Is the reverse vaccinology idea becoming exhausted?

Reverse vaccinology (RV) was originally conceived to leverage genomic information for antigen selection and promised a paradigm change in vaccine design. After a steady increment since 2000 and surge in 2021, RV-related publications have recently plateaued, accompanied by declining journal impact factors and a shift from immunology and microbiology to more technical and general categories. Despite its potential and a favorable data science scenario, the impact of RV on the vaccine portfolio concerning pandemics, antimicrobial resistant pathogens and calendar campaigns remains almost negligible. The lack of multidisciplinary collaboration in many RV studies has led to a predominance of purely theoretical studies without experimental validation, likely contributing to waning interest within the broader vaccinology community. For instance, a growing fraction of RV studies focuses on multi-epitope constructs, which limited successful antecedents make their performance questionable in practice. Additionally, target pathogens are increasingly redundant with existing vaccines or of marginal immediate relevance, further fueling skepticism about RV's real-world value. This decoupling underscores the need to renew the original idea by integrating RV with complementary frameworks such as systems vaccinology, network vaccinology, and artificial intelligence, as well as embedding RV within higher-order experimental and translational efforts. Furthermore, policymakers and the pharmaceutical sector have relied almost exclusively on classical antigenic elements such as attenuated or inactivated microorganisms, capsular components and fimbria proteins. Importantly, alignment with key stakeholders is essential to bridge early computational insights with late-stage vaccine development. Without this integration to cover the whole vaccine lifecycle, RV risks losing relevance.