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Cited by 34Antifungal resistance and susceptibilityFungal Infections and StudiesFungal and yeast genetics research

Antibodies targeting Candida albicans Als3 and Hyr1 antigens protect neonatal mice from candidiasis.

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Singh, Shakti, Nabeela, Sunna, Barbarino, Ashley, Ibrahim, Ashraf S., Uppuluri, Priya·2022·Frontiers in Immunology
DOI 10.3389/fimmu.2022.925821PMC PMC9355692
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Abstract

Pre-term infants in neonatal intensive care units are vulnerable to fungal sepsis. In this patient population, Candida albicans remains the predominant fungal pathogen causing high morbidity and mortality, despite antifungal therapy. Thus, new preventative/therapeutic strategies against neonatal candidiasis are needed. Previously, we have reported that vaccination with recombinant forms of the C. albicans N-termini of the cell wall proteins Als3 (rAls3p-N) and Hyr1 (rHyr1p-N) protected adult mice from disseminated candidiasis. Further, in a Phase 1b/2a NDV-3A (an rAls3p-N formulated with alum) protected women from recurrent vulvovaginal candidiasis, with anti-Als3p IgG2 isotype being a biomarker for efficacy. Here, we performed a proof of concept study to evaluate if anti-Als3p or anti-Hyr1p antibodies are important for prevention of disseminated candidiasis in neonates. Als3 and Hyr1 antigens when adjuvanted with complete Freund’s adjuvant (CFA)/incomplete Freund’s adjuvant (IFA) induced a robust antibody response with a ten-fold higher titer of IgG2, than attained by either antigen formulated with alum. Transplacental transfer of these antibodies significantly reduced fungal burden in the kidneys of mice pups, and adoptive transfer of vaccinated mothers’ sera into pups displayed similar levels of protection. Neutrophils were found important for this efficacy. Finally, anti-Hyr1 antisera potentiated the activity of fluconazole in protecting from C. albicans infection. Our current studies are the first in the field to emphasize the importance of anti-Als3 and anti-Hyr1 antibodies in preventing neonatal candidiasis. Considering that Candida infections in low birthweight infants is a lethal infection, active and passive vaccination strategies using these antigens could have profound clinical relevance.

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  1. [1]Martin JA Hamilton BE Osterman MJ Curtin SC Matthews TJ. Births: Final data for 2013. Natl Vital Stat Rep (2015) 64: 1– 65. 25603115
  2. [2]Bendel CM. Nosocomial neonatal candidiasis. Pediatr Infect Dis J (2005) 24: 831–2. doi: 10.1097/01.inf.0000178291.40568.ef 16148852 · DOI
  3. [3]Trofa D Gacser A Nosanchuk JD. Candida parapsilosis, an emerging fungal pathogen. Clin Microbiol Rev (2008) 21: 606–25. doi: 10.1128/CMR.00013-08 PMC2570155 18854483 · DOI
  4. [4]Hoffmann-Santos HD Paula CR Yamamoto AC Tadano T Hahn RC. Six-year trend analysis of nosocomial candidemia and risk factors in two intensive care hospitals in mato grosso, Midwest region of Brazil. Mycopathologia (2013) 176: 409–15. doi: 10.1007/s11046-013-9705-5 24113801 · DOI
  5. [5]Leibovitz E Livshiz-Riven I Borer A Taraboulos-Klein T Zamir O Shany E. A prospective study of the patterns and dynamics of colonization with candida spp. in very low birth weight neonates. Scand J Infect Dis (2013) 45: 842–8. doi: 10.3109/00365548.2013.814150 23919503 · DOI
  6. [6]Botero-Calderon L Benjamin DK Jr. Cohen-Wolkowiez M. Advances in the treatment of invasive neonatal candidiasis. Expert Opin Pharmacother (2015) 16: 1035–48. doi: 10.1517/14656566.2015.1031108 PMC4402277 25842986 · DOI
  7. [7]Zasada M Kwinta P Durlak W Bik-Multanowski M Madetko-Talowska A Józef Pietrzyk J. Development and maturation of the immune system in preterm neonates: Results from a whole genome expression study. BioMed Res Int (2014) 2014: 498318. doi: 10.1155/2014/498318 24982884 PMC4058491 · DOI
  8. [8]Mussi-Pinhata MM Rego MA. [Immunological peculiarities of extremely preterm infants: A challenge for the prevention of nosocomial sepsis]. J Pediatr (Rio J) (2005) 81: S59–68. doi: 10.2223/1301 15809699 · DOI
  9. [9]Lindsey B Jones C Kampmann B. Bridging the gap: Maternal immunisation as a means to reduce neonatal deaths from infectious diseases. Pathog Glob Health (2012) 106: 137–8. doi: 10.1179/204777312X13462106637684 PMC4001569 23265367 · DOI
  10. [10]Lindsey B Kampmann B Jones C. Maternal immunization as a strategy to decrease susceptibility to infection in newborn infants. Curr Opin Infect Dis (2013) 26: 248–53. doi: 10.1097/QCO.0b013e3283607a58 23507974 · DOI
  11. [11]Esposito S Bosis S Morlacchi L Baggi E Sabatini C Principi N. Can infants be protected by means of maternal vaccination? Clin Microbiol Infect (2012) 18 Suppl 5: 85– 92. doi: 10.1111/j.1469-0691.2012.03936.x 22862749 · DOI
  12. [12]Holmlund E Nohynek H Quiambao B Ollgren J Kayhty H. Mother-infant vaccination with pneumococcal polysaccharide vaccine: Persistence of maternal antibodies and responses of infants to vaccination. Vaccine (2011) 29: 4565–75. doi: 10.1016/j.vaccine.2011.04.068 21550374 · DOI
  13. [13]Ohlsson A Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants. Cochrane Database Syst Rev (2013) 7: CD000361. doi: 10.1002/14651858.CD000361.pub3 23821390 · DOI
  14. [14]Keller MA Stiehm ER. Passive immunity in prevention and treatment of infectious diseases. Clin Microbiol Rev (2000) 13: 602–14. doi: 10.1128/CMR.13.4.602 PMC88952 11023960 · DOI · Paper page
  15. [15]Fischer GW. Use of intravenous immune globulin in newborn infants. Clin Exp Immunol (1994) 97 Suppl: 1, 73–77. PMC1550380 8033439
  16. [16]Jenson HB Pollock BH. Meta-analyses of the effectiveness of intravenous immune globulin for prevention and treatment of neonatal sepsis. Pediatrics (1997) 99: E2. doi: 10.1542/peds.99.2.e2 9099759 · DOI
  17. [17]Jenson HB Pollock BH. The role of intravenous immunoglobulin for the prevention and treatment of neonatal sepsis. Semin Perinatol (1998) 22: 50– 63. doi: 10.1016/S0146-0005(98)80007-4 9523399 · DOI
  18. [18]Edwards JE Jr. Schwartz MM Schmidt CS Sobel JD 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: 1928–36. doi: 10.1093/cid/ciy185 PMC5982716 29697768 · DOI · Paper page
  19. [19]Singh S Uppuluri P Mamouei Z Alqarihi A Elhassan H French S. The NDV-3A vaccine protects mice from multidrug resistant candida auris infection. PLoS Pathog (2019) 15: e1007460. doi: 10.1371/journal.ppat.1007460 31381597 PMC6695204 · DOI · Paper page
  20. [20]Alqarihi A Singh S Edwards JE Jr. Ibrahim AS Uppuluri P. NDV-3A vaccination prevents c. albicans colonization of jugular vein catheters in mice. Sci Rep (2019) 9: 6194. doi: 10.1038/s41598-019-42517-y 30996274 PMC6470131 · DOI · Paper page
  21. [21]Uppuluri P Lin L Alqarihi A Luo G Youssef EG Alkhazraji S. The Hyr1 protein from the fungus candida albicans is a cross kingdom immunotherapeutic target for acinetobacter bacterial infection. PLoS Pathog (2018) 14: e1007056. doi: 10.1371/journal.ppat.1007056 29746596 PMC5963808 · DOI · Paper page
  22. [22]Youssef EG Zhang L Alkhazraji S Gebremariam T Singh S Yount NY. Monoclonal IgM antibodies targeting candida albicans Hyr1 provide cross-kingdom protection against gram-negative bacteria. Front Immunol (2020) 11: 76. doi: 10.3389/fimmu.2020.00076 32153560 PMC7045048 · DOI
  23. [23]Ost KS O'Meara TR Zac Stephens W Chiaro T Zhou H Penman J. Adaptive immunity induces mutualism between commensal eukaryotes. Nature (2021) 596: 114–8. doi: 10.1038/s41586-021-03722-w PMC8904204 34262174 · DOI
  24. [26]Ibrahim AS. The anti-candida vaccine based on the recombinant n-terminal domain of Als1p is broadly active against disseminated candidiasis. Arch Microbiol (2006) 74: 3039–41. doi: 10.1007/s00203-006-0121-9 PMC1459699 16622247 · DOI
  25. [27]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: 1718–28. doi: 10.1086/652407 PMC3933264 20415594 · DOI · Paper page
  26. [28]Uppuluri P Singh S Alqarihi A Schmidt CS Hennessey JP Jr Yeaman MR. Human anti-Als3p antibodies are surrogate markers of NDV-3a vaccine efficacy against recurrent vulvovaginal candidiasis. Front Immunol (2018) 9: 1349. doi: 10.3389/fimmu.2018.01349 29963049 PMC6013566 · DOI · Paper page
  27. [29]Greenberg RG Benjamin DK Jr. Neonatal candidiasis: Diagnosis, prevention, and treatment. J Infect (2014) 69 Suppl 1: S19–22. doi: 10.1016/j.jinf.2014.07.012 PMC4252884 25129318 · DOI
  28. [30]Benjamin DK Jr. Stoll BJ Fanaroff AA McDonald SA Oh W Higgins RD. Neonatal candidiasis among extremely low birth weight infants: Risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics (2006) 117: 84– 92. doi: 10.1542/peds.2004-2292 16396864 · DOI
  29. [31]Stoll BJ Hansen NI Adams-Chapman I Fanaroff AA Hintz SR Vohr B. Neurodevelopmental and growth impairment among extremely low-Birth-Weight infants with neonatal infection. JAMA (2004) 292: 2357–65. doi: 10.1001/jama.292.19.2357 15547163 · DOI
  30. [32]Ibrahim AS Luo G Gebremariam T Lee H. NDV-3 protects mice from vulvovaginal candidiasis through T- and b-cell immune response. Vaccine (2013) 31: 5549–56. doi: 10.1016/j.vaccine.2013.09.016 PMC3866209 24063977 · DOI
  31. [33]Adkins B Leclerc C Marshall-Clarke S. Neonatal adaptive immunity comes of age. Nat Rev Immunol (2004) 4: 553–64. doi: 10.1038/nri1394 15229474 · DOI
  32. [35]Palmeira P Quinello C Silveira-Lessa AL Zago CA Carneiro-Sampaio M. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol (2012) 2012: 985646. doi: 10.1155/2012/985646 22235228 PMC3251916 · DOI · Paper page
  33. [36]Wiederhold NP Najvar LK Shaw KJ Jaramillo R Patterson H Olivo M. Efficacy of delayed therapy with fosmanogepix (APX001) in a murine model of candida auris invasive candidiasis. Antimicrob Agents Chemother (2019) 63. doi: 10.1128/aac.01120-19 PMC6811405 31427304 · DOI · Paper page
  34. [37]Spellberg B Ibrahim AS Edwards JE Jr. Filler SG. Mice with disseminated candidiasis die of progressive sepsis. J Infect Dis (2005) 192: 336–43. doi: 10.1086/430952 15962230 · DOI · Paper page
  35. [38]Hager CL Larkin EL Long LA Ghannoum MA. Evaluation of the efficacy of rezafungin, a novel echinocandin, in the treatment of disseminated candida auris infection using an immunocompromised mouse model. J Antimicrob Chemother (2018) 73: 2085–8. doi: 10.1093/jac/dky153 PMC6070025 29897469 · DOI
  36. [39]Biswas PS. Vaccine-induced immunological memory in invasive fungal infections - a dream so close yet so far. Front Immunol (2021) 12: 671068. doi: 10.3389/fimmu.2021.671068 33968079 PMC8096976 · DOI
  37. [40]Tso GHW Reales-Calderon JA Pavelka N. The elusive anti-candida vaccine: Lessons from the past and opportunities for the future. Front Immunol (2018) 9: 897. doi: 10.3389/fimmu.2018.00897 29755472 PMC5934487 · DOI
  38. [41]Vono M Sigrid Eberhardt C Auderset F Mastelic-Gavillet B Lemeille S Christensen D. Maternal antibodies inhibit neonatal and infant responses to vaccination by shaping the early-life b cell repertoire within germinal centers. Cell Rep (2019) 28: 1773– 84.e1775. doi: 10.1016/j.celrep.2019.07.047 31412246 · DOI
  39. [42]Yang L Dong Z Wei Q Carr MJ Li J Ding S. A neonatal mouse model for the evaluation of antibodies and vaccines against coxsackievirus A6. Antiviral Res (2016) 134: 50–7. doi: 10.1016/j.antiviral.2016.08.025 27582066 · DOI
  40. [43]Su F Patel GB Hu S Chen W. Induction of mucosal immunity through systemic immunization: Phantom or reality? Hum Vaccines Immunother (2016) 12: 1070–9. doi: 10.1080/21645515.2015.1114195 PMC4962944 26752023 · DOI
  41. [44]Ohlsson A Lacy JB. Intravenous immunoglobulin for suspected or proven infection in neonates. Cochrane Database Syst Rev (2020) 1: Cd001239. doi: 10.1002/14651858.CD001239.pub6 31995649 PMC6988993 · DOI
  42. [45]Buxmann H Stackelberg OMv Schlößer RL Enders G Gonser M Meyer-Wittkopf M. Use of cytomegalovirus hyperimmunoglobulin for prevention of congenital cytomegalovirus disease: A retrospective analysis. J Perinat Med (2012) 40: 439–46. doi: 10.1515/jpm-2011-0257 22752777 · DOI
  43. [46]Nigro G La Torre R Pentimalli H Taverna P Lituania M Martinez de Tejada B. Regression of fetal cerebral abnormalities by primary cytomegalovirus infection following hyperimmunoglobulin therapy. Prenat Diagn (2008) 28: 512–7. doi: 10.1002/pd.2013 18509871 · DOI
  44. [47]Revello MG Fornara C Arossa A Zelini P Lilleri D. Role of human cytomegalovirus (HCMV)-specific antibody in HCMV-infected pregnant women. Early Hum Dev (2014) 90(Suppl 1): S32–34. doi: 10.1016/S0378-3782(14)70011-8 24709453 · DOI
  45. [48]Simioni C de Cassia Sanchez Oliveira R Moscovi T D' Agostini Deutsch A Cordioli E Santos E. Twin pregnancy and congenital cytomegalovirus: Case report and review. J Matern Fetal Neonatal Med (2013) 26: 622–4. doi: 10.3109/14767058.2012.745503 23134112 · DOI
  46. [49]Visentin S Manara R Milanese L Da Roit A Forner G Salviato E. Early primary cytomegalovirus infection in pregnancy: Maternal hyperimmunoglobulin therapy improves outcomes among infants at 1 year of age. Clin Infect Dis (2012) 55: 497– 503. doi: 10.1093/cid/cis423 22539662 · DOI
  47. [50]Mamouei Z Alqarihi A Singh S Xu S Mansour MK Ibrahim AS. Alexidine dihydrochloride has broad-spectrum activities against diverse fungal pathogens. mSphere (2018) 3. doi: 10.1128/mSphere.00539-18 PMC6211222 30381356 · DOI

Cited by

Sorted by citations

Authors
Singh, S., Nabeela, S., Barbarino, A., Ibrahim, A. S., & Uppuluri, P.
Affiliations
University of California, Los Angeles (US)
Corresponding author
Uppuluri, Priya
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2022-07-22
Volume
13
Pages
925821-925821
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2022.925821
PMC
PMC9355692
OpenAlex
W4287093360
Cited by
34
References
3
Citations by year
2026: 8 · 2025: 11 · 2024: 7 · 2023: 8
FWCI
3.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Division of Intramural Research, National Institute of Allergy and Infectious Diseases
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords
Candida albicans, neonatal candidiasis, ALS3, passive immunization, transplacental antibody transfer, cell wall proteins, adjuvants, complete Freund's adjuvant, neutrophils, preterm infants, systemic candidiasis
MeSH terms
Animals, Animals, Newborn, Candida albicans, Candidiasis, Female, Fungal Proteins, Humans, Immunoglobulin G, Mice

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