Abstract
In the present study, the combined adjuvant effect of 7DW8-5, a potent α-GalCer-analog, and monophosphoryl lipid A (MPLA), a TLR4 agonist, on the induction of vaccine-induced CD8(+) T-cell responses and protective immunity was evaluated. Mice were immunized with peptides corresponding to the CD8(+) T-cell epitopes of a malaria antigen, a circumsporozoite protein of Plasmodium yoelii, and a tumor antigen, a Wilms Tumor antigen-1 (WT-1), together with 7DW8-5 and MPLA, as an adjuvant. These immunization regimens were able to induce higher levels of CD8(+) T-cell responses and, ultimately, enhanced levels of protection against malaria and tumor challenges compared to the levels induced by immunization with peptides mixed with 7DW8-5 or MPLA alone. Co-administration of 7DW8-5 and MPLA induces activation of memory-like effector natural killer T (NKT) cells, i.e. CD44(+)CD62L(-)NKT cells. Our study indicates that 7DW8-5 greatly enhances important synergistic pathways associated to memory immune responses when co-administered with MPLA, thus rendering this combination of adjuvants a novel vaccine adjuvant formulation.
Keywords:
Adjuvant; CD1d; Cancer vaccine; Circumsporozoite protein; Glycolipid; Malaria vaccine; Memory-like effector NKT cells; NKT cells; TLR4; WT-1.
Copyright © 2016 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Sequence
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Animals
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CD8-Positive T-Lymphocytes / drug effects*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cell Line, Tumor
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Drug Synergism
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Epitopes, T-Lymphocyte / immunology
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Galactosylceramides / administration & dosage
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Galactosylceramides / pharmacology*
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HLA-A2 Antigen / genetics
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HLA-A2 Antigen / immunology
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Humans
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Immunization / methods
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Immunologic Memory / immunology
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Killer Cells, Natural / drug effects*
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Lipid A / administration & dosage
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Lipid A / analogs & derivatives*
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Lipid A / pharmacology
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Malaria / immunology
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Malaria / parasitology
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Malaria / prevention & control
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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Models, Immunological
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Peptides / immunology
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Plasmodium yoelii / immunology
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Plasmodium yoelii / physiology
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Protective Agents / administration & dosage
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Protective Agents / pharmacology
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Protozoan Proteins / chemistry
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Protozoan Proteins / immunology
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Toll-Like Receptor 4 / agonists*
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Toll-Like Receptor 4 / metabolism
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WT1 Proteins / genetics
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WT1 Proteins / immunology
Substances
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7DW8-5 glycolipid
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Epitopes, T-Lymphocyte
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Galactosylceramides
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HLA-A2 Antigen
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Lipid A
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Peptides
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Protective Agents
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Protozoan Proteins
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Toll-Like Receptor 4
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WT1 Proteins
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circumsporozoite protein, Protozoan
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Interferon-gamma
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monophosphoryl lipid A