The NDV-3A vaccine protects mice from multidrug resistantCandida aurisinfection

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 crossreactive humoral and cellular immune responses, and protected immunosuppressed mice from lethal C. auris disseminated infection, compared to the control alum-vaccinated mice. 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. Author SummaryCandida auris has emerged as a major health concern to hospitalized patients and nursing home subjects. C. auris strains display multidrug resistance to current antifungal therapy and cause lethal infections. We have determined that C. auris harbors homologs of C. albicans Als cell surface proteins. The C. albicans NDV-3A vaccine, harboring the N-terminus of Als3p formulated with alum, generates cross-reactive antibodies against C. auris clinical isolates and protects neutropenic mice from hematogenously disseminated C. auris infection. Importantly, the NDV-3A vaccine displays an additive protective effect in neutropenic mice when combined with micafungin. Due to its proven safety and efficacy in humans against C. albicans infection, our studies support the expedited testing of the NDV-3A vaccine against C. auris in future clinical trials.C. auris contained protein homologs of the C. albicans Als3p. Als3p, a member of the agglutininlike sequence (Als) family of proteins, is also known to be conserved in other non-albicans Candida species [12][13][14], and functions as a multifunctional adhesin and invasin essential for host pathogenesis [15,16]. The N-terminus of C. albicans Als3p has been developed as a vaccine that induces protective antibody and cell-mediated immune responses [17,18], and has been shown to be safe and...

Candida auris: An emerging pathogen “incognito”?

“…albicans NDV-3A vaccine for protection against C . auris in mice [34]. Prevention would be ideal for the vulnerable population of hospitalized patients.…”

Impact of Candida auris infection in a neutropenic murine model

“…Although there are immunocompetent models of infection there are discrepancies in survival based on the murine strains and isolates used (21, 22). The immunosuppressed models use cyclophosphamide, which depletes the entire immune system to allow for C. auris dissemination but limits studies that test host immunity against this pathogen(24). Here we compare two mouse models that achieve immunosuppression by depleting neutrophils using 1A8, anti-Ly6G + which depletes neutrophils only and RB6-8C5, anti- Ly6G + -Ly6C + which depletes neutrophils and Ly6G monocytes(30).…”

“…Wang et al attributes this discrepancy to the difference in mouse strains and differences in C. auris isolates (22). The murine models of immunosuppression use the chemotherapeutic agent cyclophosphamide, or a combination of cyclophosphamide and cortisone acetate (23, 24). These models work well in achieving infection and for evaluating the efficacy of a particular treatment such as antifungal and vaccine candidates against C. auris (23, 24).…”

“…The murine models of immunosuppression use the chemotherapeutic agent cyclophosphamide, or a combination of cyclophosphamide and cortisone acetate (23, 24). These models work well in achieving infection and for evaluating the efficacy of a particular treatment such as antifungal and vaccine candidates against C. auris (23, 24). However, a limitation of using cyclophosphamide is that it depletes cells of both the innate and the adaptive immune system (25).…”

“…However, a limitation of using cyclophosphamide is that it depletes cells of both the innate and the adaptive immune system (25). At high doses of cyclophosphamide ≥200mg/kg, these deplete Tregs, CD8 + DCs, B-cells and CD4 + and CD8 + T-cells that may be important in immunological studies in response to C. auris (23, 24, 26–29).…”