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Understanding the interplay between heterologous immunity and antibody-dependent enhancement (ADE) is crucial in delineating both protective and pathogenic immune responses following infection or vaccination. This review synthesizes current advances in the molecular and cellular mechanisms underlying virus-agnostic innate defenses, adaptive receptor diversification via V(D)J recombination, and the structural and functional bases of T and B cell cross-reactivity. The dualistic nature of antibody responses is examined in the context of Fc receptor- and complement-mediated ADE, emphasizing the implications for immune protection versus immunopathology. The impact of pre-existing cross-reactive immunity, primed by prior exposures to antigenically distinct viruses or vaccines, is discussed with evidence from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and other seasonal respiratory outbreaks. Finally, the review evaluates recent progress and ongoing challenges in universal vaccine development, proposing that the rational harnessing of broad-spectrum and cross-reactive immune mechanisms will be essential for enhancing pandemic preparedness and mitigating the risks associated with immune enhancement phenomena.<\/jats:p>","DOI":"10.1007\/s11033-025-11189-5","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T09:00:18Z","timestamp":1761728418000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Heterologous immunity and antibody-dependent enhancement in respiratory virus infections"],"prefix":"10.1007","volume":"53","author":[{"given":"Nur Hidayah","family":"Nor Isamuddin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sazaly","family":"AbuBakar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim-Ling","family":"Chin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurhafiza","family":"Zainal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"key":"11189_CR1","unstructured":"Katz S (2024) Overview of Viral Respiratory Infections. https:\/\/www.msdmanuals.com\/professional\/infectious-diseases\/respiratory-viruses\/overview-of-viral-respiratory-infections. 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