Pan-pathogen vaccine approaches: Toward broad-spectrum immunity in a One Health era.

Emerging and re-emerging infectious diseases (EIDs) represent an escalating threat to global public health, as exemplified by outbreaks of COVID-19, Ebola, Zika, and other zoonotic viruses. Traditional pathogen-specific vaccines, although effective for individual diseases, face significant limitations in addressing EIDs due to long development timelines, resource intensity, and restricted adaptability to novel pathogens or variants. Pan-pathogen vaccines-designed to provide broad-spectrum immunity across multiple related or unrelated pathogens-offer a transformative approach to pandemic preparedness. This review presents a comprehensive overview of pan-pathogen vaccinology within the One Health framework, emphasizing the integration of human, animal, and environmental health for proactive disease prevention. We provide explicit definitions for "universal", "broad-spectrum", and "pan-pathogen" vaccines and embed the One Health principle into the full vaccine development lifecycle through real-world case studies, including Nipah virus and rVSV-Ebola. The review highlights strategies for epitope discovery using comparative genomics, evolutionary biology, and immunoinformatics to identify conserved antigenic regions, and details mechanisms of cross-protective immunity mediated by T cells, broadly neutralizing antibodies, mucosal responses, and trained innate immunity with emphasis on their interplay. Advanced vaccine platforms-mRNA, viral vectors, protein subunits, and nanoparticle-based systems-are evaluated for their capacity to deliver multivalent, chimeric, and mosaic antigens. Preclinical and clinical advances against influenza, coronaviruses, flaviviruses, filoviruses, and critically, bacterial, fungal, parasitic, and DNA virus targets are summarized. Ethical, regulatory, and global health considerations for equitable vaccine distribution are discussed, with expanded safety analysis addressing pan-pathogen-specific hazards such as antigenic competition, autoimmunity, and regulatory adaptation. Persistent gaps, including antigenic variability, immune imprinting, safety concerns, and challenges in clinical validation, are identified, alongside controversies surrounding the balance between broad coverage and potential immune escape. Integrating genomic surveillance, predictive modeling, and emerging technologies such as artificial intelligence, systems biology, and synthetic vaccinology is essential to optimize vaccine design and accelerate translational implementation. Collectively, pan-pathogen vaccines represent a proactive, adaptive, and globally coordinated strategy to mitigate future pandemics and strengthen long-term health security.