Structural vaccinology expedites rational design of next-generation vaccines for influenza and respiratory syncytial virus

Vaccination stands as the single most effective and cost-efficient public health intervention in human history, serving as a cornerstone of modern medicine that profoundly transforms global health outcomes. Beyond preventing disease, it acts as a catalyst for equitable socioeconomic development. In recent decades, recurrent seasonal viral outbreaks and sporadic yet catastrophic pandemics, have continued to pose challenges to global public health systems. Traditional vaccine technologies, however, not only often fall short in protection efficacy, but also fail to keep pace with the evolving demands of next-generation vaccine development. These scientific gaps have directed cutting-edge research to prioritize critical objectives in terms of enhancing antigen effectiveness, achieving stable pan-protection against diverse variant strains, and strengthening production robustness. The advent of genomics spurred the emergence of reverse vaccinology 1.0, leading to breakthroughs like the MenB vaccine. Today, the advanced reverse vaccinology 2.0 paradigm thoroughly redefines vaccine design process by organically integrating human immunology with state-of-the-art computational protein structure analysis tools. This review explores the transformative shifts in influenza and respiratory syncytial virus vaccine development, along with specific case studies, to deepen understanding of the evolving principles and methodologies in novel vaccine designs and offer strategic insights for addressing emerging infectious pathogens. • RV 2.0 supports precise epitope design and serves as a key route for targeted induction of neutralizing antibodies. • Structure-based preF designs effectively achieve protective immunity and resolves vaccine-associated ERD. • Robust HA stem-targeted immunity represents a vital goal for advancing universal influenza vaccine rational design.