Identification and validation of a novel panel of Plasmodium knowlesi biomarkers of serological exposure

Lou S. Herman, Kimberly Fornace, Jody Phelan, Matthew J. Grigg, Nicholas M. Anstey, Timothy William, Robert W. Moon, Michael J. Blackman, Chris J. Drakeley, Kevin K.A. Tetteh

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Abstract

Background: Plasmodium knowlesi is the most common cause of malaria in Malaysian Borneo, with reporting limited to clinical cases presenting to health facilities and scarce data on the true extent of transmission. Serological estimations of transmission have been used with other malaria species to garner information about epidemiological patterns. However, there are a distinct lack of suitable serosurveillance tools for this neglected disease. 

Methodology/Principal findings: Using in silico tools, we designed and expressed four novel P. knowlesi protein products to address the distinct lack of suitable serosurveillance tools: PkSERA3 antigens 1 and 2, PkSSP2/TRAP and PkTSERA2 antigen 1. Antibody prevalence to these antigens was determined by ELISA for three time-points post-treatment from a hospital-based clinical treatment trial in Sabah, East Malaysia (n = 97 individuals; 241 total samples for all time points). Higher responses were observed for the PkSERA3 antigen 2 (67%, 65/97) across all time-points (day 0: 36.9% 34/92; day 7: 63.8% 46/72; day 28: 58.4% 45/77) with significant differences between the clinical cases and controls (n = 55, mean plus 3 SD) (day 0 p<0.0001; day 7 p<0.0001; day 28 p<0.0001). Using boosted regression trees, we developed models to classify P. knowlesi exposure (cross-validated AUC 88.9%; IQR 86.1–91.3%) and identified the most predictive antibody responses. 

Conclusions/Significance: The PkSERA3 antigen 2 had the highest relative variable importance in all models. Further validation of these antigens is underway to determine the specificity of these tools in the context of multi-species infections at the population level.

Original languageEnglish
Article numbere0006457
Pages (from-to)1-21
Number of pages21
JournalPLoS Neglected Tropical Diseases
Volume12
Issue number6
DOIs
Publication statusPublished - 14 Jun 2018

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Plasmodium knowlesi
Biomarkers
Antigens
Malaysia
Malaria
Borneo
Neglected Diseases
Health Facilities
Computer Simulation
Area Under Curve
Antibody Formation
Enzyme-Linked Immunosorbent Assay
Clinical Trials
Antibodies
Therapeutics
Infection

Cite this

Herman, Lou S. ; Fornace, Kimberly ; Phelan, Jody ; Grigg, Matthew J. ; Anstey, Nicholas M. ; William, Timothy ; Moon, Robert W. ; Blackman, Michael J. ; Drakeley, Chris J. ; Tetteh, Kevin K.A. / Identification and validation of a novel panel of Plasmodium knowlesi biomarkers of serological exposure. In: PLoS Neglected Tropical Diseases. 2018 ; Vol. 12, No. 6. pp. 1-21.
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title = "Identification and validation of a novel panel of Plasmodium knowlesi biomarkers of serological exposure",
abstract = "Background: Plasmodium knowlesi is the most common cause of malaria in Malaysian Borneo, with reporting limited to clinical cases presenting to health facilities and scarce data on the true extent of transmission. Serological estimations of transmission have been used with other malaria species to garner information about epidemiological patterns. However, there are a distinct lack of suitable serosurveillance tools for this neglected disease. Methodology/Principal findings: Using in silico tools, we designed and expressed four novel P. knowlesi protein products to address the distinct lack of suitable serosurveillance tools: PkSERA3 antigens 1 and 2, PkSSP2/TRAP and PkTSERA2 antigen 1. Antibody prevalence to these antigens was determined by ELISA for three time-points post-treatment from a hospital-based clinical treatment trial in Sabah, East Malaysia (n = 97 individuals; 241 total samples for all time points). Higher responses were observed for the PkSERA3 antigen 2 (67{\%}, 65/97) across all time-points (day 0: 36.9{\%} 34/92; day 7: 63.8{\%} 46/72; day 28: 58.4{\%} 45/77) with significant differences between the clinical cases and controls (n = 55, mean plus 3 SD) (day 0 p<0.0001; day 7 p<0.0001; day 28 p<0.0001). Using boosted regression trees, we developed models to classify P. knowlesi exposure (cross-validated AUC 88.9{\%}; IQR 86.1–91.3{\%}) and identified the most predictive antibody responses. Conclusions/Significance: The PkSERA3 antigen 2 had the highest relative variable importance in all models. Further validation of these antigens is underway to determine the specificity of these tools in the context of multi-species infections at the population level.",
author = "Herman, {Lou S.} and Kimberly Fornace and Jody Phelan and Grigg, {Matthew J.} and Anstey, {Nicholas M.} and Timothy William and Moon, {Robert W.} and Blackman, {Michael J.} and Drakeley, {Chris J.} and Tetteh, {Kevin K.A.}",
year = "2018",
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Herman, LS, Fornace, K, Phelan, J, Grigg, MJ, Anstey, NM, William, T, Moon, RW, Blackman, MJ, Drakeley, CJ & Tetteh, KKA 2018, 'Identification and validation of a novel panel of Plasmodium knowlesi biomarkers of serological exposure', PLoS Neglected Tropical Diseases, vol. 12, no. 6, e0006457, pp. 1-21. https://doi.org/10.1371/journal.pntd.0006457

Identification and validation of a novel panel of Plasmodium knowlesi biomarkers of serological exposure. / Herman, Lou S.; Fornace, Kimberly; Phelan, Jody; Grigg, Matthew J.; Anstey, Nicholas M.; William, Timothy; Moon, Robert W.; Blackman, Michael J.; Drakeley, Chris J.; Tetteh, Kevin K.A.

In: PLoS Neglected Tropical Diseases, Vol. 12, No. 6, e0006457, 14.06.2018, p. 1-21.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Identification and validation of a novel panel of Plasmodium knowlesi biomarkers of serological exposure

AU - Herman, Lou S.

AU - Fornace, Kimberly

AU - Phelan, Jody

AU - Grigg, Matthew J.

AU - Anstey, Nicholas M.

AU - William, Timothy

AU - Moon, Robert W.

AU - Blackman, Michael J.

AU - Drakeley, Chris J.

AU - Tetteh, Kevin K.A.

PY - 2018/6/14

Y1 - 2018/6/14

N2 - Background: Plasmodium knowlesi is the most common cause of malaria in Malaysian Borneo, with reporting limited to clinical cases presenting to health facilities and scarce data on the true extent of transmission. Serological estimations of transmission have been used with other malaria species to garner information about epidemiological patterns. However, there are a distinct lack of suitable serosurveillance tools for this neglected disease. Methodology/Principal findings: Using in silico tools, we designed and expressed four novel P. knowlesi protein products to address the distinct lack of suitable serosurveillance tools: PkSERA3 antigens 1 and 2, PkSSP2/TRAP and PkTSERA2 antigen 1. Antibody prevalence to these antigens was determined by ELISA for three time-points post-treatment from a hospital-based clinical treatment trial in Sabah, East Malaysia (n = 97 individuals; 241 total samples for all time points). Higher responses were observed for the PkSERA3 antigen 2 (67%, 65/97) across all time-points (day 0: 36.9% 34/92; day 7: 63.8% 46/72; day 28: 58.4% 45/77) with significant differences between the clinical cases and controls (n = 55, mean plus 3 SD) (day 0 p<0.0001; day 7 p<0.0001; day 28 p<0.0001). Using boosted regression trees, we developed models to classify P. knowlesi exposure (cross-validated AUC 88.9%; IQR 86.1–91.3%) and identified the most predictive antibody responses. Conclusions/Significance: The PkSERA3 antigen 2 had the highest relative variable importance in all models. Further validation of these antigens is underway to determine the specificity of these tools in the context of multi-species infections at the population level.

AB - Background: Plasmodium knowlesi is the most common cause of malaria in Malaysian Borneo, with reporting limited to clinical cases presenting to health facilities and scarce data on the true extent of transmission. Serological estimations of transmission have been used with other malaria species to garner information about epidemiological patterns. However, there are a distinct lack of suitable serosurveillance tools for this neglected disease. Methodology/Principal findings: Using in silico tools, we designed and expressed four novel P. knowlesi protein products to address the distinct lack of suitable serosurveillance tools: PkSERA3 antigens 1 and 2, PkSSP2/TRAP and PkTSERA2 antigen 1. Antibody prevalence to these antigens was determined by ELISA for three time-points post-treatment from a hospital-based clinical treatment trial in Sabah, East Malaysia (n = 97 individuals; 241 total samples for all time points). Higher responses were observed for the PkSERA3 antigen 2 (67%, 65/97) across all time-points (day 0: 36.9% 34/92; day 7: 63.8% 46/72; day 28: 58.4% 45/77) with significant differences between the clinical cases and controls (n = 55, mean plus 3 SD) (day 0 p<0.0001; day 7 p<0.0001; day 28 p<0.0001). Using boosted regression trees, we developed models to classify P. knowlesi exposure (cross-validated AUC 88.9%; IQR 86.1–91.3%) and identified the most predictive antibody responses. Conclusions/Significance: The PkSERA3 antigen 2 had the highest relative variable importance in all models. Further validation of these antigens is underway to determine the specificity of these tools in the context of multi-species infections at the population level.

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