Immunological correlates of protection following vaccination with glucan particles containing Cryptococcus neoformans chitin deacetylases

Abstract

Vaccination with glucan particles (GP) containing the Cryptococcus neoformans chitin deacetylases Cda1 and Cda2 protect mice against experimental cryptococcosis. Here, immunological correlates of vaccine-mediated protection were explored. Studies comparing knockout and wild-type mice demonstrated CD4+ T cells are crucial, while B cells and CD8+ T cells are dispensable. Protection was abolished following CD4+ T cell depletion during either vaccination or infection but was retained if CD4+ T cells were only partially depleted. Vaccination elicited systemic and durable antigen-specific immune responses in peripheral blood mononuclear cells (PBMCs), spleens, and lungs. Following vaccination and fungal challenge, robust T-helper (Th) 1 and Th17 responses were observed in the lungs. Protection was abrogated in mice congenitally deficient in interferon (IFN) γ, IFNγ receptor, interleukin (IL)-1β, IL-6, or IL-23. Thus, CD4+ T cells and specific proinflammatory cytokines are required for GP-vaccine-mediated protection. Importantly, retention of protection in the setting of partial CD4+ T depletion suggests a pathway for vaccinating at-risk immunocompromised individuals.

Protection against experimental cryptococcosis elicited by Cationic Adjuvant Formulation 01-adjuvanted subunit vaccines

“…Therefore, we investigated the efficacy of bivalent (Cda1+Cda2, referred as 2-Ag) and quadrivalent (Cda1+Cda2+Blp4+Cpd1Δ, referred as 4-Ag) subunit vaccines in BALB/c mice, following the vaccination and challenge schedule detailed in Fig 1A. These antigen combinations were chosen based on the experiments shown in Fig 1 and published studies with GP-adjuvanted subunit cryptococcal vaccines [10, 11]. After challenge with C. neoformans , weight and survival of the mice were monitored until a mortality endpoint was reached.…”

“…Given the established importance of antigen-specific T cells for anti-cryptococcal defenses [11, 21-23], we enumerated lung CD4 + (Fig 3D) and CD8 + T cells (Fig 3E). Before infection, we did not see a difference in CD4 + T cell numbers between vaccinated and unvaccinated groups.…”

“…Cda1 and Cda2 are chitin deacetylases responsible for deacetylating cell wall chitin to chitosan, a process which is necessary for cryptococcal virulence [35]. We previously demonstrated GP-based vaccines containing Cda1 and Cda2 significantly protected BALB/c and C57BL/6 mice [10, 11].…”

“…The loss of CD4 + T cells, as notably occurs in persons with HIV/AIDS, markedly increases susceptibility to cryptococcosis [1]. CD4 + T cells, particularly those differentiating into Th1 and Th17 phenotypes, are critical orchestrators of effective immune defenses against Cryptococcus [11, 45, 46]. Additionally, vaccine-induced protection is lost in mice with a genetic deficiency in CD4 + T cells or following CD4 + T cell depletion [11, 47].…”

“…Among the twenty-three cryptococcal recombinant proteins tested in murine models, chitin deacetylase protein 1 and 2 (Cda1, Cda2), barwin-like domain protein 4 (Blp4), and carboxypeptidase 1 (Cpd1) emerged as highly promising protein antigens that afford significant survival advantages following pulmonary challenge with a highly virulent C. neoformans strain in both BALB/c and C57BL/6 mouse lines [9, 10]. Moreover, vaccination with these antigens encased in GPs elicits robust antigen-specific T helper (Th) 1 and Th17 responses critical for vaccine-induced protection [11].…”