Next-generation Candida albicans recombinant Als3p and Hyr1p dual antigen vaccine for invasive Candida infections.

species, including and , represent a growing public health concern due to their increasing prevalence and resistance to antifungal agents. is known for causing both superficial and invasive infections, while is a newly emerged, multidrug-resistant pathogen responsible for severe hospital outbreaks with a high mortality rate of ~ 60% in bloodstream infections. Vaccine candidates targeting hyphal cell wall proteins Als3p and Hyr1p have shown protective efficacy in mice. NDV-3A, an alum-formulated Als3p-based vaccine, protects against recurrent vulvovaginal candidiasis in women. We earlier showed that both Als3p and Hyr1p have orthologs in , and that the NDV-3A vaccine, alongside an anti-Hyr1p monoclonal antibody, protect mice from lethal candidemia. Here, we optimized Als3p and Hyr1p dual antigen vaccine formulations with the clinical-stage adjuvant CAF01, demonstrating robust immunity and CD4 T celldependent protection against lethal and . The vaccine formulations also showed enhanced protective efficacy when combined with antifungal drugs. This study highlights the potential of the CAF01-formulated Als3p/Hyr1p dual antigen vaccine in providing durable protective immunity against systemic and mucosal and cross-protection against systemic multidrug-resistant infections.