Heterologous immunity and antibody-dependent enhancement in respiratory virus infections

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.