Diagnostic validation of novel Borrelia antigens discovered by whole-proteome microarray: Advancing early detection and test of cure for Lyme disease

Abhijeet Nayak; M. E. Baarsma; Jacqueline A. van Eck; Arlo Z. Randall; Jeanine Ursinus; Andy A. Teng; Jozelyn V. Pablo; Chris Hung; Doris U. M. Wopereis; Freek van de Schoor; Calin D. Popa; Cees C. van den Wijngaard; Bart-Jan Kullberg; Leo A. B. Joosten; Herman Kuiper; Joseph J. Campo; Xiaouw Liang; Joppe W. Hovius

doi:10.1016/j.xcrm.2025.102097

Diagnostic validation of novel Borrelia antigens discovered by whole-proteome microarray: Advancing early detection and test of cure for Lyme disease

Abhijeet Nayak^*, M. E. Baarsma, Jacqueline A. van Eck, Arlo Z. Randall, Jeanine Ursinus, Andy A. Teng, Jozelyn V. Pablo, Chris Hung, Doris U. M. Wopereis, Freek van de Schoor, Calin D. Popa, Cees C. van den Wijngaard, Bart-Jan Kullberg, Leo A. B. Joosten, Herman Kuiper, Joseph J. Campo, Xiaouw Liang, Joppe W. Hovius

^*Corresponding author for this work

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Abstract

Lyme disease serodiagnosis has limited early sensitivity and cannot distinguish active from past infections. To address this, we screen a Borrelia afzelii whole-proteome microarray (1,296 proteins) using human (n = 149) and murine (n = 32) sera. We evaluate three early-stage antigens—BafPKo_A0001, BafPKo_D0016, and BafPKo_A0029. ELISA cutoffs are established using discovery cohort sera (n = 99) and validated with the validation (n = 242) and the prospective (n = 223) cohorts. A0001 demonstrates 87.8% sensitivity, outperforming C6 (69.4%) and STTT (22.5%) in the discovery cohort. In the validation cohort, A0001 reaches 90.5% sensitivity, surpassing C6 by 11.6% and STTT by 50%. In hyper-acute erythema migrans sera (from the prospective cohort), A0001 achieves 55.1% sensitivity, exceeding C6 and STTT by 14.6% and 33.3%, respectively. COMBO-3 and COMBO-2 yield the highest sensitivity of 92.9% and 66.1% in the validation and prospective cohort, respectively. A0001 and D0016 show enhanced and robust seroreversion after antibiotic treatment suggesting their potential as test of cure biomarkers in early Lyme disease.

Original language	English
Article number	102097
Journal	Cell Rep. Med.
Volume	6
Issue number	5
Early online date	2025
DOIs	https://doi.org/10.1016/j.xcrm.2025.102097
Publication status	Published - 20 May 2025

Keywords

Borrelia
Lyme disease
active and past infection
antigens
diagnosis
microarray
sensitivity
specificity
test-of-cure

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Nayak, A., Baarsma, M. E., van Eck, J. A., Randall, A. Z., Ursinus, J., Teng, A. A., Pablo, J. V., Hung, C., Wopereis, D. U. M., van de Schoor, F., Popa, C. D., van den Wijngaard, C. C., Kullberg, B.-J., Joosten, L. A. B., Kuiper, H., Campo, J. J., Liang, X., & Hovius, J. W. (2025). Diagnostic validation of novel Borrelia antigens discovered by whole-proteome microarray: Advancing early detection and test of cure for Lyme disease. Cell Rep. Med., 6(5), Article 102097. https://doi.org/10.1016/j.xcrm.2025.102097

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title = "Diagnostic validation of novel Borrelia antigens discovered by whole-proteome microarray: Advancing early detection and test of cure for Lyme disease",

abstract = "Lyme disease serodiagnosis has limited early sensitivity and cannot distinguish active from past infections. To address this, we screen a Borrelia afzelii whole-proteome microarray (1,296 proteins) using human (n = 149) and murine (n = 32) sera. We evaluate three early-stage antigens—BafPKo\_A0001, BafPKo\_D0016, and BafPKo\_A0029. ELISA cutoffs are established using discovery cohort sera (n = 99) and validated with the validation (n = 242) and the prospective (n = 223) cohorts. A0001 demonstrates 87.8\% sensitivity, outperforming C6 (69.4\%) and STTT (22.5\%) in the discovery cohort. In the validation cohort, A0001 reaches 90.5\% sensitivity, surpassing C6 by 11.6\% and STTT by 50\%. In hyper-acute erythema migrans sera (from the prospective cohort), A0001 achieves 55.1\% sensitivity, exceeding C6 and STTT by 14.6\% and 33.3\%, respectively. COMBO-3 and COMBO-2 yield the highest sensitivity of 92.9\% and 66.1\% in the validation and prospective cohort, respectively. A0001 and D0016 show enhanced and robust seroreversion after antibiotic treatment suggesting their potential as test of cure biomarkers in early Lyme disease.",

keywords = "Borrelia, Lyme disease, active and past infection, antigens, diagnosis, microarray, sensitivity, specificity, test-of-cure",

author = "Abhijeet Nayak and Baarsma, \{M. E.\} and \{van Eck\}, \{Jacqueline A.\} and Randall, \{Arlo Z.\} and Jeanine Ursinus and Teng, \{Andy A.\} and Pablo, \{Jozelyn V.\} and Chris Hung and Wopereis, \{Doris U. M.\} and \{van de Schoor\}, Freek and Popa, \{Calin D.\} and \{van den Wijngaard\}, \{Cees C.\} and Bart-Jan Kullberg and Joosten, \{Leo A. B.\} and Herman Kuiper and Campo, \{Joseph J.\} and Xiaouw Liang and Hovius, \{Joppe W.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = may,

day = "20",

doi = "10.1016/j.xcrm.2025.102097",

language = "English",

volume = "6",

journal = "Cell Rep. Med.",

issn = "2666-3791",

publisher = "Cell Press",

number = "5",

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Nayak, A , Baarsma, ME , van Eck, JA, Randall, AZ, Ursinus, J, Teng, AA, Pablo, JV, Hung, C, Wopereis, DUM, van de Schoor, F, Popa, CD, van den Wijngaard, CC, Kullberg, B-J, Joosten, LAB, Kuiper, H, Campo, JJ, Liang, X & Hovius, JW 2025, 'Diagnostic validation of novel Borrelia antigens discovered by whole-proteome microarray: Advancing early detection and test of cure for Lyme disease', Cell Rep. Med., vol. 6, no. 5, 102097. https://doi.org/10.1016/j.xcrm.2025.102097

TY - JOUR

T1 - Diagnostic validation of novel Borrelia antigens discovered by whole-proteome microarray

T2 - Advancing early detection and test of cure for Lyme disease

AU - Nayak, Abhijeet

AU - Baarsma, M. E.

AU - van Eck, Jacqueline A.

AU - Randall, Arlo Z.

AU - Ursinus, Jeanine

AU - Teng, Andy A.

AU - Pablo, Jozelyn V.

AU - Hung, Chris

AU - Wopereis, Doris U. M.

AU - van de Schoor, Freek

AU - Popa, Calin D.

AU - van den Wijngaard, Cees C.

AU - Kullberg, Bart-Jan

AU - Joosten, Leo A. B.

AU - Kuiper, Herman

AU - Campo, Joseph J.

AU - Liang, Xiaouw

AU - Hovius, Joppe W.

PY - 2025/5/20

Y1 - 2025/5/20

N2 - Lyme disease serodiagnosis has limited early sensitivity and cannot distinguish active from past infections. To address this, we screen a Borrelia afzelii whole-proteome microarray (1,296 proteins) using human (n = 149) and murine (n = 32) sera. We evaluate three early-stage antigens—BafPKo_A0001, BafPKo_D0016, and BafPKo_A0029. ELISA cutoffs are established using discovery cohort sera (n = 99) and validated with the validation (n = 242) and the prospective (n = 223) cohorts. A0001 demonstrates 87.8% sensitivity, outperforming C6 (69.4%) and STTT (22.5%) in the discovery cohort. In the validation cohort, A0001 reaches 90.5% sensitivity, surpassing C6 by 11.6% and STTT by 50%. In hyper-acute erythema migrans sera (from the prospective cohort), A0001 achieves 55.1% sensitivity, exceeding C6 and STTT by 14.6% and 33.3%, respectively. COMBO-3 and COMBO-2 yield the highest sensitivity of 92.9% and 66.1% in the validation and prospective cohort, respectively. A0001 and D0016 show enhanced and robust seroreversion after antibiotic treatment suggesting their potential as test of cure biomarkers in early Lyme disease.

AB - Lyme disease serodiagnosis has limited early sensitivity and cannot distinguish active from past infections. To address this, we screen a Borrelia afzelii whole-proteome microarray (1,296 proteins) using human (n = 149) and murine (n = 32) sera. We evaluate three early-stage antigens—BafPKo_A0001, BafPKo_D0016, and BafPKo_A0029. ELISA cutoffs are established using discovery cohort sera (n = 99) and validated with the validation (n = 242) and the prospective (n = 223) cohorts. A0001 demonstrates 87.8% sensitivity, outperforming C6 (69.4%) and STTT (22.5%) in the discovery cohort. In the validation cohort, A0001 reaches 90.5% sensitivity, surpassing C6 by 11.6% and STTT by 50%. In hyper-acute erythema migrans sera (from the prospective cohort), A0001 achieves 55.1% sensitivity, exceeding C6 and STTT by 14.6% and 33.3%, respectively. COMBO-3 and COMBO-2 yield the highest sensitivity of 92.9% and 66.1% in the validation and prospective cohort, respectively. A0001 and D0016 show enhanced and robust seroreversion after antibiotic treatment suggesting their potential as test of cure biomarkers in early Lyme disease.

KW - Borrelia

KW - Lyme disease

KW - active and past infection

KW - antigens

KW - diagnosis

KW - microarray

KW - sensitivity

KW - specificity

KW - test-of-cure

UR - https://www.scopus.com/pages/publications/105004242454

U2 - 10.1016/j.xcrm.2025.102097

DO - 10.1016/j.xcrm.2025.102097

M3 - Article

C2 - 40315844

SN - 2666-3791

VL - 6

JO - Cell Rep. Med.

JF - Cell Rep. Med.

IS - 5

M1 - 102097

ER -

Diagnostic validation of novel Borrelia antigens discovered by whole-proteome microarray: Advancing early detection and test of cure for Lyme disease

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