Development and validation of serological markers for detecting recent exposure to<i>Plasmodium vivax</i>infection

Longley, Rhea J.; Mt, White; Takashima, Eizo; Brewster, Jessica; Morita, Masayuki; Harbers, Matthias; Lj, Robinson; S, Zoe Liu; Csn, Li-Wai-Suen; Tham, Wai‐Hong; Healer, Julie; Huon, Christèle; Ce, Chitnis; Nguitragool, Wang; Monteiro, Wuelton Marcelo; Proietti, Carla; Doolan, Denise L.; Xc, Ding; Ij, Gonzalez; Kazura, James W.; Lacerda, Marcus Vinícius Guimarães; Sattabongkot, Jetsumon; Tsuboi, Takafumi; Müeller, Ivo

doi:10.1101/481168

Cited by 11 publications

(24 citation statements)

References 61 publications

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“…There is also substantial between-individual variation in the antibody response generated following SARS-CoV-2 infection. By measuring multiple biomarkers in large numbers of individuals, it is possible to create a serological signature of previous infection [17][18][19]. Although necessarily more complex than a single measured antibody response, such an approach has the potential of providing more accurate classification and being more stable over time.…”

Section: Discussionmentioning

confidence: 99%

“…Measured antibody responses to multiple antigens can be combined to identify individuals with previous SARS-CoV-2 infection using classification algorithms. Here we use a random forests algorithm [17].…”

Section: Statistical Evaluation Of Diagnostic Performancementioning

confidence: 99%

“…The challenge lies in selecting appropriate biomarkers and choosing between the increasing number of commercial assays, many of which have not been extensively validated and may produce conflicting results. The opportunity is that with multiple biomarkers, it is possible to generate a serological signature of infection that is robust to how antibody levels change over time [17][18][19][20], rather than relying on classification of sero-positive individuals using a single cutoff antibody level.…”

Section: Introductionmentioning

confidence: 99%

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

Rosado

Pelleau

Cockram

et al. 2020

Preprint

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BackgroundThe antibody response generated following infection with SARS-CoV-2 is expected to decline over time. This may cause individuals with confirmed SARS-CoV-2 infection to test negative according to serological diagnostic tests in the months and years following symptom onset. MethodsA multiplex serological assay was developed to measure IgG and IgM antibody responses to four SARS-CoV-2 Spike (S) antigens: spike trimeric ectodomain (S tri ), its receptor-binding domain (RBD), spike subunit 1 (S1), and spike subunit 2 (S2).Antibody responses were measured in serum samples from patients in French hospitals with RT-qPCR confirmed infection (n = 259), and negative control serum samples collected before the start of the SARS-CoV-2 epidemic in 2019 (n = 335).The multiplex antibody data was used to train a random forests algorithm for classifying 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. ResultsIgG antibody responses to one S antigen identified individuals with previous RT-qPCR confirmed SARS-CoV-2 infection with 90.3% sensitivity (95% confidence interval (CI); 86.1%, 93.4%) and 99.1% specificity (95% CI; 97.4%, 99.7%). Using a serological signature of IgG to four antigens, it was possible to identify infected individuals with 96.1% sensitivity (95% CI; 93.0%, 97.9%) and 99.1% specificity (95% CI; 97.4%, 99.7%). Antibody responses to SARS-CoV-2 increase rapidly 1-2 weeks after symptom onset, with antibody responses predicted to peak within 2-4 weeks. Informed by prior data from other coronaviruses, one year following symptom onset antibody responses are predicted to decay by approximately 60% from the peak response. Depending on the selection of sero-positivity cutoff, we estimate that the sensitivity of serological diagnostics may reduce to 56% -97% after six months, and to 49% -93% after one year. ConclusionSerological signatures based on antibody responses to multiple antigens can provide more accurate and robust serological classification of individuals with previous SARS-CoV-2 infection. Changes in antibody levels over time may cause reductions in the sensitivity of serological diagnostics leading to an underestimation of sero-prevalence. It is essential that data continue to be collected to evaluate this potential risk.

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Section: Discussionmentioning

confidence: 99%

Section: Statistical Evaluation Of Diagnostic Performancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Rosado

Pelleau

Cockram

et al. 2020

Preprint

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“…different rates of acquisition, boosting, and decay, and researchers have now started to study these antibody kinetic profiles for many antibodies to P. falciparum and P. vivax , and to characterize their suitability for estimating recent exposure in different age groups and transmission settings 23 . Several ongoing efforts are using this information to identify antibody signatures that are reliable, quantitative measures of recent exposure to malaria parasites 24– 28 . In parallel with biomarker identification, antigen production methods, analytics and technology platforms have advanced sufficiently to generate malaria antibody assays that will be field deployable in the near future.…”

Section: Introductionmentioning

confidence: 99%

Priority use cases for antibody-detecting assays of recent malaria exposure as tools to achieve and sustain malaria elimination

et al. 2019

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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.

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“…Others have shown that combining antibody responses to multiple targets more accurately reflects recent malaria infection than to one antigen though at small increments 4,31,32 . The fact that this study showed that multiplex antimalarial antibody data could be collected accurately at scale aids in ensuring representation of the variation in human immune responses.…”

mentioning

confidence: 99%

Quality control of multiplex antibody detection in samples from large-scale surveys: the example of malaria in Haiti

Hoogen

Présumé²,

Romilus³

et al. 2020

Sci Rep

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Measuring antimalarial antibodies can estimate transmission in a population. to compare outputs, standardized laboratory testing is required. Here we describe the in-country establishment and quality control (QC) of a multiplex bead assay (MBA) for three sero-surveys in Haiti. Total IgG data against 21 antigens were collected for 32,758 participants. Titration curves of hyperimmune sera were included on assay plates, assay signals underwent 5-parameter regression, and inspection of the median and interquartile range (IQR) for the y-inflection point was used to determine assay precision. The medians and IQRs were similar for Surveys 1 and 2 for most antigens, while the IQRs increased for some antigens in Survey 3. Levey-Jennings charts for selected antigens provided a pass/fail criterion for each assay plate and, of 387 assay plates, 13 (3.4%) were repeated. Individual samples failed if IgG binding to the generic glutathione-S-transferase protein was observed, with 659 (2.0%) samples failing. An additional 455 (1.4%) observations failed due to low bead numbers (<20/analyte). The final dataset included 609,438 anti-malaria IgG data points from 32,099 participants; 96.6% of all potential data points if no Qc failures had occurred. the MBA can be deployed with high-throughput data collection and low interplate variability while ensuring data quality.Measurement of antibody responses to malaria at the population-level can describe recent and historical transmission patterns 1-4 and is informative for malaria research and program policies 5-7 . Antibodies can be quantitatively measured by a variety of techniques including the enzyme-linked immunosorbent assay (ELISA) and multiplex bead assays (MBAs). The latter allows the simultaneous detection of antibodies to multiple antigenic targets and has been utilized now for Plasmodium serology for over a decade 8 . Since the advent of Plasmodium-specific MBAs, numerous assay optimisation and implementation studies 9-17 , as well as epidemiological application studies 18-21 , have been published by various groups.In generating responses to many antigens simultaneously, MBAs have the advantage of reducing needed reagent quantities, sample volume, and time in the laboratory compared to the ELISA 8,9 . Assays of any type require controls or standards to assess variability across runs or batches and to compare research studies, and with a broad panel of antigens in the MBA, it is potentially difficult to find standards for all targets being assayed. Recently, standardization using curves of known concentrations of total human IgG has been suggested, but this was problematic in showing insufficient reproducibility between operators 13 . Moreover, these do not allow for the assessment of antigen-specific responses which are important for quality control in assessing the stability of www.nature.com/scientificreports www.nature.com/scientificreports/ specific antibodies over time. In-house pools of hyperimmune sera are commonly employed for serological studies, and recently, a World H...

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Development and validation of serological markers for detecting recent exposure toPlasmodium vivaxinfection

Cited by 11 publications

References 61 publications

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

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

Priority use cases for antibody-detecting assays of recent malaria exposure as tools to achieve and sustain malaria elimination

Quality control of multiplex antibody detection in samples from large-scale surveys: the example of malaria in Haiti

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