{"doi":"10.3389/fimmu.2025.1683070","title":"COVID-19 vaccination induces cross-reactive dengue virus antibodies with altered isotype profiles and in vitro antibody-dependent enhancement","abstract":"Background SARS-CoV-2 infection and COVID-19 vaccination can induce antibodies that cross-react with dengue virus (DENV). Pre-existing IgG antibodies against DENV are known to enhance infection through antibody-dependent enhancement (ADE) via Fcγ receptors. COVID-19 vaccines induce an altered IgG subclass distribution with modified Fcγ receptor affinity. This study investigates the isotype profile of DENV cross-reactive antibodies induced by COVID-19 vaccination and their potential to mediate ADE. Methods We retrospectively collected 271 serum samples from individuals in Taiwan who were either SARS-CoV-2-unvaccinated, vaccinated with 1–3 doses of COVID-19 vaccine, recipients of an Omicron-era booster, or previously recovered from dengue infection. Antibody titers (IgM, IgA, and IgG subclasses 1–4) against SARS-CoV-2 spike (S) glycoprotein and DENV serotype 2 envelope (E) protein were measured by enzyme-linked immunosorbent assay (ELISA). Selective depletion of anti-S or anti-E antibodies was performed to confirm cross-reactivity. ADE activity was assessed in vitro by incubating DENV-2 particles with serum antibodies followed by infection of Fcγ receptor-bearing THP-1 monocytic cells. Results Cross-reactive anti-E antibodies in COVID-19-vaccinated individuals were predominantly IgM and IgA, whereas anti-S antibodies in vaccinated individuals and anti-E antibodies in dengue-recovered patients were dominated by IgG1. Low levels of cross-reactive anti-E IgG detected in vaccinated individuals were mainly of the low-affinity IgG2 and IgG4 subclasses. These vaccine-induced cross-reactive antibodies mediated significantly stronger in vitro ADE compared with antibodies from natural DENV infection, particularly after the first or second vaccine dose and after Omicron-variant boosters. Inactivation of complement reduced ADE in COVID-19-vaccinated sera but enhanced it in sera from dengue-recovered individuals. Conclusion COVID-19 vaccination induces DENV cross-reactive antibodies with a distinct isotype profile and distinct ADE compared with natural dengue infection. Due to low Fc-affinity these antibodies likely do not pose a threat of dengue. These findings highlight the importance of considering off-target immunity and ADE risk in future vaccine design.","journal":"Frontiers in Immunology","year":2025,"id":549498,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1188649,"name":"Chin Hwa Kuo","orcid":null,"position":1,"is_corresponding":false},{"id":713309,"name":"Sheng‐Yu Huang","orcid":"0000-0002-7626-688X","position":2,"is_corresponding":false},{"id":439332,"name":"Kuei-Ching Hsiung","orcid":"0000-0002-2107-6368","position":3,"is_corresponding":false},{"id":1443705,"name":"Po-Kai Chen","orcid":"0009-0006-7830-0590","position":4,"is_corresponding":false},{"id":120069,"name":"Etsuro Ito","orcid":"0000-0002-1877-6566","position":5,"is_corresponding":false},{"id":923057,"name":"Ing‐Kit Lee","orcid":null,"position":6,"is_corresponding":false},{"id":1443706,"name":"Ching‐Yen Tsai","orcid":"0000-0001-7964-6661","position":7,"is_corresponding":false},{"id":922474,"name":"Shu‐Min Lin","orcid":"0000-0002-0834-564X","position":8,"is_corresponding":false},{"id":559167,"name":"Shin‐Ru Shih","orcid":"0000-0003-4874-401X","position":9,"is_corresponding":false},{"id":1070082,"name":"Sebastian Reinig","orcid":null,"position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T02:54:07.823422Z","pmid":"41479919","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}