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Cited by 56Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Infections and Studies

Human Anti-Als3p Antibodies Are Surrogate Markers of NDV-3A Vaccine Efficacy Against Recurrent Vulvovaginal Candidiasis

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Uppuluri, Priya, Singh, Shakti, Alqarihi, Abdullah, Schmidt, Clint S., Hennessey, John P., Yeaman, Michael R., Filler, Scott G., Edwards, John E. +1 more·2018·Frontiers in Immunology
DOI 10.3389/fimmu.2018.01349PMC PMC6013566

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Abstract

A Phase 1b/2a clinical trial of NDV-3A vaccine containing a Candida albicans recombinant Als3 protein 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 VVC (R) versus those who were recurrence-free (non-recurrent, NR) were evaluated. Anti-Als3p antisera obtained were evaluated for; 1) titer and subclass profile; 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.

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  • In C. albicans, targeting adhesin proteins with vaccines decreases adhesion to and biofilm formation on plastic surfaces, invasion of vaginal epithelial cells, and virulence.

    “In the model fungal pathogen C. albicans, targeting adhesin proteins with vaccines results in a decrease in adhesion to and biofilm formation on plastic surfaces, including catheters, invasion of vaginal epithelial cells, and virulence22–24.”

    From Adhesin Als4112 promotes Candida auris skin colonization through interactions with keratinocytes and extracellular matrix proteins (2025) · cites this paper as [22]

    The Results (‘Sera From NR Patients Reduced C. albicans Biofilm Development’ and ‘…Invasion of Vaginal Epithelial Cells’; pages unavailable) report reduced adhesion, biofilm formation on plastic and catheter material, and vaginal epithelial-cell invasion with sera from vaccinated patients whose candidiasis did not recur. The Introduction also reports reduced disease severity in vaccinated mice. The claim omits the restriction to particular patients’ sera for the in vitro findings and presents the effects as a general result of adhesin-targeting vaccines. (LLM, conf=0.84)

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  1. [1]Brown GD Denning DW Gow NA Levitz SM Netea MG White TC. Hidden killers: human fungal infections. Sci Transl Med (2012) 4(165): 165rv13. 10.1126/scitranslmed.3004404 23253612 · DOI · Paper page
  2. [2]Sobel JD Vaginal infections in adult women. Med Clin North Am (1990) 74(6): 1573– 602. 10.1016/S0025-7125(16)30496-5 2246954 · DOI
  3. [3]Sobel JD Faro S Force RW Foxman B Ledger WJ Nyirjesy PR Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol (1998) 178(2): 203– 11. 10.1016/S0002-9378(98)80001-X 9500475 · DOI
  4. [5]Wenzel RP. Nosocomial candidemia: risk factors and attributable mortality. Clin Infect Dis (1995) 20(6): 1531– 4. 10.1093/clinids/20.6.1531 7548504 · DOI · Paper page
  5. [6]Ramage G Rajendran R Sherry L Williams C. Fungal biofilm resistance. Int J Microbiol (2012) 2012: 528521. 10.1155/2012/528521 22518145 PMC3299327 · DOI · Paper page
  6. [7]Tsui C Kong EF Jabra-Rizk MA. Pathogenesis of Candida albicans biofilm. Pathog Dis (2016) 74(4): ftw018. 10.1093/femspd/ftw018 26960943 PMC5975230 · DOI
  7. [8]Williams DW Jordan RP Wei XQ Alves CT Wise MP Wilson MJ Interactions of Candida albicans with host epithelial surfaces. J Oral Microbiol (2013) 5: 22434. 10.3402/jom.v5i0.22434 24155995 PMC3805843 · DOI
  8. [9]Pierce CG Chaturvedi AK Lazzell AL Powell AT Saville SP McHardy SF A novel small molecule inhibitor of Candida albicans biofilm formation, filamentation and virulence with low potential for the development of resistance. NPJ Biofilms Microbiomes (2015) 1: 15012. 10.1038/npjbiofilms.2015.12 26691764 PMC4681527 · DOI · Paper page
  9. [10]Phan QT Myers CL Fu Y Sheppard DC Yeaman MR Welch WH Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells. PLoS Biol (2007) 5(3): e64. 10.1371/journal.pbio.0050064 17311474 PMC1802757 · DOI · Paper page
  10. [11]Zhao X Daniels KJ Oh SH Green CB Yeater KM Soll DR Candida albicans Als3p is required for wild-type biofilm formation on silicone elastomer surfaces. Microbiology (2006) 152(Pt 8): 2287– 99. 10.1099/mic.0.28959-0 16849795 PMC2583121 · DOI
  11. [12]Ibrahim AS Luo G Gebremariam T Lee H Schmidt CS Hennessey JP Jr NDV-3 protects mice from vulvovaginal candidiasis through T- and B-cell immune response. Vaccine (2013) 31(47): 5549– 56. 10.1016/j.vaccine.2013.09.016 24063977 PMC3866209 · DOI
  12. [13]Schmidt CS White CJ Ibrahim AS Filler SG Fu Y Yeaman MR NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults. Vaccine (2012) 30(52): 7594– 600. 10.1016/j.vaccine.2012.10.038 23099329 PMC3513491 · DOI
  13. [14]Lin L Ibrahim AS Avanesian V Edwards JE Jr Fu Y Baquir B Considerable differences in vaccine immunogenicities and efficacies related to the diluent used for aluminum hydroxide adjuvant. Clin Vaccine Immunol (2008) 15(3): 582– 4. 10.1128/CVI.00427-07 18184821 PMC2268268 · DOI
  14. [15]Spellberg B Ibrahim AS Lin L Avanesian V Fu Y Lipke P Antibody titer threshold predicts anti-candidal vaccine efficacy even though the mechanism of protection is induction of cell-mediated immunity. J Infect Dis (2008) 197(7): 967– 71. 10.1086/529204 18419471 PMC2717621 · DOI
  15. [16]Edwards JJE Schwartz MS Schmidt CS Sobel J Nyirjesy P Schodel F A fungal immunotherapeutic vaccine (NDV-3A) for treatment of recurrent vulvovaginal candidiasis—a phase 2 randomized, double-blind, placebo-controlled trial. Clin Infect Dis (2018) 66(12): 1928– 36. 10.1093/cid/ciy185 29697768 PMC5982716 · DOI · Paper page
  16. [18]Ibrahim AS Spellberg BJ Avanesian V Fu Y Edwards JE Jr. The anti-Candida vaccine based on the recombinant N-terminal domain of Als1p is broadly active against disseminated candidiasis. Infect Immun (2006) 74(5): 3039– 41. 10.1128/IAI.74.5.3039-3041.2006 16622247 PMC1459699 · DOI
  17. [19]Uppuluri P Chaturvedi AK Srinivasan A Banerjee M Ramasubramaniam AK Kohler JR Dispersion as an important step in the Candida albicans biofilm developmental cycle. PLoS Pathog (2010) 6(3): e1000828. 10.1371/journal.ppat.1000828 20360962 PMC2847914 · DOI · Paper page
  18. [20]Pierce CG Uppuluri P Tristan AR Wormley FL Jr Mowat E Ramage G A simple and reproducible 96-well plate-based method for the formation of fungal biofilms and its application to antifungal susceptibility testing. Nat Protoc (2008) 3(9): 1494– 500. 10.1038/nprot.2008.141 18772877 PMC2741160 · DOI · Paper page
  19. [21]Steele C Fidel PL Jr. Cytokine and chemokine production by human oral and vaginal epithelial cells in response to Candida albicans. Infect Immun (2002) 70(2): 577– 83. 10.1128/IAI.70.2.577-583.2002 11796585 PMC127706 · DOI
  20. [22]Hanley JA McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology (1982) 143(1): 29– 36. 10.1148/radiology.143.1.7063747 7063747 · DOI · Paper page
  21. [24]Luo G Ibrahim AS Spellberg B Nobile CJ Mitchell AP Fu Y. Candida albicans Hyr1p confers resistance to neutrophil killing and is a potential vaccine target. J Infect Dis (2010) 201(11): 1718– 28. 10.1086/652407 20415594 PMC3933264 · DOI · Paper page
  22. [25]Vilanova M Teixeira L Caramalho I Torrado E Marques A Madureira P Protection against systemic candidiasis in mice immunized with secreted aspartic proteinase 2. Immunology (2004) 111(3): 334– 42. 10.1111/j.1365-2567.2004.01819.x 15009435 PMC1782415 · DOI
  23. [26]Xin H Cartmell J Bailey JJ Dziadek S Bundle DR Cutler JE. Self-adjuvanting glycopeptide conjugate vaccine against disseminated candidiasis. PLoS One (2012) 7(4): e35106. 10.1371/journal.pone.0035106 22563378 PMC3338514 · DOI
  24. [27]Xin H Cutler JE. Vaccine and monoclonal antibody that enhance mouse resistance to candidiasis. Clin Vaccine Immunol (2011) 18(10): 1656– 67. 10.1128/CVI.05215-11 21832099 PMC3187024 · DOI
  25. [28]Nobile CJ Andes DR Nett JE Smith FJ Yue F Phan QT Critical role of Bcr1-dependent adhesins in C. albicans biofilm formation in vitro and in vivo. PLoS Pathog (2006) 2(7): e63. 10.1371/journal.ppat.0020063 16839200 PMC1487173 · DOI · Paper page
  26. [29]Beenhouwer DO Yoo EM Lai CW Rocha MA Morrison SL. Human immunoglobulin G2 (IgG2) and IgG4, but not IgG1 or IgG3, protect mice against Cryptococcus neoformans infection. Infect Immun (2007) 75(3): 1424– 35. 10.1128/IAI.01161-06 17220317 PMC1828574 · DOI
  27. [30]Subramaniam KS Datta K Marks MS Pirofski LA. Improved survival of mice deficient in secretory immunoglobulin M following systemic infection with Cryptococcus neoformans. Infect Immun (2010) 78(1): 441– 52. 10.1128/IAI.00506-09 19901068 PMC2798234 · DOI
  28. [31]Fidel PL Jr Barousse M Espinosa T Ficarra M Sturtevant J Martin DH An intravaginal live Candida challenge in humans leads to new hypotheses for the immunopathogenesis of vulvovaginal candidiasis. Infect Immun (2004) 72(5): 2939– 46. 10.1128/IAI.72.5.2939-2946.2004 15102806 PMC387876 · DOI
  29. [32]Peters BM Yano J Noverr MC Fidel PL Jr Candida vaginitis: when opportunism knocks, the host responds. PLoS Pathog (2014) 10(4): e1003965 10.1371/journal.ppat.1003965 24699903 PMC3974868 · DOI
  30. [33]Yano J Noverr MC Fidel PL Jr. Vaginal heparan sulfate linked to neutrophil dysfunction in the acute inflammatory response associated with experimental vulvovaginal candidiasis. MBio (2017) 8(2): e211– 7. 10.1128/mBio.00211-17 28292981 PMC5350465 · DOI

Cited by

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Authors
Uppuluri, P., Singh, S., Alqarihi, A., Schmidt, C. S., Hennessey, J. P., Yeaman, M. R., Filler, S. G., Edwards, J. E., & Ibrahim, A. S.
Affiliations
  • University of California, Los Angeles (US)
  • NovaDigm Therapeutics (United States) (US)
Corresponding author
Ibrahim, Ashraf S.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2018-06-15
Volume
9
Pages
1349-1349
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2018.01349
PMC
PMC6013566
OpenAlex
W2950655724
Cited by
56
References
3
Citations by year
2026: 10 · 2025: 13 · 2024: 7 · 2023: 6 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 6 · 2018: 1
FWCI
3.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute of Allergy and Infectious Diseases (R01 AI063382)
  • U.S. Department of Defense (W81XWH-11-1-0686)
  • American Heart Association (16SDG30830012)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords
recurrent vulvovaginal candidiasis, Candida albicans, hyphal elongation, biofilm formation, neutrophil killing, vaccine adjuvants

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