Vaccine development for pathogenic fungi: current status and future directions

ABSTRACT

Introduction

Fungal infections are caused by a broad range of pathogenic fungi that are found worldwide with different geographic distributions, incidences, and mortality rates. Considering that there are relatively few approved medications available for combating fungal diseases and no vaccine formulation commercially available, multiple groups are searching for new antifungal drugs, examining drugs for repurposing and developing antifungal vaccines, in order to control deaths, sequels, and the spread of these complex infections.

Areas covered

This review provides a summary of advances in fungal vaccine studies and the different approaches under development, such as subunit vaccines, whole organism vaccines, and DNA vaccines, as well as studies that optimize the use of adjuvants. We conducted a literature search of the PubMed with terms: fungal vaccines and genus of fungal pathogens (Cryptococcus spp. Candida spp. Coccidioides spp. Aspergillus spp. Sporothrix spp. Histoplasma spp. Paracoccidioides spp. Pneumocystis spp. and the Mucorales order), a total of 177 articles were collected from database.

Expert opinion

Problems regarding the immune response development in an immunocompromised organism, the similarity between fungal and mammalian cells, and the lack of attention by health organizations to fungal infections are closely related to the fact that, at present, there are no fungal vaccines available for clinical use.

GRAPHICAL ABSTRACT

short-legendGraphic1.

KEYWORDS:

• Fungal vaccine
• prophylactic vaccine
• subunit
• therapeutic vaccine
• immune therapy
• fungal biology

Article highlights

• Candidiasis vaccines are mostly related to C. albicans infections, with the most promising approach being the application of a recombinant Als3 antigen (NDV-3A) vaccine for recurrent vulvovaginal candidiasis, already tested in a clinical trial. NDV-3A was also tested against C. auris infection, with promising results;

• Whole yeast vaccination formulations (heat-killed, genetically engineered) were evaluated for Cryptococcus neoformans and C. gattii, although most studies currently focus on subunit vaccines. The immune responses induced by these two species differ and, therefore, the ability to protect against both organisms would be ideal for a vaccine development;

• Aspergillus fumigatus is a ubiquitous environmental fungus, making it difficult to find an approach that could stimulate a protective immune response since there is regular contact with the body and the propagules. Experiments testing whole fungus and extracted proteins have been assessed in murine models;

• Histoplasma capsulatum has proteins commonly found in other fungi, such as Hsp60 and enolase, and these have been studied in in vivo models, with and without the use of adjuvants;

• Potential vaccines against coccidioidomycosis, using distinct techniques, are in advanced development. The formulation with Δcps1, an avirulent strain, led to protection against Coccidioides posadasii in mice and also in dogs; however, human clinical studies have not been reported;

• The association of Paracoccidioides brasiliensis and P. lutzii peptides, especially the peptide P10, in combination with a carrier molecule has been most rigorously explored for a vaccine against these fungi. Also, the presence of shared peptides with other fungi, such as H. capsulatum, may stimulate a pan-fungal formulation;

• Subunit vaccines are currently conceptualized for Sporothrix schenckii and S. brasiliensis, using the two most immunogenic proteins previously identified, Gp70 and enolase. rSsEno, a recombinant enolase, demonstrated a good response in mice experimental infection when associated with an adjuvant;

• During the COVID-19 pandemic, the incidence of mucormycosis and pneumocystosis markedly increased. Studies for Pneumocystis jirovecii vaccination are mostly related with proteins and peptides, as proteomic studies with Mucor circinelloides and Rhizopus oryzae are starting to emerge.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We would like to thank the funding agencies, listed under “Funding”, for their funding.

Authors contributions

J.L.C., F.A.C.C., J.M.F., C.M.S., A.F.V., D.Z.M. and A.C.C. conducted research, reviewed and contributed to the initial draft of the manuscript. C.P.T. and J.D.N. provided guidance and reviewed the manuscript. All authors revised the manuscript and critically assessed it for significant intellectual material.

Additional information

Funding

This work was supported by grants from the FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo; numbers: 2021/01904-7 and 2020/03607-7), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; Code 001) and the Inova Program of Fiocruz (Fundação Oswaldo Cruz). J.D.N. and D.Z.M. were supported in part by NIH AI71093, NIH AI124797 and NIH AI165204. The funders had no role in the design of the study; in the writing of the manuscript, in the analyses, collection, interpretation of data, or in the decision to publish the results.