Respiratory infectious diseases are among the leading causes of morbidity and mortality worldwide, particularly affecting children, older adults, and immunocompromised individuals. Traditional vaccine development approaches face limitations in addressing the rapid mutation and immune evasion mechanisms of respiratory pathogens. In recent years, structure-based protein vaccine design has emerged as a critical direction in vaccine research. This strategy utilizes the three-dimensional structural information of key pathogenic antigens, combined with reverse vaccinology, computational biology, and protein engineering to optimize antigen design and enhance immunogenicity. This review summarizes recent progress in structure-based protein vaccine development for major respiratory pathogens, including influenza viruses, respiratory syncytial virus (RSV), and coronaviruses such as SARS-CoV-2. We highlight innovative vaccine platforms, including antigen optimization strategies, nanoparticle-based vaccines, and novel adjuvant development. Additionally, we discuss the major challenges in vaccine development—such as antigenic variability, immune durability, and large-scale manufacturing—and propose future directions for research and application.

Respiratory diseases

Influenza

RSV

SARS-CoV-2

Structure-based design

Protein vaccines

Not applicable.

© 2025 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.