# Heterologous immunity and antibody-dependent enhancement in respiratory virus infections

## TL;DR

This review explores how past immune responses to different viruses can either protect or worsen infections, focusing on mechanisms and implications for vaccine development.

## Contribution

The paper provides a comprehensive synthesis of molecular and cellular mechanisms of heterologous immunity and ADE in respiratory virus infections.

## Key findings

- Cross-reactive immune responses can both protect and enhance disease severity through mechanisms like ADE.
- Pre-existing immunity from prior infections or vaccines influences outcomes of new respiratory virus infections.
- Universal vaccine strategies must account for both protective and pathogenic immune responses.

## 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.