GM1 Binding-Deficient Exotoxin Is a Potent Noninflammatory Broad Spectrum Intradermal Immunoadjuvant

Intradermal (i.d.) immunization is a promising route of vaccine administration. Suitable i.d. adjuvants are important to increase vaccine efficacy in poorly responding populations such as the elderly or for dose-sparing strategies in the face of vaccine shortages. Bacterial exotoxins, such as Escher...

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Published in:	The Journal of immunology (1950) Vol. 177; no. 2; pp. 1197 - 1207
Main Authors:	Zoeteweij, J. Paul, Epperson, Diane E, Porter, Jackie D, Zhang, Chen X, Frolova, Olga Y, Constantinides, Anita P, Fuhrmann, Steven R, El-Amine, Moustapha, Tian, Jing-Hui, Ellingsworth, Larry R, Glenn, Gregory M
Format:	Journal Article
Language:	English
Published:	United States Am Assoc Immnol 15-07-2006
Subjects:	Adjuvants, Immunologic - administration & dosage Adjuvants, Immunologic - metabolism Alum Compounds - administration & dosage Alum Compounds - metabolism Animals Antibodies, Bacterial - biosynthesis Antibodies, Bacterial - blood Antigen-Presenting Cells - cytology Antigen-Presenting Cells - immunology Bacterial Toxins - administration & dosage Cell Line, Tumor Cell Movement - immunology Cytotoxicity, Immunologic - genetics Enterotoxins - administration & dosage Escherichia coli Escherichia coli Proteins - administration & dosage Exotoxins - administration & dosage Exotoxins - metabolism Female G(M1) Ganglioside - metabolism Inflammation - immunology Inflammation - prevention & control Injections, Intradermal Lymph Nodes - cytology Lymph Nodes - immunology Melanoma, Experimental Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Knockout N-Acetylgalactosaminyltransferases - deficiency N-Acetylgalactosaminyltransferases - genetics Protein Binding - genetics Protein Binding - immunology T-Lymphocytes, Cytotoxic - immunology Tetanus - genetics Tetanus - immunology Tetanus - prevention & control Tetanus Toxoid - administration & dosage Tetanus Toxoid - immunology Tetanus Toxoid - metabolism
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Summary:	Intradermal (i.d.) immunization is a promising route of vaccine administration. Suitable i.d. adjuvants are important to increase vaccine efficacy in poorly responding populations such as the elderly or for dose-sparing strategies in the face of vaccine shortages. Bacterial exotoxins, such as Escherichia coli heat-labile enterotoxin (LT), exert strong immunostimulatory effects through binding to monosialoganglioside (GM1) cell surface receptors; however, injection is hampered by local inflammation. We demonstrate that the injection of LT formulations deficient in GM1 binding by mutation (LT(G33D)) or in vitro ligand coupling does not cause localized edema and inflammation in mice, yet these formulations retain potent adjuvant activity by enhancing functional Ab and cellular immune responses to coadministered Ags. Complete protection against in vivo lethal tetanus toxin challenge and the induction of Ag-specific CTL responses capable of killing target cells in vivo indicated in vivo efficacy of the induced immune responses. LT(G33D) proved superior to standard alum adjuvant regarding the magnitude and breadth of the induced immune responses. Immunizations in complex ganglioside knockout mice revealed a GM1-independent pathway of LT adjuvanticity. Immunostimulation by i.d. LT(G33D) is explained by its ability to induce migration of activated APCs to the proximal draining lymph nodes. LT(G33D) is a promising candidate adjuvant for human trials of parenteral vaccines in general and for current i.d. vaccine development in particular.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.177.2.1197