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A Soluble Tetrazolium-Based Reduction Assay to Evaluate the Effect of Antibodies on Candida tropicalis Biofilms
Published on: September 16, 2022
Self-adjuvanting glycopeptide conjugate vaccine against disseminated candidiasis
Hong Xin1, Jonathan Cartmell, Justin J Bailey
1Department of Pediatrics, Louisiana State University Health Sciences Center and Research Institute for Children, Children's Hospital, New Orleans, Louisiana, United States of America. hxin@chnola-research.org
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.
Insights
A novel synthetic vaccine targeting Candida albicans cell surface sugars protected mice from disseminated candidiasis. Coupling the vaccine to tetanus toxoid created a self-adjuvanting formulation, enhancing immune responses without additional adjuvants.
Area of Science:
- * Immunology
- * Vaccinology
- * Mycology
Background:
- * Disseminated candidiasis remains a significant threat, necessitating effective vaccines.
- * Antibodies targeting Candida albicans cell surface β-1, 2-mannotriose [β-(Man)(3)] demonstrate protective capabilities.
- * Previous research developed a synthetic glycopeptide vaccine, β-(Man)(3)-Fba, using a peptide carrier derived from fructose-bisphosphate aldolase.
Purpose of the Study:
- * To develop a self-adjuvanting vaccine against disseminated candidiasis by conjugating the β-(Man)(3)-Fba glycopeptide to tetanus toxoid (TT).
- * To evaluate the immunogenicity and protective efficacy of the modified β-(Man)(3)-Fba-TT vaccine in mice, with and without adjuvants suitable for human use.
- * To confirm the protective role of induced antibodies through passive transfer experiments.
Main Methods:
- * Conjugation of the β-(Man)(3)-Fba glycopeptide to tetanus toxoid (TT).
- * Immunization of mice with the β-(Man)(3)-Fba-TT conjugate, alone or with alum or monophosphoryl lipid A (MPL) adjuvants, via subcutaneous injection.
- * Assessment of antibody responses, survival rates, and fungal burden in kidneys post-lethal challenge with Candida albicans.
- * Passive transfer of immune sera to naïve mice to confirm antibody-mediated protection.
Main Results:
- * The modified β-(Man)(3)-Fba-TT conjugate induced robust antibody responses in mice, even without additional adjuvants, demonstrating self-adjuvanting properties.
- * Vaccinated mice exhibited significantly increased survival times and reduced kidney fungal loads compared to control groups after challenge with Candida albicans.
- * Passive transfer of sera from vaccinated mice conferred protection against disseminated candidiasis to naive recipients, confirming the efficacy of the induced antibodies.
- * Similar protective immune responses were observed in both inbred BALB/c and outbred Swiss Webster mouse strains.
Conclusions:
- * Conjugation of the β-(Man)(3)-Fba glycopeptide to tetanus toxoid creates a self-adjuvanting vaccine candidate for disseminated candidiasis.
- * This novel vaccine design elicits strong protective immunity without requiring external adjuvants, simplifying administration and potentially improving human applicability.
- * The findings represent a significant advancement in developing effective vaccines against invasive fungal infections like candidiasis.
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