A Fungal Immunotherapeutic Vaccine (NDV-3A) for Treatment of Recurrent Vulvovaginal Candidiasis—A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial

Edwards, John E.; Schwartz, Michael M.; Schmidt, Clint S.; Sobel, Jack D.; Nyirjesy, Paul; Schödel, Florian; Marchus, Erica; Lizakowski, Mary; DeMontigny, Elizabeth A; Hoeg, Jesse; Holmberg, Tuomas; Cooke, M. Timothy; Hoover, Keila; Edwards, Lance; Jacobs, Mark; Sussman, Steven A.; Augenbraun, Michael; Drusano, Michael F.; Yeaman, Michael R.; Ibrahim, Ashraf S.; Filler, Scott G.; Hennessey, John P.

doi:10.1093/cid/ciy185

Cited by 140 publications

(120 citation statements)

References 23 publications

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“…This topical therapeutic approach works best when it follows an induction treatment phase with a fungicidal parenteral drug such as an echinocandin to prevent recurrence of candidiasis rather than being effective as treatment of acute severe oral or esophageal candidiasis. Novel antifungal agents with remarkable in vitro and in vivo activity against azole‐susceptible and ‐resistant Candida strains require future investigation in APECED patients with severe azole‐resistant CMC, as does the Als3‐based fungal vaccine that boosts IL‐17‐mediated anti‐ Candida immunity and is the first fungal vaccine shown to display efficacy in humans . Routine screening for gastrointestinal cancers is a recommended practice for all patients.…”

Section: Management Of Apeced Patientsmentioning

confidence: 99%

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Constantine

Lionakis

2018

Immunological Reviews

118

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Summary: The discovery of the Autoimmune Regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire-deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.

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Section: Management Of Apeced Patientsmentioning

confidence: 99%

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Constantine

Lionakis

2018

Immunological Reviews

118

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“…This calls for a new and a more effective version of these vaccines. 24,[27][28][29][30][31][32] This study aims to introduce a new possible vaccine for C. albicans through analyzing peptides of its pyruvate kinase (PK) protein as an immunogenic stimulant computationally. Vaccine production that depends on biochemical experiments can be expensive, time consuming, hazardous and more likely to give unsatisfactory results, that's why bioinformatics approaches provide more affordable, efficient and faster techniques for vaccine development.…”

Section: Introductionmentioning

confidence: 99%

Multi-epitope Peptide Vaccine Prediction for Candida albicans targeting Pyruvate Kinase Protein; an Immunoinformatics Approach

Sati¹,

Abdelmoneim²,

Dawoud³

et al. 2019

Preprint

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The fungus Candida albicans is an opportunistic pathogen that causes a wide range of infections. It's the primary cause of candidiasis and the fourth most common cause of nosocomial infection. In addition, disseminated invasive candidiasis which is a major complication of the disease has an estimated mortality rate of 40%-60% even with the use of antifungal drugs. Over the last decades, several different anti-Candida vaccines have been suggested with different strategies for immunization against candidiasis such as, live-attenuated fungi, recombinant proteins, and glycoconjugates but none has been approved by the FDA, yet. This study aims to introduce a new possible vaccine for C. albicans through analyzing peptides of its pyruvate kinase (PK) protein as an immunogenic stimulant computationally.A total number of 28 C. albicans, pyruvate kinase proteins were obtained from NCBI on the 9 th of February 2019 and were subjected to multiple sequence alignment using Bioedit for conservancy. The main analytical tool was IEDB, Chimera for homology modelling, and MOE for docking.Among the tested peptides, fifteen promising T-cell peptides were predicted. Five peptides were more important than the others (HMIFASFIR, YRGVYPFIY, AVAAVSAAY, LRWAVSEAV, and IFASFIRTA) They show high Binding Affinity to MHC molecules, low binding energy required indicating more stable bonds, and their ideal length of nine peptides. (PTRAEVSDV) peptide is the most promising linear B-cell peptide due to its physiochemical parameters and optimal length (nine amino acids). It's highly recommended to have these five strong candidates in future in vivo and in vitro analysis studies.Keywords: candida albicans, immunoinformatics, multi-epitope, peptide-based vaccine, pyruvate kinase, vaccine design Non-linear B-cell epitopes 1.3.2.1 ElliPro Antibody epitopes prediction:It's a tool that works using the PDB ID of the protein, providing minimum score of (0.5) and maximum distance of (6) to predict non-linear peptides. It provides 3D model of the clustered peptides with the result. 42 (available at: http://tools.iedb.org/ellipro/) T-cell epitopes prediction:1.4.2 Binding to MHC class I prediction tool:

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“…Als3p is also required for iron uptake from the host 10 . Our group has used Als3p for the development of an antiCandida funga vaccinel called NDV-3A 11 . NDV-3, containing a His-tagged recombinant version of the C. albicans Als3 protein N-terminus (rAls3p-N), formulated with alum, prevents both mucosal and hematogenously disseminated candidiasis in mice [12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

“…NDV-3 was highly immunogenic, well-tolerated and had minimal minor side effects in a Phase I clinical trial 16 . Furthermore, the latest version of the vaccine, prepared with rAls3p-N without the His-tag, formulated with alum, (NDV-3A), was equally safe and immunogenic, and protective against vaginal infections, in an exploratory 1b/2a clinical trial of patients with a history of recurrent vulvovaginal candidiasis (RVVC) 11 . Subsequently, our group showed that serum antibodies from patients who responded to NDV-3A (but not those of the unresponsive patients) could prevent C.…”

Section: Introductionmentioning

confidence: 99%

NDV-3A vaccination protects mice fromCandida albicansbiofilm infection

Alqarihi

Singh

et al. 2018

Preprint

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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.The anti-rAls3p-N antibodies also protect against C. albicans biofilm formation in a central venous catheter mouse model. Finally, anti-rAls3p-N antibodies significantly inhibit yeast dispersal from the hyphal layers of biofilms. Overall these preclinical studies suggest that NDV-3A may serve as an immunotherapeutic strategy for prevention of infections on indwelling medical devices.

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A Fungal Immunotherapeutic Vaccine (NDV-3A) for Treatment of Recurrent Vulvovaginal Candidiasis—A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial

Abstract: NCT01926028.

Cited by 140 publications

References 23 publications

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Multi-epitope Peptide Vaccine Prediction for Candida albicans targeting Pyruvate Kinase Protein; an Immunoinformatics Approach

NDV-3A vaccination protects mice fromCandida albicansbiofilm infection

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