The NDV-3A vaccine protects mice from multidrug resistant Candida auris infection
Shakti Singh1, Priya Uppuluri1,2, Zeinab Mamouei1
1Division of Infectious Disease, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center, Torrance, California, United States of America.
Abstract:
Candida auris is an emerging, multi-drug resistant, health care-associated fungal pathogen. Its predominant prevalence in hospitals and nursing homes indicates its ability to adhere to and colonize the skin, or persist in an environment outside the host-a trait unique from other Candida species. Besides being associated globally with life-threatening disseminated infections, C. auris also poses significant clinical challenges due to its ability to adhere to polymeric surfaces and form highly drug-resistant biofilms. Here, we performed bioinformatic studies to identify the presence of adhesin proteins in C. auris, with sequence as well as 3-D structural homologies to the major adhesin/invasin of C. albicans, Als3. Anti-Als3p antibodies generated by vaccinating mice with NDV-3A (a vaccine based on the N-terminus of Als3 protein formulated with alum) recognized C. auris in vitro, blocked its ability to form biofilms and enhanced macrophage-mediated killing of the fungus. Furthermore, NDV-3A vaccination induced significant levels of C. auris cross-reactive humoral and cellular immune responses, and protected immunosuppressed mice from lethal C. auris disseminated infection, compared to the control alum-vaccinated mice. The mechanism of protection is attributed to anti-Als3p antibodies and CD4+ T helper cells activating tissue macrophages. Finally, NDV-3A potentiated the protective efficacy of the antifungal drug micafungin, against C. auris candidemia. Identification of Als3-like adhesins in C. auris makes it a target for immunotherapeutic strategies using NDV-3A, a vaccine with known efficacy against other Candida species and safety as well as efficacy in clinical trials. Considering that C. auris can be resistant to almost all classes of antifungal drugs, such an approach has profound clinical relevance.
Insights
A novel vaccine targeting Als3-like adhesins in Candida auris demonstrated protective immunity against this multidrug-resistant fungus. The vaccine enhanced immune responses and improved outcomes in infected mice, offering a promising immunotherapeutic strategy.
Area of Science:
- * Mycology and Infectious Diseases
- * Immunology and Vaccinology
- * Bioinformatics and Structural Biology
Background:
- * Candida auris is a multidrug-resistant, healthcare-associated fungal pathogen known for its ability to colonize surfaces and form biofilms.
- * Its adhesin proteins share similarities with Candida albicans Als3, suggesting potential therapeutic targets.
- * Existing antifungal drugs face challenges due to widespread resistance.
Purpose of the Study:
- * To identify adhesin proteins in Candida auris with sequence and structural homology to Candida albicans Als3.
- * To evaluate the efficacy of a vaccine (NDV-3A) targeting Als3 in preventing and treating Candida auris infections.
- * To explore the immunotherapeutic potential of targeting Als3-like adhesins in Candida auris.
Main Methods:
- * Bioinformatic analysis to identify adhesin proteins in Candida auris.
- * Vaccination of mice with NDV-3A (anti-Als3p vaccine) and assessment of immune responses.
- * In vitro and in vivo studies to evaluate vaccine efficacy against Candida auris biofilms and disseminated infections, including combination therapy with micafungin.
Main Results:
- * Candida auris possesses Als3-like adhesins, recognized by anti-Als3p antibodies.
- * NDV-3A vaccination blocked biofilm formation and enhanced macrophage-mediated killing of Candida auris.
- * Vaccination induced cross-reactive immune responses and protected mice from lethal disseminated infections, potentiating micafungin efficacy.
Conclusions:
- * Als3-like adhesins are viable targets for immunotherapeutic strategies against Candida auris.
- * NDV-3A vaccine shows promise for preventing and treating Candida auris infections, including multidrug-resistant strains.
- * This approach offers a clinically relevant alternative or adjunct to conventional antifungal therapies.
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