Novel Intravenous Immunoglobulin Therapy for the Prevention and Treatment of Candida auris and Candida albicans Disseminated Candidiasis.

Disseminated candidiasis is a life-threatening disease and remains the most common bloodstream infection in hospitalized patients in the United States. Despite the availability of modern antifungal therapy, the crude mortality rate in the last decade has remained unacceptably high. Novel approaches are urgently needed to supplement or replace current antifungal therapies. In our study, we show that human intravenous immunoglobulin (IVIG) can provide protection against Candida auris and Candida albicans disseminated infections in A/J and C57BL/6 mouse models. The protective efficacy of IVIG is evidenced by the prolonged survival of mice with invasive candidiasis that were treated with human IVIG alone or in combination with amphotericin B. Our previous studies have led to the identification of a panel of Candida cell surface peptide and glycan epitopes, which are targeted by protective mouse monoclonal antibodies (mAbs) against invasive candidiasis. Of interest, the peptide- and glycan-specific IgGs could be detected in all 18 human IVIG samples. In particular, the specific IVIG lots with the highest protective peptide- and glycan-related IgGs provided the best protection. The combination of IVIG and amphotericin B had enhanced efficacy in protection compared to monotherapy against both multidrug-resistant (MDR) C. auris and C. albicans, with evidence of significantly prolonged survival and lower fungal burdens in targeted organs. This study provides evidence that the protective effects of IVIG were associated with the protective antibodies found in normal human donor sera against pathogenic Candida, and IVIG can be a novel therapy or adjunctive therapy with modern antifungal drugs against disseminated candidiasis. IMPORTANCE Since current antifungal treatments are ineffective in the immunocompromised population and no vaccine is available for humans, hope remains that antibody preparations selected for specific fungal antigens may make it possible to reduce the incidence and mortality of invasive candidiasis. Intravenous immunoglobulin (IVIG) has long been approved as a standard treatment for patients with immunodeficiency disorders who are also susceptible to fungal infection. IVIG has been widely used as prophylaxis or supplemental treatment for sepsis and septic shock; however, this form of adjunctive therapy lacks convincing data to establish its efficacy. In this study, 18 samples from commercial IVIG preparations were screened and evaluated by enzyme-linked immunosorbent assays (ELISAs); Candida peptide- and glycan-specific IgGs were detected with various titers among all IVIG lots. Importantly, significantly reduced organ fungal burdens and mortality were demonstrated in IVIG-treated mouse models of invasive candidiasis. IVIG lots with higher titers of Candida-specific IgGs provided better protection. These findings are important in (i) selecting Candida-specific IVIG therapy that may overcome several shortcomings of conventional IVIG therapy by targeting specific antigens responsible for disease pathogenesis, (ii) enhancing protective efficacy, and (iii) validating data from our previous studies and those of others showing that antibodies combined with conventional antifungal drugs provided enhanced resistance to disease. To our knowledge, this study is the first to demonstrate that human IVIG samples contain protective IgGs targeting Candida cell surface antigens and can be a novel therapy or adjunctive therapy with modern antifungal drugs against disseminated candidiasis.

Candida Cell-Surface-Specific Monoclonal Antibodies Protect Mice against Candida auris Invasive Infection.

Candida auris is a multidrug-resistant fungal pathogen that can cause disseminated bloodstream infections with up to 60% mortality in susceptible populations. Of the three major classes of antifungal drugs, most C. auris isolates show high resistance to azoles and polyenes, with some clinical isolates showing resistance to all three drug classes. We reported in this study a novel approach to treating C. auris disseminated infections through passive transfer of monoclonal antibodies (mAbs) targeting cell surface antigens with high homology in medically important Candida species. Using an established A/J mouse model of disseminated infection that mimics human candidiasis, we showed that C3.1, a mAb that targets ß-1,2-mannotriose (ß-Man3), significantly extended survival and reduced fungal burdens in target organs, compared to control mice. We also demonstrated that two peptide-specific mAbs, 6H1 and 9F2, which target hyphal wall protein 1 (Hwp1) and phosphoglycerate kinase 1 (Pgk1), respectively, also provided significantly enhanced survival and reduction of fungal burdens. Finally, we showed that passive transfer of a 6H1+9F2 cocktail induced significantly enhanced protection, compared to treatment with either mAb individually. Our data demonstrate the utility of ß-Man3- and peptide-specific mAbs as an effective alternative to antifungals against medically important Candida species including multidrug-resistant C. auris.