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Med Microbiol Immunol. 2017 Oct;206(5):383-401. doi: 10.1007/s00430-017-0517-y. Epub 2017 Aug 29.

Compensating for cross-reactions using avidity and computation in a suspension multiplex immunoassay for serotyping of Zika versus other flavivirus infections.

Author information

1
Section of Clinical Microbiology, Department of Medical Sciences, Uppsala Academic Hospital, Uppsala University, 751 85, Uppsala, Sweden.
2
Department of Medical Biochemistry and Microbiology, Zoonosis Science Center, Uppsala University, Uppsala, Sweden.
3
Laboratory of Clinical Microbiology, Uppsala University Hospital, Uppsala, Sweden.
4
Department of Veterinary Biosciences and Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
5
WHO Collaborating Centre for Arbovirus and Haemorrhagic Fever Reference and Research, Bernhard Nocht Institute for Tropical Medicine, 20359, Hamburg, Germany.
6
Department of Tropical Medicine and Infectious Diseases, Center of Internal Medicine II, University of Rostock, 18057, Rostock, Germany.
7
German Centre for Infection Research (DZIF), Partner Site Hamburg-Luebeck-Borstel, Hamburg, Germany.
8
Section of Clinical Microbiology, Department of Medical Sciences, Uppsala Academic Hospital, Uppsala University, 751 85, Uppsala, Sweden. jonas.blomberg@medsci.uu.se.
9
Department of Medical Biochemistry and Microbiology, Zoonosis Science Center, Uppsala University, Uppsala, Sweden. jonas.blomberg@medsci.uu.se.

Abstract

The recent spread of Zika virus (ZIKV) in the Americas and Asia necessitates an increased preparedness for improved maternal and perinatal health and blood safety. However, serological cross-reactions, especially to Dengue virus (DENV), complicate ZIKV antibody serodiagnosis. A novel "pan-Flavi" suspension multiplex immunoassay (PFSMIA) using 25 antigens, whole virus (WV), non-structural protein 1 (NS1), and envelope (E) proteins, from 7 zoonotic flaviviruses for specific detection of ZIKV and DENV IgM and IgG was developed. Patterns of antibody cross-reactivity, avidity, and kinetics were established in 104 sera from returning travelers with known ZIKV and DENV infections. PFSMIA gave IgM- and IgG-sensitivities for both viruses of 96-100%, compared to an immunofluorescence assay. Main IgM cross-reactions were to NS1, for IgG to the E and WV antigens. Infecting virus yielded reactivity to several antigens of the homologous virus, while cross-reactions tended to occur only to a single antigen from heterologous virus(es). A specificity-enhancing computer procedure took into account antibody isotype, number of antibody-reactive antigens per virus, avidity, average degree of cross-reactivity to heterologous flavivirus antigens, and reactivity changes in serial sera. It classified all 50 cases correctly. Applied to sera from 200 pregnant women and 173 blood donors from Sweden, one blood donor was found ZIKV NS1 IgM positive, and another as ZIKV NS1 IgG positive. These samples did not react with other ZIKV antigens and were thereby judged as false-positives. PFSMIA provided sensitive and specific ZIKV and DENV serology, warranting high-throughput serological surveillance and a minimized need for laborious and expensive virus neutralization assays.

KEYWORDS:

Dengue virus; Flavivirus; Pathogen surveillance; Serological cross-reaction; Suspension multiplex immunoassay; Zika virus

PMID:
28852878
PMCID:
PMC5599479
DOI:
10.1007/s00430-017-0517-y
[Indexed for MEDLINE]
Free PMC Article

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