Combination Adjuvants Enhance Recombinant Protein Vaccine Protection against Fungal Infection

ABSTRACT The development of effective vaccines against fungal infections requires the induction of protective, pathogen-specific cell-mediated immune responses. Here, we asked whether combination adjuvants based on delta inulin (Advax) formulated with Toll-like receptor (TLR) agonists could improve...

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Autores principales:	Marcel Wüthrich, Hannah E. Dobson, Cleison Ledesma Taira, Uju Joy Okaa, Lucas dos Santos Dias, Marcos Isidoro-Ayza, Nikolai Petrovsky, Bruce S. Klein
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	fungi T cells adjuvants immunization Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/56e44bbade2946e58ea31d694fa2764b
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spelling	oai:doaj.org-article:56e44bbade2946e58ea31d694fa2764b2021-11-10T18:37:52ZCombination Adjuvants Enhance Recombinant Protein Vaccine Protection against Fungal Infection10.1128/mBio.02018-212150-7511https://doaj.org/article/56e44bbade2946e58ea31d694fa2764b2021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02018-21https://doaj.org/toc/2150-7511ABSTRACT The development of effective vaccines against fungal infections requires the induction of protective, pathogen-specific cell-mediated immune responses. Here, we asked whether combination adjuvants based on delta inulin (Advax) formulated with Toll-like receptor (TLR) agonists could improve vaccine protection mediated by a fungal recombinant protein, Bl-Eng2 (i.e., Blastomyces endoglucanase 2), which itself harbors an immunodominant antigen and dectin-2 agonist/adjuvant. We found that Bl-Eng2 formulated with Advax3 containing TLR9 agonist or Advax8 containing TLR4 agonist provided the best protection against pulmonary infection with Blastomyces dermatitidis, being more effective than complete Freund’s adjuvant or Adjuplex. Advax3 was most efficient in inducing gamma interferon (IFN-γ)- and interleukin-17 (IL-17)-producing antigen-specific T cells that migrated to the lung upon Blastomyces dermatitidis infection. Mechanistic studies revealed Bl-Eng2/Advax3 protection was tempered by neutralization of IL-17 and particularly IFN-γ. Likewise, greater numbers of lung-resident T cells producing IFN-γ, IL-17, or both IFN-γ and IL-17 correlated with fewer fungi recovered from lung. Protection was maintained after depletion of CD4+ T cells, partially reduced by depletion of CD8+ T cells, and completely eliminated after depletion of both CD4+ and CD8+ T cells. We conclude that Bl-Eng2 formulated with Advax3 is promising for eliciting vaccine-induced antifungal immunity, through a previously uncharacterized mechanism involving CD8+ and also CD4+ T cells producing IFN-γ and/or IL-17. Although no licensed vaccine exists as yet against any fungal disease, these findings indicate the importance of adjuvant selection for the development of effective fungal vaccines. IMPORTANCE Fungal disease remains a challenging clinical and public health problem. Despite medical advances, invasive fungal infections have skyrocketed over the last decade and pose a mounting health threat in immunocompetent and -deficient hosts, with worldwide mortality rates ranking 7th, even ahead of tuberculosis. The development of safe, effective vaccines remains a major hurdle for fungi. Critical barriers to progress include the lack of defined fungal antigens and suitable adjuvants. Our research is significant in identifying adjuvant combinations that elicit optimal vaccine-induced protection when formulated with a recombinant protective antigen and uncovering the mechanistic bases of the underlaying vaccine protection, which will foster the strategic development of antifungal vaccines.Marcel WüthrichHannah E. DobsonCleison Ledesma TairaUju Joy OkaaLucas dos Santos DiasMarcos Isidoro-AyzaNikolai PetrovskyBruce S. KleinAmerican Society for MicrobiologyarticlefungiT cellsadjuvantsimmunizationMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	fungi T cells adjuvants immunization Microbiology QR1-502
spellingShingle	fungi T cells adjuvants immunization Microbiology QR1-502 Marcel Wüthrich Hannah E. Dobson Cleison Ledesma Taira Uju Joy Okaa Lucas dos Santos Dias Marcos Isidoro-Ayza Nikolai Petrovsky Bruce S. Klein Combination Adjuvants Enhance Recombinant Protein Vaccine Protection against Fungal Infection
description	ABSTRACT The development of effective vaccines against fungal infections requires the induction of protective, pathogen-specific cell-mediated immune responses. Here, we asked whether combination adjuvants based on delta inulin (Advax) formulated with Toll-like receptor (TLR) agonists could improve vaccine protection mediated by a fungal recombinant protein, Bl-Eng2 (i.e., Blastomyces endoglucanase 2), which itself harbors an immunodominant antigen and dectin-2 agonist/adjuvant. We found that Bl-Eng2 formulated with Advax3 containing TLR9 agonist or Advax8 containing TLR4 agonist provided the best protection against pulmonary infection with Blastomyces dermatitidis, being more effective than complete Freund’s adjuvant or Adjuplex. Advax3 was most efficient in inducing gamma interferon (IFN-γ)- and interleukin-17 (IL-17)-producing antigen-specific T cells that migrated to the lung upon Blastomyces dermatitidis infection. Mechanistic studies revealed Bl-Eng2/Advax3 protection was tempered by neutralization of IL-17 and particularly IFN-γ. Likewise, greater numbers of lung-resident T cells producing IFN-γ, IL-17, or both IFN-γ and IL-17 correlated with fewer fungi recovered from lung. Protection was maintained after depletion of CD4+ T cells, partially reduced by depletion of CD8+ T cells, and completely eliminated after depletion of both CD4+ and CD8+ T cells. We conclude that Bl-Eng2 formulated with Advax3 is promising for eliciting vaccine-induced antifungal immunity, through a previously uncharacterized mechanism involving CD8+ and also CD4+ T cells producing IFN-γ and/or IL-17. Although no licensed vaccine exists as yet against any fungal disease, these findings indicate the importance of adjuvant selection for the development of effective fungal vaccines. IMPORTANCE Fungal disease remains a challenging clinical and public health problem. Despite medical advances, invasive fungal infections have skyrocketed over the last decade and pose a mounting health threat in immunocompetent and -deficient hosts, with worldwide mortality rates ranking 7th, even ahead of tuberculosis. The development of safe, effective vaccines remains a major hurdle for fungi. Critical barriers to progress include the lack of defined fungal antigens and suitable adjuvants. Our research is significant in identifying adjuvant combinations that elicit optimal vaccine-induced protection when formulated with a recombinant protective antigen and uncovering the mechanistic bases of the underlaying vaccine protection, which will foster the strategic development of antifungal vaccines.
format	article
author	Marcel Wüthrich Hannah E. Dobson Cleison Ledesma Taira Uju Joy Okaa Lucas dos Santos Dias Marcos Isidoro-Ayza Nikolai Petrovsky Bruce S. Klein
author_facet	Marcel Wüthrich Hannah E. Dobson Cleison Ledesma Taira Uju Joy Okaa Lucas dos Santos Dias Marcos Isidoro-Ayza Nikolai Petrovsky Bruce S. Klein
author_sort	Marcel Wüthrich
title	Combination Adjuvants Enhance Recombinant Protein Vaccine Protection against Fungal Infection
title_short	Combination Adjuvants Enhance Recombinant Protein Vaccine Protection against Fungal Infection
title_full	Combination Adjuvants Enhance Recombinant Protein Vaccine Protection against Fungal Infection
title_fullStr	Combination Adjuvants Enhance Recombinant Protein Vaccine Protection against Fungal Infection
title_full_unstemmed	Combination Adjuvants Enhance Recombinant Protein Vaccine Protection against Fungal Infection
title_sort	combination adjuvants enhance recombinant protein vaccine protection against fungal infection
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/56e44bbade2946e58ea31d694fa2764b
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Combination Adjuvants Enhance Recombinant Protein Vaccine Protection against Fungal Infection

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