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Pre-dominance of dengue non-cross-reacting SARS-CoV-2 spike antibodies during the Omicron era and their role in the ADE-mediated surge of Dengue virus serotype 3

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In India, the SARS-CoV-2 Delta wave (2020-21) gradually faded away with the advent of the Omicron variants (2021-present). Dengue incidences were observably less in Southeast Asia during the active years of the pandemic (2020-21). However, Dengue virus type 3 (DV3) cases were increasingly reported in India and many other dengue-endemic countries concurrent with the progression of the Omicron wave since 2022. This observation prompted us to investigate the current state of cross-reactivity between prevalent SARS-CoV-2 variants and different DV serotypes. Fifty-five COVID-19 serum samples (collected between January-September, 2022) and three pre-pandemic healthy serum samples were tested for DV or SARS-CoV-2 Immunoglobulin G/Immunoglobulin M (IgG/IgM) using the lateral flow immunoassays (LFIAs). The SARS-CoV-2 antibody (Ab)-positive samples were further tested for their ability to cross-neutralize DV types 1-4 (DV1-4) in Huh7 cell lines. Cross-reactivity between SARS-CoV-2 and DV diminished with the shift from Delta to Omicron prevalence. COVID-19 serum samples that were DV cross-reactive neutralized all DV serotypes, including DV3. However, Omicron wave serum samples were predominantly DV non-cross-reactive (about 70%) in LFIAs and coincided with the prevalence of BA.2 Omicron variant. They also cross-neutralized DV1, 2 and 4 but enhanced DV3 infectivity as evident from increased DV3 titres in virus neutralization test (VNT) compared to control serum samples. In conclusion, DV non-cross-reactive COVID-19 serum samples are becoming increasingly prominent in the present times. These non-cross-reactive serums could neutralize DV1, 2 and 4 but they are contributing to the surge in DV3 cases worldwide by means of ADE.