Harnessing the Immune Response to Fungal Pathogens for Vaccine Development

Abstract

Invasive fungal infections are emerging diseases that kill over 1.5 million people per year worldwide. With the increase of immunocompromised populations, the incidence of invasive fungal infections is expected to continue to rise. Vaccines for viral and bacterial infectious diseases have had a transformative impact on human health worldwide. However, no fungal vaccines are currently in clinical use. Recently, interest in fungal vaccines has grown significantly. One Candida vaccine has completed phase 2 clinical trials, and research on vaccines against coccidioidomycosis continues to advance. Additionally, multiple groups have discovered various Cryptococcus mutant strains that promote protective responses to subsequent challenge in mouse models. There has also been progress in antibody-mediated fungal vaccines. In this review, we highlight recent fungal vaccine research progress, outline the wealth of data generated, and summarize current research for both fungal biology and immunology studies relevant to fungal vaccine development. We also review technological advancements in vaccine development and highlight the future prospects of a human vaccine against invasive fungal infections.

Keywords: T cells; adaptive immunity; fungal infections; fungal vaccines; innate immunity; trained immunity.

Figure 1

Overview of adaptive immunity. Innate cells recognize molecular patterns present in fungal pathogens via innate receptors. The C-type lectins Dectin-1, Dectin-2, and Mincle have been identified as critical activators of host immune responses in the context of fungal infection. Toll-like receptors (TLRs) are also engaged during fungal infection and together with C-type lectins help activate dendritic cells (DCs). In turn, DCs are critical for the activation of T cell responses via presentation of fungus-derived antigens in the context of MHC together with proper costimulation and secretion of cytokines that shape T cell differentiation. The differentiation of CD4⁺ T cells toward Th1 and Th17 cells is critical for antifungal defense and the activation of effective vaccine-mediated immunity. Th1 and Th17 cells produce critical cytokines, such as IFN-γ, IL-17, and IL-22, that act on innate cell effectors to further amplify the effective control of fungal infection. Effector cytokines also help induce the expression of antimicrobial peptides that can have direct toxic effects on fungal cells. Effector cytokines also act on innate cell targets. These include macrophages and neutrophils, which are significantly involved in direct eradiation of various fungal pathogens and morphotypes that range from yeast to hyphal forms. The activation of robust antifungal immunity also involves CD8⁺ T cells, which can also serve as an important source of protective cytokines. CD8⁺ T cells are particularly important in the context of CD4⁺ T cell deficiency, where an expansion of CD8⁺ T cells can compensate for loss of CD4⁺ T cells and help mediate vaccine-induced protection.

Figure 2

Overview of trained immunity. In the context of fungal infection, vaccination with formulations that include fungus-derived adjuvants such as β-glucan can mediate the programing of monocytes and macrophages for enhanced secondary responses, known as trained immunity. (a) Recognition of β-glucan via Dectin-1, for example, has been found to activate innate cells for increased transcription, cytokine secretion, and effector functions during initial encounter with fungi. (b) This primary response also triggers epigenetic changes in the now experienced cells and leads to alterations in their chromatin structure such that they are poised for rapid and robust production of cytokines during a secondary insult. (c) Importantly, enhanced secondary responses in trained innate cells not only help mediate homologous protection but also can be potent inducers of heterologous defense.