The increasing complexity of arbovirus serology: An in-depth systematic review on cross-reactivity.

Diagnosis of arbovirus infection or exposure by antibody testing is becoming increasingly difficult due to global expansion of arboviruses, which induce antibodies that may (cross-)react in serological assays. We provide a systematic review of the current knowledge and knowledge gaps in differential arbovirus serology. The search included Medline, Embase and Web of Science databases and identified 911 publications which were reduced to 102 after exclusion of studies not providing data on possible cross-reactivity or studies that did not meet the inclusion criteria regarding confirmation of virus exposure of reference population sets. Using a scoring system to further assess quality of studies, we show that the majority of the selected papers (N = 102) provides insufficient detail to support conclusions on specificity of serological outcomes with regards to elucidating antibody cross-reactivity. Along with the lack of standardization of assays, metadata such as time of illness onset, vaccination, infection and travel history, age and specificity of serological methods were most frequently missing. Given the critical role of serology for diagnosis and surveillance of arbovirus infections, better standards for reporting, as well as the development of more (standardized) specific serological assays that allow discrimination between exposures to multiple different arboviruses, are a large global unmet need. Author summary: Arboviruses are notorious for triggering antibodies that may cross-react with (closely) related arboviruses, complicating interpretation of serology-based arbovirus diagnostics and of epidemiological surveys. This is further complicated by the rapid global spread of arboviruses, that may lead to increasing co-circulation of antigenically related arboviruses, and by the lack of detailed background information on the population tested, methods used and background arbovirus exposures such as prior infections or vaccinations. Here, we aim to provide a better understanding of the complex cross-reactivity patterns as well as the current knowledge and knowledge gaps in differential arbovirus serology. We have done a systematic analysis of reported cross-reactivity patterns from published peer-reviewed articles, using a system that allows assessment of the quality of reported cross-reactivity results. We show that using this approach, the majority of studies lack details needed to reliably assess whether reactivity to antigens from different, related arboviruses is caused by antibody cross-reactivity, or if it reflects antibodies from multiple exposures to these different viruses. Furthermore, there is a strong need for standardization of assays and study designs in future serological studies to compare cross-reactivity results from different studies. Tackling this may lead to improved diagnosis and surveillance of (newly) emerging and/or rapidly spreading arboviruses. [ABSTRACT FROM AUTHOR]