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

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 con-trolled 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 differ-ent 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 NS1-specific 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 serolo-gical assays should be undertaken with a great caution. Furthermore, research on novel diag-nostic signatures for differential diagnosis of flaviviruses is needed.