proximity to P. vivax endemic areas. In this study, we investigated the infectivity of symptomatic Plasmodium infections to Anopheles farauti colony mosquitoes in Papua New Guinea (PNG). A total of 182 DMFAs were performed with venous blood collected from rapid diagnostic test (RDT) positive symptomatic malaria patients and subsequently analysed by light microscopy and quantitative real time polymerase chain reaction (qPCR). DMFAs resulted in mosquito infections in 20.9% (38/182) of cases. By light microscopy and qPCR, 10 - 11% of P. falciparum and 32 - 44% of P. vivax positive individuals infected An. farauti. Fifty-eight percent of P. vivax and 15% of P. falciparum gametocytaemic infections infected An farauti.
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    Comparison of total immunoglobulin G antibody responses to different protein fragments of Plasmodium vivax Reticulocyte binding protein 2b
    Bourke, C ; Takashima, E ; Chan, L-J ; Dietrich, MH ; Mazhari, R ; White, M ; Sattabongkot, J ; Tham, W-H ; Tsuboi, T ; Mueller, I ; Longley, R (BMC, 2022-03-04)
    BACKGROUND: Plasmodium vivax is emerging as the dominant and prevalent species causing malaria in near-elimination settings outside of Africa. Hypnozoites, the dormant liver stage parasite of P. vivax, are undetectable to any currently available diagnostic test, yet are a major reservoir for transmission. Advances have been made to harness the naturally acquired immune response to identify recent exposure to P. vivax blood-stage parasites and, therefore, infer the presence of hypnozoites. This in-development diagnostic is currently able to detect infections within the last 9-months with 80% sensitivity and 80% specificity. Further work is required to optimize protein expression and protein constructs used for antibody detection. METHODS: The antibody response against the top performing predictor of recent infection, P. vivax reticulocyte binding protein 2b (PvRBP2b), was tested against multiple fragments of different sizes and from different expression systems. The IgG induced against the recombinant PvRBP2b fragments in P. vivax infected individuals was measured at the time of infection and in a year-long observational cohort; both conducted in Thailand. RESULTS: The antibody responses to some but not all different sized fragments of PvRBP2b protein are highly correlated with each other, significantly higher 1-week post-P. vivax infection, and show potential for use as predictors of recent P. vivax infection. CONCLUSIONS: To achieve P. vivax elimination goals, novel diagnostics are required to aid in detection of hidden parasite reservoirs. PvRBP2b was previously shown to be the top candidate for single-antigen classification of recent P. vivax exposure and here, it is concluded that several alternative recombinant PvRBP2b fragments can achieve equal sensitivity and specificity at predicting recent P. vivax exposure.
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    PacBio long-read amplicon sequencing enables scalable high-resolution population allele typing of the complex CYP2D6 locus.
    Charnaud, S ; Munro, JE ; Semenec, L ; Mazhari, R ; Brewster, J ; Bourke, C ; Ruybal-Pesántez, S ; James, R ; Lautu-Gumal, D ; Karunajeewa, H ; Mueller, I ; Bahlo, M (Springer Science and Business Media LLC, 2022-02-25)
    The CYP2D6 enzyme is estimated to metabolize 25% of commonly used pharmaceuticals and is of intense pharmacogenetic interest due to the polymorphic nature of the CYP2D6 gene. Accurate allele typing of CYP2D6 has proved challenging due to frequent copy number variants (CNVs) and paralogous pseudogenes. SNP-arrays, qPCR and short-read sequencing have been employed to interrogate CYP2D6, however these technologies are unable to capture longer range information. Long-read sequencing using the PacBio Single Molecule Real Time (SMRT) sequencing platform has yielded promising results for CYP2D6 allele typing. However, previous studies have been limited in scale and have employed nascent data processing pipelines. We present a robust data processing pipeline "PLASTER" for accurate allele typing of SMRT sequenced amplicons. We demonstrate the pipeline by typing CYP2D6 alleles in a large cohort of 377 Solomon Islanders. This pharmacogenetic method will improve drug safety and efficacy through screening prior to drug administration.