Abstract
A Phase 1b/2a clinical trial of NDV-3A vaccine containing a Candida albicans recombinant Als3 protein formulated with alum protected women <40 years old from recurrent vulvovaginal candidiasis (RVVC). We investigated the potential use of anti-Als3p sera as surrogate marker of NDV-3A efficacy. Pre- and post-vaccination sera from subjects who experienced recurrence of vulvovaginal candidiasis (R) vs. those who were recurrence-free [non-recurrent (NR)] were evaluated. Anti-Als3p antisera obtained were evaluated for (1) titer and subclass profile and (2) their ability to influence C. albicans virulence traits including hyphal elongation, adherence to plastic, invasion of vaginal epithelial cells, biofilm formation on plastic and catheter material, and susceptibility to neutrophil killing in vitro. Serum IgG titers in NR patients were consistently higher than in R patients, particularly for anti-Als3 subclass IgG2. Sera from vaccinated NR patients reduced hyphal elongation, adhesion to plastic, invasion of vaginal epithelial cells, and biofilm formation significantly more than pre-immune sera, or sera from R- or placebo-group subjects. Pre-adsorption of sera with C. albicans germ tubes eliminated these effects, while heat inactivation did not. Finally, sera from NR subjects enhanced neutrophil-mediated killing of C. albicans relative to pre-immune sera or sera from R patients. Our results suggest that higher Als3p antibody titers are associated with protection from RVVC, attenuate C. albicans virulence, and augment immune clearance of the fungus in vitro. Thus, Als3p serum IgG antibodies are likely useful markers of efficacy in RVVC patients vaccinated with NDV-3A.
Highlights
Candida species cause distressing mucocutaneous infections of the integument, oral, and genitourinary tracts
Sera from R vs. NR subjects could be compared for their ability to impede key virulence functions of C. albicans in vitro
Our studies focused on determining the impact of serum antibodies on selected putative virulence factors of C. albicans for three reasons: [1] the NDV-3 vaccine induced high antibody titers [13], [2] high antibody titers predict NDV-3 vaccine efficacy in mice [15], and [3] antibodies, including those targeting hyphal regulating protein 1 [23, 24], secreted aspartyl proteinase 2 [25], and Candida cell wall glycopeptides [26, 27], protect against experimental candidiasis
Summary
Candida species cause distressing mucocutaneous infections of the integument, oral, and genitourinary tracts. Despite the use of antifungal therapy, candidemia is associated with ~40% attributable mortality [5] Compounding these concerns is the alarming rise in emergence of Candida species resistant to antifungal drugs [6]. Candida albicans has multiple putative virulence capabilities including avid adherence to abiotic and host surfaces [7], the capacity to produce tissue-invading filaments (hyphae) [8], and the development of biofilms that promote immune evasion and impede efficacy of antifungal therapy [6]. Targeting of these key virulence mechanisms provides opportunities for developing novel therapeutic interventions with minimal effects on the host mycobiome, and reduction in selection pressures that favor drug resistance [9]
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