Rethinking Candida Vaccine Translation: Barriers, Immunotherapies and a One Health Imperative

Over the past decade, antifungal vaccinology has produced genuine proof of concept: adhesin-based candidates such as NDV-3A have completed Phase II human trials, and reverse-vaccinology pipelines now routinely generate multi-epitope constructs with high predicted population coverage against Candida albicans and the multidrug-resistant Candida auris. However, no antifungal vaccine has reached the market, and the reasons for this gap are rarely examined together in a single, critical account. This review argues that the bottleneck is not primarily antigen discovery, but a layered set of translational barriers: biological constraints inherent to a commensal, morphologically plastic pathogen; manufacturing and purity requirements that complicate subunit vaccine production; a historical bias in preclinical animal models toward chemically immunosuppressed, rather than genetically susceptible, hosts; an underutilization of key insights from veterinary medicine; and a fragmented regulatory and commercial landscape that structurally disincentivizes investment in niche, high-risk patient populations. We further examine emerging immunotherapeutic strategies-passive antibody engineering, cytokine-based adjuvant approaches, phytocompound-derived antifungals, and dual-action nanovaccines-as partial, rather than complete, solutions to the immunocompromised-host paradox that limits active immunization in the patients who need protection most. Finally, we situate Candida vaccine development within a One Health and global-equity framework, arguing that diagnostic infrastructure, HLA population diversity, and cold-chain economics must be addressed as part of vaccine design rather than as an afterthought.