Magnitude of Antibody Cross-Reactivity in Medically Important Mosquito-Borne Flaviviruses: A Systematic Review

Abstract

Introduction:Flaviviruses are a genus of enveloped single-stranded RNA viruses that include dengue virus (DENV), yellow fever virus, West Nile virus (WNV), Japanese encephalitis virus, and Zika virus. Nowadays, diverse serological assays are available to diagnose flaviviruses. However, infection with flaviviruses induces cross-reactive antibodies, which are a challenge for serological diagnosis. Objective: This systematic review aimed to assess the magnitude of medically important mosquito-borne flavivirus-induced antibody cross-reactivity and its influence on serological test outcomes. Methods: This study was designed based on the PRISMA guidelines. It includes original research articles published between 1994 and 2019 that reported serological cross-reactions between medically important mosquito-borne flaviviruses. Articles were searched on PubMed using controlled vocabulary. Eligibility was assessed by title, abstract, and finally by reading the full paper. The articles included are compared, evaluated, and summarized narratively. Results: A total of 2,911 articles were identified, and finally 14 were included. About 15.4%-84% of antibodies produced against non-DENV flaviviruses were cross-reactive with DENV on different assays. Up to 30% IgM and up to 60% IgG antibodies produced against non-WNV flaviviruses were cross-reactive with WNV on EIA assays. The magnitude of antibodies produced against flaviviruses that are cross-reactive with chikungunya virus (Alphavirus) was minimal (only about 7%). The highest antibody cross-reactivity of flaviviruses was reported in IgG-based assays compared to IgM-based assays and assays based on E-specific immunoglobulin compared to NS1specific immunoglobulin. It was found that preexisting immunity due to vaccination or prior flavivirus exposure to antigenetically related species enhanced the cross-reactive antibody titer. Conclusion: This review found the highest cross-reaction between DENV and non-DENV flaviviruses, especially yellow fever virus, and the least between chikungunya virus and DENV. Moreover, cross-reaction was higher on IgG assays than IgM ones and assays based on Eprotein compared to NS1protein. This implies that the reliability of serological test results in areas where more than one flavivirus exists is questionable. Therefore, interpretation of the existing serological assays should be undertaken with a great caution. Furthermore, research on novel diagnostic signatures for differential diagnosis of flaviviruses is needed.

Simultaneous detection of Zika, chikungunya, dengue, yellow fever, West Nile, and Japanese encephalitis viruses by a two‐tube multiplex real‐time RT‐PCR assay

“…37 In addition, the cross-reactions of YFV/DENV/WNV/JEV against each other were also found. [37][38][39][40] qRT-PCR could provide rapid, sensitive, and specific detection of target pathogens, therefore, it is replacing the laborious and time-consuming method of viral isolation or neutralization assays. 19 Previous studies have reported several singleplex and also some multiplex qRT-PCR assays for the detection of ZIKV, CHIKV, DENV, WNV, JEV, and YFV.…”

“…(A) to (E) show the representative amplification plot and standard curves for 10-fold serial dilutions of viral RNAs from ZIKV African lineage (A, strain MR_766), ZIKV Asian lineage (B, strain SMGC-1), YFV (C, strain SH01), JEV (D, strain SA14), and CHIKV (E, strain SZ-SMGC-1), respectively flaviviruses were cross-reactive with DENV on different assays. 37 In addition, the cross-reactions of YFV/DENV/WNV/JEV against each other were also found. [37][38][39][40] qRT-PCR could provide rapid, sensitive, and specific detection of target pathogens, therefore, it is replacing the laborious and time-consuming method of viral isolation or neutralization assays.…”

“…The co‐circulation of these medically important arboviruses not only increased the public health burden but also raised challenges for the differential diagnosis, especially for the serologically and genetically related ones 2 . For example, the cross‐reactivity of neutralizing antibody responses between ZIKV and DENVs was well‐characterized, 35,36 and one recent systematic review showed that about 15.4%–84% of antibodies produced against non‐DENV flaviviruses were cross‐reactive with DENV on different assays 37 . In addition, the cross‐reactions of YFV/DENV/WNV/JEV against each other were also found 37–40 .…”

“…For example, the cross‐reactivity of neutralizing antibody responses between ZIKV and DENVs was well‐characterized, 35,36 and one recent systematic review showed that about 15.4%–84% of antibodies produced against non‐DENV flaviviruses were cross‐reactive with DENV on different assays 37 . In addition, the cross‐reactions of YFV/DENV/WNV/JEV against each other were also found 37–40 . qRT‐PCR could provide rapid, sensitive, and specific detection of target pathogens, therefore, it is replacing the laborious and time‐consuming method of viral isolation or neutralization assays 19 .…”

Performance of VIDAS® Diagnostic Tests for the Automated Detection of Dengue Virus NS1 Antigen and of Anti-Dengue Virus IgM and IgG Antibodies: a Multicentre, International Study

“…The VIDAS ® DENGUE NS1 Ag assay showed very low cross-reactivity (1.5%) with samples positive for other infectionspecific antigens. The VIDAS ® Anti-DENGUE IgM and IgG assays presented higher cross-reactivity (15.4% and 7.8%, respectively) with samples positive for IgM or IgG directed against other pathogen-specific antigens, as previously described for immunoassays [5,6,16,18,22,[31][32][33][34][35]. These included cross-reactions with antibodies directed against other flaviviruses (4/53 [7.5%] for IgM and 2/31 [6.5%] for IgG).…”