ORCID Profile
0000-0001-9070-8499
Current Organisations
Ehime University
,
University of Tokyo
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Publisher: Public Library of Science (PLoS)
Date: 04-12-2020
DOI: 10.1371/JOURNAL.PONE.0238010
Abstract: Multiplexed bead-based assays that use Luminex ® xMAP ® technology have become popular for measuring antibodies against proteins of interest in many fields, including malaria and more recently SARS-CoV-2/COVID-19. There are currently two formats that are widely used: non-magnetic beads or magnetic beads. Data are lacking regarding the comparability of results obtained using these two types of beads, and for assays run on different instruments. Whilst non-magnetic beads can only be run on flow-based instruments (such as the Luminex ® 100/200™ or Bio-Plex ® 200), magnetic beads can be run on both these and the newer MAGPIX ® instruments. In this study we utilized a panel of purified recombinant Plasmodium vivax proteins and s les from malaria-endemic areas to measure P . vivax -specific IgG responses using different combinations of beads and instruments. We directly compared: i) non-magnetic versus magnetic beads run on a Bio-Plex ® 200, ii) magnetic beads run on the Bio-Plex ® 200 versus MAGPIX ® and iii) non-magnetic beads run on a Bio-Plex ® 200 versus magnetic beads run on the MAGPIX ® . We also performed an external comparison of our optimized assay. We observed that IgG antibody responses, measured against our panel of P . vivax proteins, were moderately-strongly correlated in all three of our comparisons (pearson r .5 for 18/19 proteins), however higher amounts of protein were required for coupling to magnetic beads. Our external comparison indicated that results generated in different laboratories using the same coupled beads are also highly comparable (pearson r .7), particularly if a reference standard curve is used.
Publisher: Frontiers Media SA
Date: 09-08-2022
DOI: 10.3389/FCIMB.2022.950909
Abstract: A more sensitive surveillance tool is needed to identify Plasmodium vivax infections for treatment and to accelerate malaria elimination efforts. To address this challenge, our laboratory has developed an eight-antigen panel that detects total IgG as serological markers of P. vivax exposure within the prior 9 months. The value of these markers has been established for use in areas with low transmission. In moderate–high transmission areas, there is evidence that total IgG is more long-lived than in areas with low transmission, resulting in poorer performance of these markers in these settings. Antibodies that are shorter-lived may be better markers of recent infection for use in moderate–high transmission areas. Using a multiplex assay, the antibody temporal kinetics of total IgG, IgG1, IgG3, and IgM against 29 P . vivax antigens were measured over 36 weeks following asymptomatic P. vivax infection in Papua New Guinean children ( n = 31), from an area with moderate–high transmission intensity. IgG3 declined faster to background than total IgG, IgG1, and IgM. Based on these kinetics, IgG3 performance was then assessed for classifying recent exposure in a cohort of Peruvian in iduals ( n = 590 age 3–85 years) from an area of moderate transmission intensity. Using antibody responses against in idual antigens, the highest performance of IgG3 in classifying recent P. vivax infections in the prior 9 months was to one of the Pv-fam-a proteins assessed (PVX_125728) (AUC = 0.764). Surprisingly, total IgG was overall a better marker of recent P. vivax infection, with the highest in idual classification performance to RBP2b 1986-2653 (PVX_094255) (AUC = 0.838). To understand the acquisition of IgG3 in this Peruvian cohort, relevant epidemiological factors were explored using a regression model. IgG3 levels were positively associated with increasing age, living in an area with (relatively) higher transmission intensity, and having three or more PCR-detected blood-stage P. vivax infections within the prior 13 months. Overall, we found that IgG3 did not have high accuracy for detecting recent exposure to P. vivax in the Peruvian cohort, with our data suggesting that this is due to the high levels of prior exposure required to acquire high IgG3 antibody levels.
Publisher: Public Library of Science (PLoS)
Date: 11-09-2017
Publisher: Cold Spring Harbor Laboratory
Date: 07-08-2020
DOI: 10.1101/2020.08.07.20169862
Abstract: To achieve malaria elimination, new tools are required to explicitly target Plasmodium vivax . Recently, a novel panel of P. vivax proteins were identified and validated as serological markers for detecting recent exposure to P. vivax within the last 9 months. In order to improve the sensitivity and specificity of these markers, IgM in addition to IgG antibody responses were assessed to a down-selected panel of 20 P. vivax proteins. IgM was tested using archival plasma s les from observational cohort studies conducted in malaria-endemic regions of Thailand and Brazil. IgM responses to these proteins generally had poorer classification performance than IgG.
Publisher: Cold Spring Harbor Laboratory
Date: 10-08-2020
DOI: 10.1101/2020.08.10.243980
Abstract: Multiplexed bead-based assays that use Luminex xMAP ® technology have become popular for measuring antibodies against proteins of interest in many fields, including malaria and more recently SARS-CoV-2/COVID-19. There are currently two formats that are widely used: non-magnetic beads or magnetic beads. Data is lacking regarding the comparability of results obtained using these two types of beads, and for assays run on different instruments. Whilst non-magnetic beads can only be run on flow-based instruments (such as the Luminex ® 100/200™ or Bio-Plex ® 200), magnetic beads can be run on both these and the newer MAGPIX ® instruments. In this study we utilized a panel of purified recombinant Plasmodium vivax proteins and s les from malaria-endemic areas to measure P. vivax -specific IgG responses using different combinations of beads and instruments. We directly compared: i) non-magnetic versus magnetic beads run on a Bio-Plex ® 200, ii) magnetic beads run on the Bio-Plex ® 200 versus MAGPIX ® and iii) non-magnetic beads run on a Bio-Plex ® 200 versus magnetic beads run on the MAGPIX ® . We also performed an external validation of our optimized assay. We observed that IgG antibody responses, measured against our panel of P. vivax proteins, were strongly correlated in all three of our comparisons, however higher amounts of protein were required for coupling to magnetic beads. Our external validation indicated that results generated in different laboratories using the same coupled beads are also highly comparable, particularly if a reference standard curve is used.
Publisher: Oxford University Press (OUP)
Date: 15-06-2022
Abstract: Understanding the effect of immunity on Plasmodium falciparum clearance is essential for interpreting therapeutic efficacy studies designed to monitor emergence of artemisinin drug resistance. In low-transmission areas of Southeast Asia, where resistance has emerged, P. falciparum antibodies confound parasite clearance measures. However, variation in naturally acquired antibodies across Asian and sub-Saharan African epidemiological contexts and their impact on parasite clearance re yet to be quantified. In an artemisinin therapeutic efficacy study, antibodies to 12 pre-erythrocytic and erythrocytic P. falciparum antigens were measured in 118 children with uncomplicated P. falciparum malaria in the Democratic Republic of Congo (DRC) and compared with responses in patients from Asian sites, described elsewhere. Parasite clearance half-life was shorter in DRC patients (median, 2 hours) compared with most Asian sites (median, 2–7 hours), but P. falciparum antibody levels and seroprevalences were similar. There was no evidence for an association between antibody seropositivity and parasite clearance half-life (mean difference between seronegative and seropositive, −0.14 to +0.40 hour) in DRC patients. In DRC, where artemisinin remains highly effective, the substantially shorter parasite clearance time compared with Asia was not explained by differences in the P. falciparum antibody responses studied.
Publisher: American Society for Microbiology
Date: 17-02-2022
DOI: 10.1128/IAI.00435-21
Abstract: Severe Plasmodium falciparum malaria kills many African children, and lack of antibody immunity predisposes to severe disease. A critical antibody target is the P. falciparum erythrocyte membrane 1 (PfEMP1) family of multidomain proteins, which are expressed on the infected erythrocyte surface and mediate parasite sequestration in deep organs.
Publisher: Springer Science and Business Media LLC
Date: 04-03-2022
DOI: 10.1186/S12936-022-04085-X
Abstract: 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. 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 in iduals was measured at the time of infection and in a year-long observational cohort both conducted in Thailand. 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. 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.
Publisher: Elsevier BV
Date: 06-2022
Publisher: Proceedings of the National Academy of Sciences
Date: 13-03-2017
Abstract: Slow-clearing artemisinin-resistant malaria parasites are now well established in the Greater Mekong Subregion. This large multinational therapy efficacy study incorporating clinical data, molecular drug-resistance markers, and immune profiling aimed to understand how variations in population levels of naturally acquired malarial immunity affect the slow-clearing phenotype, emergence of artemisinin resistance-associated mutations, and assessment of the geographical spread of artemisinin resistance. We found that slow-clearing mutant parasites occur at higher frequencies in areas where immunity is lowest, patients with higher immunity have faster clearance times, and immunity has the greatest effect on clearance in patients with slow-clearing mutant parasites. Immunity plays an important role in the emergence of resistant parasites and can confound the World Health Organization’s phenotype and genotype definitions of artemisinin resistance.
Publisher: Public Library of Science (PLoS)
Date: 03-12-2015
Publisher: Springer Science and Business Media LLC
Date: 05-05-2016
Publisher: Cold Spring Harbor Laboratory
Date: 30-11-2018
DOI: 10.1101/481168
Abstract: In order to accelerate towards malaria elimination, improved targeting of limited resources is essential. A major gap in our elimination toolkit for Plasmodium vivax malaria is the identification of in iduals carrying arrested liver stages, called hypnozoites. These clinically silent but frequently relapsing hypnozoites are key to P. vivax persistence. Whilst hypnozoites cannot be directly detected, in iduals who have had recent exposure to P. vivax and have not been treated are likely to harbor these parasites. By measuring IgG antibody responses to over 300 P. vivax proteins, a panel of serological markers capable of detecting exposure to P. vivax infections in the prior 9-month period was identified and validated. Using antibody responses to 8 P. vivax proteins, 80% sensitivity and specificity for detecting recent infections were achieved in three independent studies conducted in Thailand, Brazil and the Solomon Islands. As these in iduals have a high likelihood of harboring hypnozoites, the suite of these 8 antibody responses can serve as biomarkers for the identification of in iduals who should be targeted for treatment with liver-stage drugs such as primaquine and tafenoquine in mass drug administration programs aimed at controlling and eliminating P. vivax malaria. The manuscript describes identification and validation of a novel panel of P. vivax proteins that can be used to detect recent exposure to P. vivax infections within the prior 9 months.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2019
DOI: 10.1038/S41467-019-08528-Z
Abstract: Antibodies against P . falciparum merozoites fix complement to inhibit blood-stage replication in naturally-acquired and vaccine-induced immunity however, specific targets of these functional antibodies and their importance in protective immunity are unknown. Among malaria-exposed in iduals, we show that complement-fixing antibodies to merozoites are more strongly correlated with protective immunity than antibodies that inhibit growth quantified using the current reference assay for merozoite vaccine evaluation. We identify merozoite targets of complement-fixing antibodies and identify antigen-specific complement-fixing antibodies that are strongly associated with protection from malaria in a longitudinal study of children. Using statistical modelling, combining three different antigens targeted by complement-fixing antibodies could increase the potential protective effect to over 95%, and we identify antigens that were common in the most protective combinations. Our findings support antibody-complement interactions against merozoite antigens as important anti-malaria immune mechanisms, and identify specific merozoite antigens for further evaluation as vaccine candidates.
Publisher: Cold Spring Harbor Laboratory
Date: 23-10-2021
DOI: 10.1101/2021.10.21.464164
Abstract: Plasmodium 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. 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. 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 in iduals 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. 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.
Publisher: Cold Spring Harbor Laboratory
Date: 11-12-2021
DOI: 10.1101/2021.12.09.21266664
Abstract: Serological exposure markers are a promising tool for surveillance and targeted interventions for Plasmodium vivax malaria. P. vivax is closely related to the zoonotic parasite P. knowlesi , which also infects humans. P. vivax and P. knowlesi are co-endemic across much of South East Asia, making it important to design P. vivax serological markers that minimise cross-reactivity in this region. Our objective was to determine the degree of IgG antibody cross-reactivity against a panel of P. vivax serological markers in s les from human participants with P. knowlesi malaria. We observed higher levels of IgG antibody reactivity against P. vivax proteins that had high levels of sequence identity with their P. knowlesi ortholog. IgG reactivity peaked at 7 days post P. knowlesi infection and was short-lived, with minimal responses detected at 1-year post-infection. Using these data, we designed a panel of 8 P. vivax proteins with low-levels of cross-reactivity with P. knowlesi . This panel was able to accurately classify recent P. vivax infections whilst reducing misclassification of recent P. knowlesi infections.
Publisher: eLife Sciences Publications, Ltd
Date: 26-09-2017
DOI: 10.7554/ELIFE.28673
Abstract: The study of antigenic targets of naturally-acquired immunity is essential to identify and prioritize antigens for further functional characterization. We measured total IgG antibodies to 38 P. vivax antigens, investigating their relationship with prospective risk of malaria in a cohort of 1–3 years old Papua New Guinean children. Using simulated annealing algorithms, the potential protective efficacy of antibodies to multiple antigen-combinations, and the antibody thresholds associated with protection were investigated for the first time. High antibody levels to multiple known and newly identified proteins were strongly associated with protection (IRR 0.44–0.74, p .001–0.041). Among five-antigen combinations with the strongest protective effect ( %), EBP, DBPII, RBP1a, CyRPA, and PVX_081550 were most frequently identified several of them requiring very low antibody levels to show a protective association. These data identify in idual antigens that should be prioritized for further functional testing and establish a clear path to testing a multicomponent P. vivax vaccine.
Publisher: Frontiers Media SA
Date: 07-04-2022
DOI: 10.3389/FCIMB.2022.804470
Abstract: Understanding the human immune response to Plasmodium falciparum gametocytes and its association with gametocytemia is essential for understanding the transmission of malaria as well as progressing transmission blocking vaccine candidates. In a multi-national clinical efficacy trial of artemisinin therapies (13 sites of varying transmission over South-East Asia and Africa), we measured Immunoglobulin G (IgG) responses to recombinant P. falciparum gametocyte antigens expressed on the gametocyte plasma membrane and leading transmission blocking vaccine candidates Pf s230 ( Pf s230c and Pf s230D1M) and Pf s48/45 at enrolment in 1,114 participants with clinical falciparum malaria. Mixed effects linear and logistic regression were used to determine the association between gametocyte measures (gametocytemia and gametocyte density) and antibody outcomes at enrolment. Microscopy detectable gametocytemia was observed in 11% (127/1,114) of participants at enrolment, and an additional 9% (95/1,114) over the follow-up period (up to day 42) (total 20% of participants [222/1,114]). IgG levels in response to Pf s230c, Pf s48/45 and Pf s230D1M varied across study sites at enrolment ( p & 0.001 ), as did IgG seroprevalence for anti- Pf s230c and D1M IgG ( p & 0.001 ), but not for anti- Pf s48/45 IgG ( p = 0.159 ). In adjusted analyses, microscopy detectable gametocytemia at enrolment was associated with an increase in the odds of IgG seropositivity to the three gametocyte antigens ( Pf s230c OR [95% CI], p : 1.70 [1.10, 2.62], 0.017 Pf s48/45: 1.45 [0.85, 2.46], 0.174 Pf s230D1M: 1.70 [1.03, 2.80], 0.037 ), as was higher gametocyte density at enrolment (per two-fold change in gametocyte density Pf s230c OR [95% CI], p : 1.09 [1.02, 1.17], 0.008 Pf s48/45: 1.05 [0.98, 1.13], 0.185 Pf s230D1M: 1.07 [0.99, 1.14], 0.071 ). Pf s230 and Pf s48/45 antibodies are naturally immunogenic targets associated with patent gametocytemia and increasing gametocyte density across multiple malaria endemic settings, including regions with emerging artemisinin-resistant P. falciparum .
Publisher: F1000 Research Ltd
Date: 12-02-2019
DOI: 10.12688/GATESOPENRES.12897.1
Abstract: Measurement of malaria specific antibody responses represents a practical and informative method for malaria control programs to assess recent exposure to infection. Technical advances in recombinant antigen production, serological screening platforms, and analytical methods have enabled the identification of several target antigens for laboratory based and point-of-contact tests. Questions remain as to how these serological assays can best be integrated into malaria surveillance activities to inform programmatic decision-making. This report synthesizes discussions from a convening at Institut Pasteur in Paris in June 2017 aimed at defining practical and informative use cases for serology applications and highlights five programmatic uses for serological assays including: documenting the absence of transmission stratification of transmission measuring the effect of interventions informing a decentralized immediate response and testing and treating P. vivax hypnozoite carriers.
Publisher: Oxford University Press (OUP)
Date: 22-05-2021
DOI: 10.1093/OFID/OFAB228
Abstract: To achieve malaria elimination, new tools are required to explicitly target Plasmodium vivax. Recently, a novel panel of P. vivax proteins were identified and validated as serological markers for detecting recent exposure to P. vivax within the last 9 months. In order to improve the sensitivity and specificity of these markers, immunoglobulin M (IgM) in addition to immunoglobulin G (IgG) antibody responses were compared with a down-selected panel of 20 P. vivax proteins. IgM was tested using archival plasma s les from observational cohort studies conducted in malaria-endemic regions of Thailand and Brazil. IgM responses to these proteins generally had poorer classification performance than IgG.
Publisher: Springer Science and Business Media LLC
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 09-03-2022
DOI: 10.1186/S12916-022-02281-9
Abstract: 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. 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. 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 in iduals 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. 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.
Publisher: Frontiers Media SA
Date: 29-06-2021
DOI: 10.3389/FMICB.2021.643501
Abstract: Thailand is aiming for malaria elimination by the year 2030. However, the high proportion of asymptomatic infections and the presence of the hidden hypnozoite stage of Plasmodium vivax are impeding these efforts. We hypothesized that a validated surveillance tool utilizing serological markers of recent exposure to P. vivax infection could help to identify areas of ongoing transmission. The objective of this exploratory study was to assess the ability of P. vivax serological exposure markers to detect residual transmission “hot-spots” in Western Thailand. Total IgG levels were measured against a panel of 23 candidate P. vivax serological exposure markers using a multiplexed bead-based assay. A total of 4,255 plasma s les from a cross-sectional survey conducted in 2012 of endemic areas in the Kanchanaburi and Ratchaburi provinces were assayed. We compared IgG levels with multiple epidemiological factors that are associated with an increased risk of P. vivax infection in Thailand, including age, gender, and spatial location, as well as Plasmodium infection status itself. IgG levels to all proteins were significantly higher in the presence of a P. vivax infection ( n = 144) ( T -test, p & 0.0001). Overall seropositivity rates varied from 2.5% (PVX_097625, merozoite surface protein 8) to 16.8% (PVX_082670, merozoite surface protein 7), with 43% of in iduals seropositive to at least 1 protein. Higher IgG levels were associated with older age (& years, p & 0.05) and males (17/23 proteins, p & 0.05), supporting the paradigm that men have a higher risk of infection than females in this setting. We used a Random Forests algorithm to predict which in iduals had exposure to P. vivax parasites in the last 9-months, based on their IgG antibody levels to a panel of eight previously validated P. vivax proteins. Spatial clustering was observed at the village and regional level, with a moderate correlation between PCR prevalence and sero-prevalence as predicted by the algorithm. Our data provides proof-of-concept for application of such surrogate markers as evidence of recent exposure in low transmission areas. These data can be used to better identify geographical areas with asymptomatic infection burdens that can be targeted in elimination c aigns.
Publisher: Frontiers Media SA
Date: 05-04-2019
Publisher: Public Library of Science (PLoS)
Date: 21-11-2013
No related grants have been discovered for Eizo Takashima.