Heterologous immunity and antibody-dependent enhancement in respiratory virus infections

Document Type

Review

Publication Date

12-1-2026

Abstract

Respiratory viruses such as influenza viruses and coronaviruses pose persistent and evolving threats to global public health, driven by diverse mechanisms of immune evasion, cross-species transmission, and pandemic potential. 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.

Keywords

Antibody-dependent enhancement, Cross-reactivity, Heterologous immunity, Respiratory virus, Universal vaccine

Publication Title

Molecular Biology Reports

ISSN

0301-4851

DOI

10.1007/s11033-025-11189-5

Volume

53

Issue

1

Publisher

Springer

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