NDV-3A vaccination prevents C. albicans colonization of jugular vein catheters in mice.

NDV-3A, a novel fungal vaccine undergoing clinical trials, contains a recombinant version of the Candida albicans rAls3 N-terminus protein (rAls3p-N) in aluminum hydroxide. In a Phase 1b/2a clinical trial, NDV-3A protected women from recurrent vulvovaginal candidiasis. Here, we reveal that active immunization in mice with NDV-3A induces high titers of anti-rAls3p-N antibodies that interfere with C. albicans ability to adhere to and invade endothelial cells, and form biofilm in vitro. Anti-rAls3p-N antibodies also significantly inhibit yeast dispersal from the hyphal layers of biofilms. Compared to placebo, NDV-3A vaccination inhibited C. albicans dissemination to kidneys and prevented colonization of central venous catheters in mice. Overall, these preclinical studies suggest that NDV-3A may serve as an immunotherapeutic strategy for prevention of infections on indwelling medical devices.

Novel nanoscale bacteriophage-based single-domain antibodies for the therapy of systemic infection caused by Candida albicans.

Candida albicans (C. albicans) is an important human commensal and opportunistic fungal pathogen. Secreted aspartyl proteinases (Saps) are a major virulence trait of C. albicans, and among these proteases Sap2 has the highest expression levels. It is possible that antibodies against Sap2 could provide an antifungal effect. In this study, two phages displaying anti-rSap2 single chain variable fragments (scFvs) were screened from human single fold scFv libraries, and their potential therapeutic roles were evaluated using a murine model infected by C. albicans. The in vivo efficacies were assessed by mortality rates, fungal burden and histological examination. Overall survival rates were significantly increased while the colony counts and infectious foci were significantly decreased after treatment with the scFv-phages relative to the control groups. In order to investigate the immune response provoked by scFv-phages, three kinds of cytokines (Th1, Th2 and Th17 types) were measured and a clear immune response was observed. These findings suggest that anti-rSap2 scFv-phages have potential in the therapy of systemic infection caused by C. albicans.

Monoclonal antibodies against the 43,000 Da glycoprotein from Paracoccidioides brasiliensis modulate laminin-mediated fungal adhesion to epithelial cells and pathogenesis.

The surface glycoprotein gp43, a highly immunogenic component of Paracoccidioides brasiliensis, is used in the serodiagnosis of paracoccidioidomycosis (PCM) and has recently been shown to specifically bind the extracellular matrix protein laminin. Binding to laminin induces the increased adhesion of the fungus to epithelial cells; a hamster testicle infection model has shown that the gp43-dependent binding of fungal cells to laminin enhances their pathogenicity in vivo. We report on the production and characterization of 12 monoclonal antibodies against the gp43 that recognize peptide sequences in the molecule detecting at least three different epitopes as well as different isoforms of this antigen. MAbs interfered in the fungal pathogenicity in vivo either by inhibiting or enhancing granuloma formation and tissue destruction. Results suggest that P. brasiliensis propagules may start infection in man by strongly adhering to human lung cells. Thus, laminin-mediated fungal adhesion to human lung carcinoma (A549) cells was much more intense than to Madin-Darby canine kidney cells (MDCK), indicating differences in binding affinity. Subsequent growth of fungi bound to the lung cells could induce the granulomatous inflammatory reaction characteristic of PCM. Both steps are greatly stimulated by laminin binding in infective cells expressing gp43.

Effect of attachment of anticandidal antibody to the surfaces of liposomes encapsulating amphotericin B in the treatment of murine candidiasis.

The effect produced by antibody specific to Candida albicans when attached to liposomes containing amphotericin B was studied in vivo. Liposomal amphotericin B bearing specific immunoglobulin (LAMB-Ab) was compared with the unencapsulated drug (fAMB) and other liposomal amphotericin B formulations in the short-term survival (21 days) of mice with disseminated candidiasis. Both the treatment and prophylaxis of the murine model of candidiasis were explored in these trials. LAMB-Ab increased survival rates in the model more than other liposomal preparations containing amphotericin B. Liposomal amphotericin B compounds as a group prolonged survival over fAMB. Liposomal preparations used for comparison included liposomes with attached nonspecific antibody (LAMB-Ab-), liposomes without antibody (LAMB), and liposomes with unattached specific antibody (LAMB+).