Abstract
Our research on pathogenesis of disseminated candidiasis led to the discovery that antibodies specific for Candida albicans cell surface β-1, 2–mannotriose [β-(Man)3] protect mice. A 14 mer peptide Fba, which derived from the N-terminal portion of the C. albicans cytosolic/cell surface protein fructose-bisphosphate aldolase, was used as the glycan carrier and resulted in a novel synthetic glycopeptide vaccine β-(Man)3-Fba. By a dendritic cell-based immunization approach, this conjugate induced protective antibody responses against both the glycan and peptide parts of the vaccine. In this report, we modified the β-(Man)3-Fba conjugate by coupling it to tetanus toxoid (TT) in order to improve immunogenicity and allow for use of an adjuvant suitable for human use. By new immunization procedures entirely compatible with human use, the modified β-(Man)3-Fba-TT was administered either alone or as a mixture made with alum or monophosphoryl lipid A (MPL) adjuvants and given to mice by a subcutaneous (s.c.) route. Mice vaccinated with or, surprisingly, without adjuvant responded well by making robust antibody responses. The immunized groups showed a high degree of protection against a lethal challenge with C. albicans as evidenced by increased survival times and reduced kidney fungal burden as compared to control groups that received only adjuvant or DPBS buffer prior to challenge. To confirm that induced antibodies were protective, sera from mice immunized against the β-(Man)3-Fba-TT conjugate transferred protection against disseminated candidiasis to naïve mice, whereas C. albicans-absorbed immune sera did not. Similar antibody responses and protection induced by the β-(Man)3-Fba-TT vaccine was observed in inbred BALB/c and outbred Swiss Webster mice. We conclude that addition of TT to the glycopeptide conjugate results in a self-adjuvanting vaccine that promotes robust antibody responses without the need for additional adjuvant, which is novel and represents a major step forward in vaccine design against disseminated candidiasis.
Highlights
Disseminated candidiasis in humans has become the third or fourth leading cause of hospital-acquired blood stream infections and despite antifungal therapy at least 40% of affected individuals will die of this disease [1,2]
We derived dendritic cells in vitro as described before [7] and used the same immunization dendritic cells and complete Freund adjuvant (DC/CFA)-strategy on the C57BL/6 mice as was used in our work on BALB/c mice [7], which included a priming dose followed by two boosters; the last booster consisted of the vaccine emulsified in CFA
The discovery of numerous antigens on the fungal cell wall that elicit protective antibody responses raises the possibility of obtaining combined or even synergistic efficacious effects of vaccines designed with multiple antigens, and/or passive therapies that combine antibodies with different specificities [27,28]
Summary
Disseminated candidiasis in humans has become the third or fourth leading cause of hospital-acquired blood stream infections and despite antifungal therapy at least 40% of affected individuals will die of this disease [1,2]. Antibodies have long been considered irrelevant in host defense against invasive candidiasis, but over the last two decades a number of antibodies or their engineered derivatives directed against C. albicans cell-wall polysaccharides and glycopeptides, as well as against some protein or peptide epitopes, have been shown to confer protection [6,12,16,17]. The antibody dependency of protection was evident by protection transferred to naıve mice by immune serum, but not by serum pre-absorbed with C. albicans. These results enabled elucidation of an efficacious vaccine, but the immunization protocol utilized dendritic cells and complete Freund adjuvant (DC/CFA), which are cost prohibitive and incompatible for human use, respectively. We have investigated alternative vaccine presentation strategies to test our hypothesis that an approved human adjuvant can be substituted for the DC/CFA approach provided that the vaccine conjugate can be appropriately modified to improve immunogenicity
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