Distinguishing Secondary Dengue Virus Infection From Zika Virus Infection With Previous Dengue by a Combination of 3 Simple Serological Tests

Clin Infect Dis. 2017 Nov 13;65(11):1829-1836. doi: 10.1093/cid/cix672.

Abstract

Background: The explosive spread of Zika virus (ZIKV) and associated microcephaly present an urgent need for sensitive and specific serodiagnostic tests, particularly for pregnant women in dengue virus (DENV)-endemic regions. Recent reports of enhanced ZIKV replication by dengue-immune sera have raised concerns about the role of previous DENV infection on the risk and severity of microcephaly and other ZIKV complications.

Methods: Enzyme-linked immunosorbent assays (ELISAs) based on ZIKV and DENV nonstructural protein 1 (NS1) were established to test acute, convalescent phase, and post-convalescent phase serum/plasma samples from reverse-transcription polymerase chain reaction-confirmed cases including 20 primary ZIKV, 25 ZIKV with previous DENV, 58 secondary DENV, and 16 primary DENV1 infections.

Results: ZIKV-NS1 immunoglobulin M (IgM) and immunoglobulin G (IgG) ELISAs combined can detect ZIKV infection with a sensitivity of 95% and specificity of 66.7%. The ZIKV-NS1 IgG cross-reactivity by samples from secondary DENV infection cases ranged from 66.7% to 28.1% (within 1 month to 1-2 years post-illness, respectively). Addition of DENV1-NS1 IgG ELISA can distinguish primary ZIKV infection; the ratio of absorbance of ZIKV-NS1 to DENV1-NS1 IgG ELISA can distinguish ZIKV with previous DENV and secondary DENV infections with a sensitivity of 87.5% and specificity of 81.3%. These findings were supported by analysis of sequential samples.

Conclusions: An algorithm for ZIKV serodiagnosis based on 3 simple ELISAs is proposed to distinguish primary ZIKV, ZIKV with previous DENV, and secondary DENV infections; this could be applied to serodiagnosis for ZIKV, serosurveillance, and monitoring ZIKV infection during pregnancy to understand the epidemiology, pathogenesis, and complications of ZIKV in dengue-endemic regions.

Keywords: Zika virus; cross-reactivity; dengue virus; non-structural protein 1; serological test.

MeSH terms

  • Adult
  • Antibodies, Viral / blood
  • Coinfection / diagnosis*
  • Coinfection / immunology
  • Coinfection / virology
  • Cross Reactions
  • Dengue / blood
  • Dengue / diagnosis*
  • Dengue / immunology
  • Dengue / virology
  • Dengue Virus / immunology
  • Enzyme-Linked Immunosorbent Assay / methods
  • Female
  • Humans
  • Immunoglobulin G / blood
  • Immunoglobulin M / blood
  • Sensitivity and Specificity
  • Serologic Tests / methods*
  • Viral Nonstructural Proteins / immunology
  • Zika Virus / immunology
  • Zika Virus Infection / diagnosis*
  • Zika Virus Infection / immunology
  • Zika Virus Infection / virology

Substances

  • Antibodies, Viral
  • Immunoglobulin G
  • Immunoglobulin M
  • NS1 protein, dengue-1 virus
  • NS1 protein, zika virus
  • Viral Nonstructural Proteins