Publication
Combination adjuvants enhance recombinant protein vaccine protection against fungal infection
Publisher:
Cold Spring Harbor Laboratory
Date:
12-03-2021
DOI:
10.1101/2021.03.11.434977
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 TLR agonists could improve vaccine protection mediated by a fungal recombinant protein, Bl-Eng2, 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 Freund’s complete adjuvant or Adjuplex. Advax3 was most efficient in inducing IFN-γ and 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 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. 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 immune-competent 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 anti-fungal vaccines.