Review
Fungal vaccines: real progress from real challenges

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Summary

Among viral, bacterial, and fungal diseases, the latter are the only branch of infectious diseases without a vaccine for any of their causative agents. This is at odds with a disease burden that remains unabated by conventional chemotherapy and infection control measures. Since most fungal infections occur in immunocompromised patients, the generation of tools relying on host immunity for effectiveness is a notable challenge. Nevertheless, with improved knowledge of the host–fungus relation, and the spectacular advances in genome sequencing, genetic engineering, and proteomics, strong progress in fungal vaccine research is being made. Some vaccines induce the generation of directly fungicidal antibodies; others are protective in animals carrying major risk factors for fungal infections, such as CD4+ T-cell-deficiency or neutropenia. Together with the demonstrated efficacy of various antibodies in passive vaccination approaches, there is growing confidence in the future availability of safe and efficacious immunological tools to combat deadly microbes in a weak host.

Introduction

Vaccines against fungal diseases are gaining ever increasing medical attention, as witnessed by the recent flood of relevant articles, reviews, and commentaries on the subject.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 This renewed interest has mainly been caused by the growing impact of fungal diseases in modern medicine and the largely perceived need to invest in immunological tools to integrate with or replace chemotherapy, therefore minimising antibiotic use and consequent resistance. Another important contributory factor is an increased understanding of the host–fungus relation, which has been fuelled by genomic and proteomic approaches. In this Review, I will discuss the medical need for fungal vaccines, the challenging nature of fungi as vaccine targets, and new approaches in the generation of fungal vaccines and protective antibodies.

Section snippets

The case for fungal vaccines

Recent figures have revealed the alarming impact of fungal infections on human health. Data from older studies29, 30 on patients in health-care institutions have recently been confirmed by reports31, 32, 33, 34 showing that fungal infections rank among the first five causes of infections, with an absolute incidence rate above 1%. The spectrum of fungal pathogens is widening, in parallel with a rise in immunosuppression caused by other medical conditions, including HIV infection, population

Challenging vaccine targets

Most fungal diseases pose daunting obstacles to the concept and practice of vaccination, at least in its active immunisation modality. Leaving aside the primary, geographically limited, and low-incidence deep-seated diseases such as coccidiomycosis, histoplasmosis, blastomycosis, and paracoccidioidomycosis, most other widespread illnesses such as aspergillosis, cryptococcosis, and candidiasis (in this last case, with the possible exception of some forms of mucosal candidiasis) typically occur

Immune responses against fungi

As for other human pathogens, a close collaboration between innate and adaptive immunity is crucial for antifungal defence. The protective role of well-known factors of innate immunity, such as mechanical barriers and phagocytes (eg, polymorphonuclear cells and macrophages), is indirectly but extensively illustrated by the existence of classic risk factors for opportunistic fungal infections, including indwelling central venous catheters, neutropenia, and use of corticosteroids. Complement and

Antibodies and passive vaccination

Clinical inferences and the results of some experimental models, particularly in endemic primary mycosis, have clearly confirmed the main protective role of cell-mediated immunity.4, 7 However, protective immune sera, mucosal antibodies, some murine and human monoclonal antibodies, and genetically engineered antibody fragments have all shown remarkable efficacy in fighting fungi.4, 13, 14 These observations have special relevance for vaccination, particularly in partly or totally

Specific vaccines and antibodies

Table 3 summarises some of the antifungal vaccines that have successfully provided both active and passive immunisation. These vaccines have all shown consistent activity in at least one experimental model of fungal disease. The few preparations that have undergone clinical trials are dealt with below.

Nearly all types of chemical and antigenic formulation, including antigen-encoding DNA, have been considered for active vaccination and nearly all major fungal pathogens have been addressed.102,

Clinical trials of active and passive vaccination

There is no fungal vaccine approved or currently undergoing advanced clinical trials for active immunisation in human beings. However, several vaccine manufacturers have fungal antigens under development as candidate vaccines. Two vaccine formulations have undergone limited phase I and phase II trials: the first against vulvovaginal candidiasis by a candida ribosomal preparation,103 and the second against cryptococcosis by the tetanus toxoid-conjugate of the capsular polysaccharide

Conclusions

The increased awareness of the medical threat represented by fungal diseases and the persistent inability of chemotherapy to reduce their incidence and lethality have renewed interest in the search for vaccines against human pathogenic fungi. Novel approaches for developing fungal vaccines, particularly genome sequencing and proteomics, promise a real breakthrough in this area. Similarly, knowledge of the immune response against fungi, as well as the practice of selecting adjuvants that

Search strategy and selection criteria

Data for this Review were identified by searches of Medline up to June, 2007, for relevant articles in English language. Searches of the author's own files were also done. For the section on clinical trials, the EBM Cochrane Central Register of Controlled Trials database and public US government files were consulted. Papers on vaccines and antibodies were selected if they included consistent data from at least one established in-vivo model of fungal infection. Priority was given to

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