Cross-reactivity of SARS-CoV-2 with other pathogens, especially dengue virus: A historical perspective.

Dengue is a vector-borne viral disease caused by a Flavivirus whereas the COVID-19 pandemic was caused by a highly contagious virus, SARS-CoV-2 belonging to the family Coronaviridae. However, COVID-19 severity was observably less in dengue-endemic countries and vice versa especially during the active years of the pandemic (2019-2021). We observed that dengue virus (DENV) antibodies (Abs) could cross-react with SARS-CoV-2 spike antigen. This resulted in SARS-CoV-2 false positivity by rapid Ab test kits. DENV Abs binding to SARS-CoV-2 receptor-binding domain (and the reverse scenario), as revealed by docking studies further validated DENV and SARS-CoV-2 cross-reactivity. Finally, SARS-CoV-2 Abs were found to cross-neutralize DENV1 and DENV2 in virus neutralization test (VNT). Abs to other pathogens like Plasmodium were also cross-reactive but non-neutralizing for SARS-CoV-2. Here, we analyze the existing data on SARS-CoV-2 cross-reactivity with other pathogens, especially dengue to assess its impact on health (cross-protection?) and differential sero-diagnosis/surveillance.

Dengue virus (DV) non-cross-reactive Omicron wave COVID-19 serums enhanced DV3 infectivity in vitro.

Introduction. In India, the SARS-CoV-2 Delta wave (2020-2021) faded away with the advent of the Omicron variants (2021-present). Dengue incidences were observed to be less in Southeast Asia during the active years of the pandemic (2020-2021). However, dengue virus type 3 (DV3) cases were increasingly reported in this region (including India) concurrent with the progression of the Omicron waves since 2022.Hypothesis. What could be the reason(s) behind this unusual DV3 surge after an overall dip in dengue incidences in many parts of Southeast Asia?Aim. We, therefore, investigated the current state of cross-reactivity of prevalent (Omicron era) SARS-CoV-2 serums with different DV serotypes and evaluated the impact of such serums on DV neutralization in cell culture.Methodology. Fifty-five COVID-19 serum samples (January-September 2022) and three pre-pandemic archived serum samples from apparently healthy individuals were tested for DV or SARS-CoV-2 IgM/IgG using the lateral flow immunoassays. DV1-4 virus neutralization tests (VNTs) were done with the SARS-CoV-2 antibody (Ab)-positive serums in Huh7 cells. DV3 envelope (env) gene was PCR amplified and sequenced for three archived DV isolates, one from 2017 and two from 2021.Results. SARS-CoV-2 Ab-positive samples constituted 74.5 % of the serums. Of these, 41.5 % were DV cross-reactive and 58.5 % were not. The DV cross-reactive serums neutralized all DV serotypes (DV1-4), as per previous results and this study. The DV non-cross-reactive serums (58.5 %) also cross-neutralized DV1, 2 and 4 but increased DV3 infectivity by means of antibody-dependent enhancement of infection as evident from significantly higher DV3 titres in VNT compared to control serums. The DV3 envelope was identical among the three isolates, including isolate 1 used in VNTs. Our results suggest that DV cross-reactivity of SARS-CoV-2 serums diminished with the shift from Delta to Omicron prevalence. Such COVID-19 serums (DV non-cross-reactive) might have played a major role in causing DV3 surge during the Omicron waves.Conclusion. Patients suspected of dengue or COVID-19 should be subjected to virus/antigen tests and serological tests for both the diseases for definitive diagnosis, prognosis and disease management.