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
ReviewFungal vaccines: real progress from real challenges
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
References (138)
- et al.
Polysaccharide-containing conjugate vaccines for fungal diseases
Trends Mol Med
(2006) - et al.
Fungal vaccines and immunotherapy
J Mycolog Med
(2006) - et al.
Induced humoral immunity and vaccination against major human fungal pathogens
Curr Opin Microbiol
(2002) - et al.
Recombinant antibodies: a natural partner in combinatorial antifungal therapy
Vaccine
(2004) - et al.
Dendritic cell-based vaccination against opportunistic fungi
Vaccine
(2004) - et al.
Prospects for dendritic cell vaccination against fungal infections in hematopoietic transplantation
Blood Cells Mol Dis
(2004) - et al.
Invasive candidiasis in immunocompromised hospitalized patients
Arch Med Res
(2005) Echinocandin antifungal drugs
Lancet
(2003)- et al.
The fungal cell wall as a drug target
Trends Microbiol
(1995) New approaches to invasive fungal infections in acute leukemia and hematopoietic stem cell transplant patients
Best Pract Res Clin Haematol
(2007)