Transition from In Vivo to In Vitro and In Silico: A New Paradigm in Vaccinology

For over a century, laboratory animals have been central to vaccine development, providing models to evaluate safety and efficacy before clinical use. Despite major public health successes, this approach has limitations because animal immune systems do not fully replicate human biology, leading to translational failures alongside growing ethical and economic concerns. Advances in preclinical science are now reshaping this landscape. Organoid systems, derived from stem cells, recreate key structural and functional features of organs, enabling physiologically relevant studies of infection and immune response in controlled laboratory settings. In silico immunology uses artificial intelligence and machine learning to predict antigen behaviour, simulate immune interactions, and prioritize vaccine candidates before experimental testing, accelerating early-stage development. Synthetic biology further enhances predictability by engineering precise cellular assays and highly defined vaccine platforms such as mRNA constructs, reducing reliance on exploratory animal studies. However, complete replacement of animal models remains challenging because vaccines act within complex, systemic biological networks where integrated immune responses and rare adverse effects are difficult to replicate in vitro or computationally. Consequently, regulatory frameworks continue to require rigorous validation. A hybrid paradigm is emerging in which AI guides discovery, organoids provide biologically relevant validation, and animals are used selectively for targeted safety assessment, making vaccine development increasingly predictive, efficient, and ethically aligned.