Abstract
Background: Human brucellosis remains an important One Health problem, yet no vaccine is licensed for human use despite decades of antigen discovery and experimental vaccine development. This review examines why promising Brucella vaccine candidates have not progressed toward human application, with particular attention to the relationship between immune-evasion mechanisms, experimental evidence of protection, and the barriers that arise during translation. Methods: A critical narrative review of peer-reviewed literature on Brucella immunopathogenesis, immune evasion, protective immunity, antigen discovery, vaccine platforms, and human translational requirements was conducted. The evidence was interpreted according to experimental maturity, distinguishing computational or hypothesis-generating studies, mechanistic in vitro or ex vivo evidence, animal immunogenicity studies without challenge, and challenge-supported protection. Additional consideration was given to safety, durability, cross-species protection, model relevance, manufacturing, and regulatory requirements. Results: Brucella uses multiple mechanisms to limit innate recognition, alter intracellular trafficking and antigen presentation, and modulate host immune responses. These mechanisms provide a biological rationale for mechanism-informed vaccine design, but direct evidence that individual vaccine strategies overcome specific immune-evasion pathways remains limited. Across the vaccine literature, many candidates remain at the computational, antigen-production, or immunogenicity stages, whereas fewer have demonstrated protection after experimental challenge. Even challenge-supported candidates rarely address durability, cross-species breadth, human-relevant correlates of protection, extended safety, reproducible manufacturing, or readiness for clinical development. Conclusions: The absence of a licensed human brucellosis vaccine is better explained by attrition across successive stages of development than by a shortage of candidate antigens or vaccine platforms. Progress is likely to depend on advancing fewer, better-supported candidates through an integrated evidence pathway that links mechanistic rationale and challenge protection with durability, safety, species breadth, product quality, and human clinical relevance.