scholarly journals IgG antibody responses are preferential compared to IgM for use as serological markers for detecting recent exposure to Plasmodium vivax infection

2020 ◽  
Author(s):  
Rhea Longley ◽  
Michael White ◽  
Jessica Brewster ◽  
Zoe Liu ◽  
Caitlin Bourke ◽  
...  
Keyword(s):  
Cohort Studies ◽  
Plasmodium Vivax ◽  
Malaria Elimination ◽  
Classification Performance ◽  
Antibody Responses ◽  
Plasma Samples ◽  
Serological Markers ◽  
Igg Antibody ◽  
Recent Exposure ◽  
Observational Cohort

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 samples 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.

scholarly journals IgG antibody responses are preferential compared to IgM for use as serological markers for detecting recent exposure to Plasmodium vivax infection

2021 ◽  
Author(s):  
Rhea J Longley ◽  
Michael T White ◽  
Jessica Brewster ◽  
Zoe S J Liu ◽  
Caitlin Bourke ◽  
...  
Keyword(s):  
Cohort Studies ◽  
Plasmodium Vivax ◽  
Malaria Elimination ◽  
Classification Performance ◽  
Antibody Responses ◽  
Plasma Samples ◽  
Serological Markers ◽  
Igg Antibody ◽  
Recent Exposure ◽  
Observational Cohort

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 samples 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.

scholarly journals Development and validation of serological markers for detecting recent exposure to Plasmodium vivax infection

2018 ◽  
Author(s):  
Rhea J. Longley ◽  
Michael T. White ◽  
Eizo Takashima ◽  
Jessica Brewster ◽  
Masayuki Morita ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Solomon Islands ◽  
Antibody Responses ◽  
Limited Resources ◽  
Serological Markers ◽  
High Likelihood ◽  
Igg Antibody ◽  
Liver Stage ◽  
Recent Exposure ◽  
Development And Validation

AbstractIn 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 individuals 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, individuals 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 individuals have a high likelihood of harboring hypnozoites, the suite of these 8 antibody responses can serve as biomarkers for the identification of individuals 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.One Sentence SummaryThe 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.

scholarly journals Application of 23 novel serological markers for identifying recent exposure to Plasmodium vivax parasites in an endemic population of western Thailand

2021 ◽  
Author(s):  
Sadudee Chotirat ◽  
Narimane Nekkab ◽  
Chalermpon Kumpitak ◽  
Jenni Hietanen ◽  
Michael T White ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Spatial Clustering ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Serological Markers ◽  
Igg Antibody ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Recent Exposure ◽  
Increased Risk

AbstractThailand 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 4255 plasma samples 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 individuals seropositive to at least 1 protein. Higher IgG levels were associated with older age (>18 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 individuals had exposure to P. vivax parasites in the last 9-months, based on their IgG antibody levels to a panel of 8 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 campaigns.

scholarly journals Heterogeneity in response to serological exposure markers of recent Plasmodium vivax infections

2020 ◽  
Author(s):  
Jason Rosado ◽  
Michael T. White ◽  
Rhea J. Longley ◽  
Wuelton Monteiro ◽  
Marcus Lacerda ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Malaria Elimination ◽  
Antibody Responses ◽  
Blood Stage ◽  
Transmission Intensity ◽  
Low Transmission ◽  
Recent Exposure ◽  
High Transmission ◽  
Antibody Titers

AbstractBackgroundAntibody responses to serological markers of Plasmodium vivax infection have been shown to correlate with exposure, but little is known about the other factors which affect antibody responses in naturally infected people from endemic settings. To address this question, we studied IgG responses to novel serological exposure markers (SEMs) of P. vivax in three settings with different transmission intensity.MethodologyWe validated a panel of 34 SEMs in a Peruvian cohort with up to three years’ longitudinal follow-up using the Luminex® platform and compared results to data from cohorts in Thailand and Brazil. Linear regression models were used to characterize the association between antibody responses and age, the number of detected blood-stage infections during follow-up, and time since the last infection. Receiver Operating Characteristic (ROC) analysis was used to test the performance of SEMs to identify P. vivax infections in the last 9 months.Principal findingsAntibody titers were associated with age, the number of blood-stage infections, and time since last P. vivax infection in all three study sites. The association between antibody titers and time since last P. vivax infection was stronger in the low transmission settings of Thailand and Brazil compared to the high transmission setting in Peru. Of the SEMs tested, antibody responses to RBP2b had the highest performance of classifying recent exposure in all sites, with area under the ROC curve (AUC) = 0.83 in Thailand, AUC = 0.79 in Brazil, and AUC = 0.68 in Peru.ConclusionsIn low transmission settings, P. vivax SEMs can accurately identify individuals with recent blood-stage infections. In high transmission settings, the accuracy of this approach diminishes substantially. We recommend the application of P. vivax SEMs for use in low transmission settings pursuing malaria elimination, but they appear less useful in high transmission settings focused on malaria control.Author SummaryPlasmodium vivax still poses a threat in many countries due to its ability to cause recurrent infections. Key to achieving the goal of malaria elimination is the ability to quickly detect and treat carriers of relapsing parasites. Failing to identify this transmission reservoir will hinder progress towards malaria elimination. Recently, novel serological markers of recent exposure to P. vivax (SEM) have been developed and validated in low transmission settings. It is still poorly understood what factors affect the antibody response to these markers when evaluated in contrasting endemic contexts. To determine the factors that influence the antibody response to SEM, we compare the antibody levels in three sites with different transmission intensity: Thailand (low), Brazil (moderate) and Peru (high). In this study, we found that transmission intensity plays a key role in the acquisition of the antibody repertoire to P. vivax. In highly endemic sites, the immunological memory resulting from a constant and sustained exposure will impact the performance of SEMs to detect individuals with recent exposure to P. vivax. In summary, SEMs that perform well in low transmission sites do not perform as well in high transmission regions.

scholarly journals Application of 23 Novel Serological Markers for Identifying Recent Exposure to Plasmodium vivax Parasites in an Endemic Population of Western Thailand

2021 ◽  
Vol 12 ◽  
Author(s):  
Sadudee Chotirat ◽  
Narimane Nekkab ◽  
Chalermpon Kumpitak ◽  
Jenni Hietanen ◽  
Michael T. White ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Spatial Clustering ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Serological Markers ◽  
Igg Antibody ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Recent Exposure ◽  
Increased Risk

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 samples 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 &lt; 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 individuals seropositive to at least 1 protein. Higher IgG levels were associated with older age (&gt;18 years, p &lt; 0.05) and males (17/23 proteins, p &lt; 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 individuals 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 campaigns.

scholarly journals Polymorphisms in B Cell Co-Stimulatory Genes Are Associated with IgG Antibody Responses against Blood–Stage Proteins of Plasmodium vivax

PLoS ONE ◽  
2016 ◽  
Vol 11 (2) ◽  
pp. e0149581 ◽  
Author(s):  
Gustavo C. Cassiano ◽  
Adriana A. C. Furini ◽  
Marcela P. Capobianco ◽  
Luciane M. Storti-Melo ◽  
Maristela G. Cunha ◽  
...  
Keyword(s):  
B Cell ◽  
Plasmodium Vivax ◽  
Antibody Responses ◽  
Blood Stage ◽  
Igg Antibody

scholarly journals A comparison of non-magnetic and magnetic beads for measuring IgG antibodies against Plasmodium vivax antigens in a multiplexed bead-based assay using Luminex technology (Bio-Plex 200 or MAGPIX)

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0238010
Author(s):  
Ramin Mazhari ◽  
Jessica Brewster ◽  
Rich Fong ◽  
Caitlin Bourke ◽  
Zoe S. J. Liu ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Magnetic Beads ◽  
Antibody Responses ◽  
Strongly Correlated ◽  
Igg Antibodies ◽  
Igg Antibody ◽  
Standard Curve ◽  
Luminex Technology ◽  
Specific Igg ◽  
Comparability Of Results

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 samples 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>0.5 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>0.7), particularly if a reference standard curve is used.

scholarly journals Distinct kinetics in antibody responses to 111 Plasmodium falciparum antigens identifies novel serological markers of recent malaria exposure

2020 ◽  
Author(s):  
Victor Yman ◽  
James Tuju ◽  
Michael T White ◽  
Gathoni Kamuyu ◽  
Kennedy Mwai ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Disease Burden ◽  
Antibody Responses ◽  
Serological Markers ◽  
Limited Data ◽  
Malaria Surveillance ◽  
Igg Antibody ◽  
Malaria Exposure ◽  
C And N ◽  
Antibody Kinetics

Strengthening malaria surveillance is a key intervention needed to reduce the global disease burden. Reliable serological markers of recent malaria exposure could dramatically improve current surveillance methods by allowing for accurate estimates of infection incidence from limited data. We studied the IgG antibody response to 111 Plasmodium falciparum proteins in travellers followed longitudinally after a natural malaria infection in complete absence of re-exposure. We identified a novel combination of five serological markers (GAMA, MSP1, MSPDBL1 C- and N-terminal, and PfSEA1) that detect exposure within the previous 3-months with >80% sensitivity and specificity. Using mathematical modelling, we examined the antibody kinetics and determined that responses informative of recent exposure display several distinct characteristics: rapid initial boosting and decay, less inter-individual variation in response kinetics, and minimal persistence over time. These serological exposure markers can be incorporated into routine malaria surveillance to guide efforts for malaria control and elimination.

scholarly journals Natural infections with different Plasmodium species induce antibodies reactive to a chimeric Plasmodium vivax recombinant protein

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Jessica N. McCaffery ◽  
Balwan Singh ◽  
Douglas Nace ◽  
Alberto Moreno ◽  
Venkatachalam Udhayakumar ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Malaria Elimination ◽  
Malaria Incidence ◽  
Binding Capacity ◽  
Specific Antigen ◽  
Plasmodium Species ◽  
Population Level ◽  
Antibody Detection ◽  
Plasma Samples ◽  
High Responders

Abstract Background As malaria incidence and transmission in a region decreases, it becomes increasingly difficult to identify areas of active transmission. Improved methods for identifying and monitoring foci of active malaria transmission are needed in areas of low parasite prevalence in order to achieve malaria elimination. Serological assays can provide population-level infection history to inform elimination campaigns. Methods A bead-based multiplex antibody detection assay was used to evaluate a chimeric Plasmodium vivax MSP1 protein (PvRMC-MSP1), designed to be broadly immunogenic for use in vaccine studies, to act as a pan-malaria serological tool based on its ability to capture IgG in plasma samples obtained from naturally exposed individuals. Samples from 236 US travellers with PCR confirmed infection status from all four major Plasmodium species infecting humans, Plasmodium falciparum (n = 181), Plasmodium vivax (n = 38), Plasmodium malariae (n = 4), and Plasmodium ovale (n = 13) were tested for IgG capture using PvRMC-MSP1 as well as the four recombinant MSP1-19 kD isoforms representative of these Plasmodium species. Results Regardless of infecting Plasmodium species, a large proportion of plasma samples from infected US travellers provided a high assay signal to the PvRMC-MSP1 chimeric protein, with 115 high responders out of 236 samples assessed (48.7%). When grouped by active infection, 38.7% P. falciparum-, 92.1% of P. vivax-, 75.0% P. malariae-, and 53.4% of P. ovale-infected individuals displayed high assay signals in response to PvRMC-MSP1. It was also determined that plasma from P. vivax-infected individuals produced increased assay signals in response to the PvRMC-MSP1 chimera as compared to the recombinant PvMSP1 for 89.5% (34 out of 38) of individuals. PvRMC-MSP1 also showed improved ability to capture IgG antibodies from P. falciparum-infected individuals when compared to the capture by recombinant PvMSP1, with high assay signals observed for 38.7% of P. falciparum-infected travellers in response to PvRMC-MSP1 IgG capture compared to just 1.1% who were high responders to capture by the recombinant PvMSP1 protein. Conclusions These results support further study of designed antigens as an approach for increasing sensitivity or broadening binding capacity to improve existing serological tools for determining population-level exposure to Plasmodium species. Including both broad-reacting and Plasmodium species-specific antigen-coated beads in an assay panel could provide a nuanced view of population-level exposure histories, an extensive IgG profile, and detailed seroestimates. A more sensitive serological tool for detection of P. vivax exposure would aid malaria elimination campaigns in co-endemic areas and regions where P. vivax is the dominant parasite.

scholarly journals Serological signatures of SARS-CoV-2 infection: Implications for antibody-based diagnostics

2020 ◽  
Author(s):  
Jason Rosado ◽  
Stéphane Pelleau ◽  
Charlotte Cockram ◽  
Sarah Hélène Merkling ◽  
Narimane Nekkab ◽  
...  
Keyword(s):  
Population Level ◽  
Classification Performance ◽  
Negative Control ◽  
Antibody Responses ◽  
Serum Samples ◽  
Igg Antibody ◽  
Low Transmission ◽  
Control Serum ◽  
Challenges And Opportunities ◽  
Serological Diagnostics

AbstractBackgroundInfection with SARS-CoV-2 induces an antibody response targeting multiple antigens that changes over time. This complexity presents challenges and opportunities for serological diagnostics.MethodsA multiplex serological assay was developed to measure IgG and IgM antibody responses to seven SARS-CoV-2 spike or nucleoprotein antigens, two antigens for the nucleoproteins of the 229E and NL63 seasonal coronaviruses, and three non-coronavirus antigens. Antibodies were measured in serum samples from patients in French hospitals with RT-qPCR confirmed SARS-CoV-2 infection (n = 259), and negative control serum samples collected before the start of the SARS-CoV-2 epidemic (n = 335). A random forests algorithm was trained with the multiplex data to classify individuals with previous SARS-CoV-2 infection. A mathematical model of antibody kinetics informed by prior information from other coronaviruses was used to estimate time-varying antibody responses and assess the potential sensitivity and classification performance of serological diagnostics during the first year following symptom onset. A statistical estimator is presented that can provide estimates of seroprevalence in very low transmission settings.ResultsIgG antibody responses to trimeric Spike protein identified individuals with previous RT-qPCR confirmed SARS-CoV-2 infection with 91.6% sensitivity (95% confidence interval (CI); 87.5%, 94.5%) and 99.1% specificity (95% CI; 97.4%, 99.7%). Using a serological signature of IgG and IgM to multiple antigens, it was possible to identify infected individuals with 98.8% sensitivity (95% CI; 96.5%, 99.6%) and 99.3% specificity (95% CI; 97.6%, 99.8%). Informed by prior data from other coronaviruses, we estimate that one year following infection a monoplex assay with optimal anti-Stri IgG cutoff has 88.7% sensitivity (95% CI: 63.4%, 97.4%), and that a multiplex assay can increase sensitivity to 96.4% (95% CI: 80.9%, 100.0%). When applied to population-level serological surveys, statistical analysis of multiplex data allows estimation of seroprevalence levels less than 1%, below the false positivity rate of many other assays.ConclusionSerological signatures based on antibody responses to multiple antigens can provide accurate and robust serological classification of individuals with previous SARS-CoV-2 infection. This provides potential solutions to two pressing challenges for SARS-CoV-2 serological surveillance: classifying individuals who were infected greater than six months ago, and measuring seroprevalence in serological surveys in very low transmission settings.

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