45 results on '"Ishii, Ken"'
Search Results
2. Discovery of Self-Assembling Small Molecules as Vaccine Adjuvants.
- Author
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Jin S, Vu HT, Hioki K, Noda N, Yoshida H, Shimane T, Ishizuka S, Takashima I, Mizuhata Y, Beverly Pe K, Ogawa T, Nishimura N, Packwood D, Tokitoh N, Kurata H, Yamasaki S, Ishii KJ, and Uesugi M
- Subjects
- Amides immunology, Amides pharmacology, Animals, Antibodies, Viral blood, Antibodies, Viral immunology, Dendritic Cells cytology, Dendritic Cells immunology, Dendritic Cells metabolism, Deoxycholic Acid chemistry, Drug Evaluation, Preclinical, Fluorescent Dyes chemistry, Immunity, Innate, Immunoglobulin G blood, Influenza Vaccines chemistry, Influenza Vaccines immunology, Interleukin-6 metabolism, Macrophages cytology, Macrophages drug effects, Macrophages metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Nanostructures chemistry, RAW 264.7 Cells, Structure-Activity Relationship, Toll-Like Receptor 7 metabolism, Adjuvants, Immunologic chemistry, Amides chemistry
- Abstract
Immune potentiators, termed adjuvants, trigger early innate immune responses to ensure the generation of robust and long-lasting adaptive immune responses of vaccines. Presented here is a study that takes advantage of a self-assembling small-molecule library for the development of a novel vaccine adjuvant. Cell-based screening of the library and subsequent structural optimization led to the discovery of a simple, chemically tractable deoxycholate derivative (molecule 6, also named cholicamide) whose well-defined nanoassembly potently elicits innate immune responses in macrophages and dendritic cells. Functional and mechanistic analyses indicate that the virus-like assembly enters the cells and stimulates the innate immune response through Toll-like receptor 7 (TLR7), an endosomal TLR that detects single-stranded viral RNA. As an influenza vaccine adjuvant in mice, molecule 6 was as potent as Alum, a clinically used adjuvant. The studies described here pave the way for a new approach to discovering and designing self-assembling small-molecule adjuvants against pathogens, including emerging viruses., (© 2020 Wiley-VCH GmbH.)
- Published
- 2021
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3. IL-33 Is Essential for Adjuvant Effect of Hydroxypropyl-β-Cyclodexrin on the Protective Intranasal Influenza Vaccination.
- Author
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Kobari S, Kusakabe T, Momota M, Shibahara T, Hayashi T, Ozasa K, Morita H, Matsumoto K, Saito H, Ito S, Kuroda E, and Ishii KJ
- Subjects
- 2-Hydroxypropyl-beta-cyclodextrin administration & dosage, Administration, Intranasal, Animals, Influenza Vaccines administration & dosage, Mice, Mice, Inbred C57BL, Organ Specificity, Protein Serine-Threonine Kinases physiology, Th2 Cells immunology, 2-Hydroxypropyl-beta-cyclodextrin pharmacology, Adjuvants, Immunologic pharmacology, Influenza Vaccines immunology, Interleukin-33 physiology
- Abstract
Vaccine adjuvants are traditionally used to augment and modulate the immunogenicity of vaccines, although in many cases it is unclear which specific molecules contribute to their stimulatory activity. We previously reported that both subcutaneous and intranasal administration of hydroxypropyl-β-cyclodextrin (HP-β-CD), a pharmaceutical excipient widely used to improve solubility, can act as an effective adjuvant for an influenza vaccine. However, the mechanisms by which mucosal immune pathway is critical for the intranasal adjuvant activity of HP-β-CD have not been fully delineated. Here, we show that intranasally administered HP-β-CD elicits a temporary release of IL-33 from alveolar epithelial type 2 cells in the lung; notably, IL-33 expression in these cells is not stimulated following the use of other vaccine adjuvants. The experiments using gene deficient mice suggested that IL-33/ST2 signaling is solely responsible for the adjuvant effect of HP-β-CD when it is administered intranasally. In contrast, the subcutaneous injection of HP-β-CD and the intranasal administration of alum, as a damage-associated molecular patterns (DAMPs)-inducing adjuvant, or cholera toxin, as a mucosal adjuvant, enhanced humoral immunity in an IL-33-independent manner, suggesting that the IL-33/ST2 pathway is unique to the adjuvanticity of intranasally administered HP-β-CD. Furthermore, the release of IL-33 was involved in the protective immunity against influenza virus infection which is induced by the intranasal administration of HP-β-CD-adjuvanted influenza split vaccine. In conclusion, our results suggest that an understanding of administration route- and tissue-specific immune responses is crucial for the design of unique vaccine adjuvants., (Copyright © 2020 Kobari, Kusakabe, Momota, Shibahara, Hayashi, Ozasa, Morita, Matsumoto, Saito, Ito, Kuroda and Ishii.)
- Published
- 2020
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4. Development of screening method for intranasal influenza vaccine and adjuvant safety in preclinical study.
- Author
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Hiradate Y, Sasaki E, Momose H, Asanuma H, Furuhata K, Takai M, Aoshi T, Yamada H, Ishii KJ, Tanemura K, Mizukami T, and Hamaguchi I
- Subjects
- Administration, Intranasal, Animals, Drug Evaluation, Preclinical, Female, Mice, Mice, Inbred BALB C, Adjuvants, Immunologic chemistry, Adjuvants, Immunologic pharmacology, Influenza A Virus, H1N1 Subtype chemistry, Influenza A Virus, H1N1 Subtype immunology, Influenza Vaccines chemistry, Influenza Vaccines immunology, Influenza Vaccines pharmacology
- Abstract
Recently, many vaccine adjuvants have been developed; however, most of the newly developed adjuvants have been dropped out of preclinical and clinical trials owing to their unexpected toxicity. Thus, the development of highly quantitative and comparable screening methods for evaluating adjuvant safety is needed. In a previous study, we identified specific biomarkers for evaluating the safety of an intranasal influenza vaccine with CpG K3 adjuvant by comparing biomarker expression. We hypothesized that these biomarkers might be useful for screening newly developed adjuvant safety. We compared the expression of biomarkers in mouse lungs by the intranasal administration of 4 types of adjuvants: Alum, Pam
3 CSK4 , NanoSiO2 , and DMXAA with subvirion influenza vaccine. The control adjuvant alum did not show any significant increase in biomarker expression or preclinical parameters; however, NanoSiO2 and Pam3 CSK4 increased the expression of biomarkers, such as Timp1 and Csf1. DMXAA at 300 μg induced the expression of over 80% of biomarkers. Hierarchical clustering analysis showed that 300 μg DMXAA was classified in the toxicity reference whole-particle influenza vaccine cluster. FACS analysis to confirm specific phenotypes that the number of T cells decreased in DMXAA-treated mouse lungs. Thus, our biomarkers are useful for initial adjuvant safety and toxicity screening., (Copyright © 2018 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.)- Published
- 2018
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5. Combination and inducible adjuvants targeting nucleic acid sensors.
- Author
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Temizoz B, Kuroda E, and Ishii KJ
- Subjects
- Humans, Membrane Proteins agonists, Membrane Proteins metabolism, Receptors, Pattern Recognition, Toll-Like Receptor 9 agonists, Toll-Like Receptor 9 metabolism, Adjuvants, Immunologic pharmacology, Communicable Diseases drug therapy, Communicable Diseases immunology, Neoplasms drug therapy, Neoplasms immunology, Nucleic Acids drug effects, Nucleic Acids metabolism
- Abstract
Innate immune sensing of nucleic acids derived from invading pathogens or tumor cells via pattern recognition receptors is crucial for mounting protective immune responses against infectious disease and cancer. Recently, discovery of tremendous amounts of nucleic acid sensors as well as identification of natural and synthetic ligands for these receptors revealed the potential of adjuvants targeting nucleic acid sensing pathways for designing efficacious vaccines. Especially, current data indicated that unique adjuvants targeting TLR9 and stimulator of interferon genes (STING)-dependent cytosolic nucleic acid sensing pathways along with the combinations of already existing adjuvants are promising candidates for this purpose. Here, we review current vaccine adjuvants targeting nucleic acid sensors and their modes of action., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2018
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6. Carbonate Apatite Nanoparticles Act as Potent Vaccine Adjuvant Delivery Vehicles by Enhancing Cytokine Production Induced by Encapsulated Cytosine-Phosphate-Guanine Oligodeoxynucleotides.
- Author
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Takahashi H, Misato K, Aoshi T, Yamamoto Y, Kubota Y, Wu X, Kuroda E, Ishii KJ, Yamamoto H, and Yoshioka Y
- Subjects
- Adjuvants, Immunologic chemistry, Animals, Apatites immunology, Cytokines biosynthesis, Drug Carriers chemistry, Humans, Mice, Oligodeoxyribonucleotides administration & dosage, Oligodeoxyribonucleotides immunology, Adjuvants, Immunologic administration & dosage, Apatites administration & dosage, Drug Carriers pharmacology, Nanoparticles, Vaccines immunology
- Abstract
Vaccine adjuvants that can induce not only antigen-specific antibody responses but also Th1-type immune responses and CD8
+ cytotoxic T lymphocyte responses are needed for the development of vaccines against infectious diseases and cancer. Of many available adjuvants, oligodeoxynucleotides (ODNs) with unmethylated cytosine-phosphate-guanine (CpG) motifs are the most promising for inducing the necessary immune responses, and these adjuvants are currently under clinical trials in humans. However, the development of novel delivery vehicles that enhance the adjuvant effects of CpG ODNs, subsequently increasing the production of cytokines such as type-I interferons (IFNs), is highly desirable. In this study, we demonstrate the potential of pH-responsive biodegradable carbonate apatite (CA) nanoparticles as CpG ODN delivery vehicles that can enhance the production of type-I IFNs (such as IFN-α) relative to that induced by CpG ODNs and can augment the adjuvant effects of CpG ODNs in vivo . In contrast to CpG ODNs, CA nanoparticles containing CpG ODNs (designated CA-CpG) induced significant IFN-α production by mouse dendritic cells and human peripheral blood mononuclear cells in vitro ; and production of interleukin-12, and IFN-γ was higher in CA-CpG-treated groups than in CpG ODNs groups. In addition, treatment with CA-CpG resulted in higher cytokine production in draining lymph nodes than did treatment with CpG ODNs in vivo . Furthermore, vaccination with CA-CpG plus an antigen, such as ovalbumin or influenza virus hemagglutinin, resulted in higher antigen-specific antibody responses and CD8+ cytotoxic T lymphocyte responses in vivo , in an interleukin-12- and type-I IFN-dependent manner, than did vaccination with the antigen plus CpG ODNs; in addition, the efficacy of the vaccine against influenza virus was higher with CA-CpG as the adjuvant than with CpG ODNs as the adjuvant. These data show the potential of CA nanoparticles to serve as CpG ODN delivery vehicles that increase the production of cytokines, especially IFN-α, induced by CpG ODNs and thus augment the efficacy of CpG ODNs as adjuvants. We expect that the strategy reported herein will facilitate the design and development of novel adjuvant delivery vehicles for vaccines.- Published
- 2018
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7. Modeling for influenza vaccines and adjuvants profile for safety prediction system using gene expression profiling and statistical tools.
- Author
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Sasaki E, Momose H, Hiradate Y, Furuhata K, Takai M, Asanuma H, Ishii KJ, Mizukami T, and Hamaguchi I
- Subjects
- Animals, Mice, Mice, Inbred BALB C, Adjuvants, Immunologic adverse effects, Gene Expression Profiling, Influenza Vaccines adverse effects, Models, Biological
- Abstract
Historically, vaccine safety assessments have been conducted by animal testing (e.g., quality control tests and adjuvant development). However, classical evaluation methods do not provide sufficient information to make treatment decisions. We previously identified biomarker genes as novel safety markers. Here, we developed a practical safety assessment system used to evaluate the intramuscular, intraperitoneal, and nasal inoculation routes to provide robust and comprehensive safety data. Influenza vaccines were used as model vaccines. A toxicity reference vaccine (RE) and poly I:C-adjuvanted hemagglutinin split vaccine were used as toxicity controls, while a non-adjuvanted hemagglutinin split vaccine and AddaVax (squalene-based oil-in-water nano-emulsion with a formulation similar to MF59)-adjuvanted hemagglutinin split vaccine were used as safety controls. Body weight changes, number of white blood cells, and lung biomarker gene expression profiles were determined in mice. In addition, vaccines were inoculated into mice by three different administration routes. Logistic regression analyses were carried out to determine the expression changes of each biomarker. The results showed that the regression equations clearly classified each vaccine according to its toxic potential and inoculation amount by biomarker expression levels. Interestingly, lung biomarker expression was nearly equivalent for the various inoculation routes. The results of the present safety evaluation were confirmed by the approximation rate for the toxicity control. This method may contribute to toxicity evaluation such as quality control tests and adjuvant development.
- Published
- 2018
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8. Efficacy comparison of adjuvants in PcrV vaccine against Pseudomonas aeruginosa pneumonia.
- Author
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Hamaoka S, Naito Y, Katoh H, Shimizu M, Kinoshita M, Akiyama K, Kainuma A, Moriyama K, Ishii KJ, and Sawa T
- Subjects
- Aluminum Hydroxide administration & dosage, Animals, Bacterial Load, Freund's Adjuvant administration & dosage, Lung microbiology, Lung pathology, Male, Mice, Mice, Inbred ICR, Oligodeoxyribonucleotides administration & dosage, Pseudomonas Vaccines administration & dosage, Survival Analysis, Treatment Outcome, Adjuvants, Immunologic administration & dosage, Antigens, Bacterial immunology, Bacterial Toxins immunology, Pneumonia, Bacterial prevention & control, Pore Forming Cytotoxic Proteins immunology, Pseudomonas Infections prevention & control, Pseudomonas Vaccines immunology, Pseudomonas aeruginosa immunology
- Abstract
Vaccination against the type III secretion system of P. aeruginosa is a potential prophylactic strategy for reducing the incidence and improving the poor prognosis of P. aeruginosa pneumonia. In this study, the efficacies of three different adjuvants, Freund's adjuvant (FA), aluminum hydroxide (alum) and CpG oligodeoxynucleotide (ODN), were examined from the viewpoint of inducing PcrV-specific immunity against virulent P. aeruginosa. Mice that had been immunized intraperitoneally with recombinant PcrV formulated with one of the above adjuvants were challenged intratracheally with a lethal dose of P. aeruginosa. The PcrV-FA immunized group attained a survival rate of 91%, whereas the survival rates of the PcrV-alum and PcrV-CpG groups were 73% and 64%, respectively. In terms of hypothermia recovery after bacterial instillation, PcrV-alum was the most protective, followed by PcrV-FA and PcrV-CpG. The lung edema index was lower in the PcrV-CpG vaccination group than in the other groups. PcrV-alum immunization was associated with the greatest decrease in myeloperoxidase in infected lungs, and also decreased the number of lung bacteria to a similar number as in the PcrV-FA group. There was less neutrophil recruitment in the lungs of mice vaccinated with PcrV-alum or PcrV-CpG than in those of mice vaccinated with PcrV-FA or PcrV alone. Overall, in terms of mouse survival the PcrV-CpG vaccine, which could be a relatively safe next-generation vaccine, showed a comparable effect to the PcrV-alum vaccine., (© 2017 The Societies and John Wiley & Sons Australia, Ltd.)
- Published
- 2017
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9. A novel vaccinological evaluation of intranasal vaccine and adjuvant safety for preclinical tests.
- Author
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Sasaki E, Kuramitsu M, Momose H, Kobiyama K, Aoshi T, Yamada H, Ishii KJ, Mizukami T, and Hamaguchi I
- Subjects
- Administration, Intranasal, Animals, Biomarkers metabolism, Cytokines genetics, Cytokines immunology, Dose-Response Relationship, Immunologic, Drug Evaluation, Preclinical, Female, Gene Expression, Humans, Membrane Transport Proteins genetics, Membrane Transport Proteins immunology, Mice, Mice, Inbred BALB C, Orthomyxoviridae Infections immunology, Orthomyxoviridae Infections virology, Vaccines, Inactivated, Adjuvants, Immunologic administration & dosage, Antibodies, Viral biosynthesis, Influenza Vaccines administration & dosage, Oligodeoxyribonucleotides administration & dosage, Orthomyxoviridae Infections prevention & control
- Abstract
Vaccines are administered to healthy humans, including infants, so the safety and efficacy must be very high. Therefore, evaluating vaccine safety in preclinical and clinical studies, according to World Health Organization guidelines, is crucial for vaccine development and clinical use. A change in the route of administration is considered to alter a vaccine's immunogenicity. Several adjuvants have also been developed and approved for use in vaccines. However, the addition of adjuvants to vaccines may cause unwanted immune responses, including facial nerve paralysis and narcolepsy. Therefore, a more accurate and comprehensive strategy must be used to develope next-generation vaccines for ensuring vaccine safety. Previously, we have developed a system with which to evaluate vaccine safety in rats using a systematic vaccinological approach and 20 marker genes. In this study, we developed a safety evaluation system for nasally administered influenza vaccines and adjuvanted influenza vaccines using these marker genes. Expression of these genes increased dose-dependent manner when mice were intranasally administered the toxicity reference vaccine. When the adjuvant CpG K3 or a CpG-K3-combined influenza vaccine was administered intranasally, marker gene expression increased in a CpG-K3-dose-dependent way. A histopathological analysis indicated that marker gene expression correlated with vaccine- or adjuvant-induced phenotypic changes in the lung and nasal mucosa. We believe that the marker genes expression analyses will be useful in preclinical testing, adjuvant development, and selecting the appropriate dose of adjuvant in nasal administration vaccines., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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10. Advax, a Delta Inulin Microparticle, Potentiates In-built Adjuvant Property of Co-administered Vaccines.
- Author
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Hayashi M, Aoshi T, Haseda Y, Kobiyama K, Wijaya E, Nakatsu N, Igarashi Y, Standley DM, Yamada H, Honda-Okubo Y, Hara H, Saito T, Takai T, Coban C, Petrovsky N, and Ishii KJ
- Subjects
- Animals, Antigens immunology, Biomarkers, Cytokines biosynthesis, Dendritic Cells immunology, Dendritic Cells metabolism, Female, Immunization, Inulin administration & dosage, Liposomes, Lymphocyte Activation, Macrophages immunology, Macrophages metabolism, Male, Mice, Mice, Knockout, Models, Animal, Phagocytosis immunology, Signal Transduction, Th2 Cells immunology, Th2 Cells metabolism, Adjuvants, Immunologic administration & dosage, Inulin analogs & derivatives, Vaccines administration & dosage, Vaccines immunology
- Abstract
Advax, a delta inulin-derived microparticle, has been developed as an adjuvant for several vaccines. However, its immunological characteristics and potential mechanism of action are yet to be elucidated. Here, we show that Advax behaves as a type-2 adjuvant when combined with influenza split vaccine, a T helper (Th)2-type antigen, but behaves as a type-1 adjuvant when combined with influenza inactivated whole virion (WV), a Th1-type antigen. In addition, an adjuvant effect was not observed when Advax-adjuvanted WV vaccine was used to immunize toll-like receptor (TLR) 7 knockout mice which are unable to respond to RNA contained in WV antigen. Similarly, no adjuvant effect was seen when Advax was combined with endotoxin-free ovalbumin, a neutral Th0-type antigen. An adjuvant effect was also not seen in tumor necrosis factor (TNF)-α knockout mice, and the adjuvant effect required the presences of dendritic cells (DCs) and phagocytic macrophages. Therefore, unlike other adjuvants, Advax potentiates the intrinsic or in-built adjuvant property of co-administered antigens. Hence, Advax is a unique class of adjuvant which can potentiate the intrinsic adjuvant feature of the vaccine antigens through a yet to be determined mechanism., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2017
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11. RNA is an Adjuvanticity Mediator for the Lipid-Based Mucosal Adjuvant, Endocine.
- Author
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Hayashi M, Aoshi T, Ozasa K, Kusakabe T, Momota M, Haseda Y, Kobari S, Kuroda E, Kobiyama K, Coban C, and Ishii KJ
- Subjects
- A549 Cells, Alarmins metabolism, Animals, Antibody Formation drug effects, Female, Humans, Inflammasomes metabolism, Lipids pharmacology, Mice, Inbred BALB C, Mice, Inbred C57BL, Mucous Membrane immunology, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Nucleic Acids metabolism, Toll-Like Receptor 2 metabolism, Toll-Like Receptor 4 metabolism, Adjuvants, Immunologic pharmacology, Lipids chemistry, Mucous Membrane drug effects, RNA pharmacology
- Abstract
Nasal vaccination has the potential to elicit systemic and mucosal immunity against pathogens. However, split and subunit vaccines lack potency at stimulating mucosal immunity, and an adjuvant is indispensable for eliciting potent mucosal immune response to nasal vaccines. Endocine, a lipid-based mucosal adjuvant, potentiates both systemic and mucosal immune responses. Although Endocine has shown efficacy and tolerability in animal and clinical studies, its mechanism of action remains unknown. It has been reported recently that endogenous danger signals are essential for the effects of some adjuvants such as alum or MF59. However, the contribution of danger signals to the adjuvanticity of Endocine has not been explored. Here, we show that RNA is likely to be an important mediator for the adjuvanticity of Endocine. Administration of Endocine generated nucleic acids release, and activated dendritic cells (DCs) in draining lymph nodes in vivo. These results suggest the possibility that Endocine indirectly activates DCs via damage-associated molecular patterns. Moreover, the adjuvanticity of Endocine disappeared in mice lacking TANK-binding kinase 1 (Tbk1), which is a downstream molecule of nucleic acid sensing signal pathway. Furthermore, co-administration of RNase A reduced the adjuvanticity of Endocine. These data suggest that RNA is important for the adjuvanticity of Endocine.
- Published
- 2016
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12. Vaccine adjuvants as potential cancer immunotherapeutics.
- Author
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Temizoz B, Kuroda E, and Ishii KJ
- Subjects
- Animals, Clinical Trials as Topic, Humans, Immunomodulation, Neoplasms immunology, Vaccination, Adjuvants, Immunologic therapeutic use, Alum Compounds therapeutic use, Cancer Vaccines immunology, Immunotherapy methods, Lectins, C-Type therapeutic use, Neoplasms therapy, Oligodeoxyribonucleotides therapeutic use
- Abstract
Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund's adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy., (© The Author 2016. Published by Oxford University Press on behalf of The Japanese Society for Immunology.)
- Published
- 2016
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13. Intranasal hydroxypropyl-β-cyclodextrin-adjuvanted influenza vaccine protects against sub-heterologous virus infection.
- Author
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Kusakabe T, Ozasa K, Kobari S, Momota M, Kishishita N, Kobiyama K, Kuroda E, and Ishii KJ
- Subjects
- 2-Hydroxypropyl-beta-cyclodextrin, Administration, Intranasal, Animals, Antibodies, Viral blood, Drug Delivery Systems, Hemagglutinin Glycoproteins, Influenza Virus immunology, Immunity, Mucosal, Influenza Vaccines administration & dosage, Mice, Mice, Inbred C57BL, Vaccines, Inactivated administration & dosage, Vaccines, Inactivated immunology, Adjuvants, Immunologic administration & dosage, Influenza Vaccines immunology, Orthomyxoviridae Infections prevention & control, beta-Cyclodextrins administration & dosage
- Abstract
Intranasal vaccination with inactivated influenza viral antigens is an attractive and valid alternative to currently available influenza (flu) vaccines; many of which seem to need efficient and safe adjuvant, however. In this study, we examined whether hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used pharmaceutical excipient to improve solubility and drug delivery, can act as a mucosal adjuvant for intranasal flu vaccines. We found that intranasal immunization of mice with hemagglutinin split- as well as inactivated whole-virion influenza vaccine with HP-β-CD resulted in secretion of antigen-specific IgA and IgGs in the airway mucosa and the serum as well. As a result, both HP-β-CD adjuvanted-flu intranasal vaccine protected mice against lethal challenge with influenza virus, equivalent to those induced by experimental cholera toxin-adjuvanted ones. Of note, intranasal use of HP-β-CD as an adjuvant induced significantly lower antigen-specific IgE responses than that induced by aluminum salt adjuvant. These results suggest that HP-β-CD may be a potent mucosal adjuvant for seasonal and pandemic influenza vaccine., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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14. Current status of synthetic hemozoin adjuvant: A preliminary safety evaluation.
- Author
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Lee MS, Igari Y, Tsukui T, Ishii KJ, and Coban C
- Subjects
- Adjuvants, Immunologic chemical synthesis, Animals, Hemeproteins chemical synthesis, Humans, Influenza Vaccines chemistry, Malaria Vaccines chemistry, Plasmodium chemistry, Toxicity Tests, Adjuvants, Immunologic chemistry, Hemeproteins chemistry
- Abstract
Although adjuvants are a "must-have" component of successful vaccines, there are very few adjuvants licensed for use in humans, there is therefore an urgent need to develop new and safer adjuvants. Synthetic hemozoin (sHZ), a chemical analog of hemozoin which is produced by the malaria parasite, exhibits a potent adjuvant effect which enhances antigen-specific immune responses to vaccines. The potency of sHZ adjuvanticity is not limited to malaria specific vaccines, it has also been demonstrated to be effective in influenza and dog allergy models. While the synthesis of uniformly sized sHZ with consistent characteristics has proven difficult, we have recently successfully optimized the manufacture of sHZ product with an optimal adjuvant effect. Here, we summarize recent developments on the adjuvant properties of optimized sHZ adjuvant, including its good laboratory practice (GLP) non-clinical safety profile in animals. These studies ensure the safety of optimized sHZ product to be readily used as vaccine adjuvant beforehand in veterinary medicine., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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15. Optimization of physiological properties of hydroxyapatite as a vaccine adjuvant.
- Author
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Hayashi M, Aoshi T, Kogai Y, Nomi D, Haseda Y, Kuroda E, Kobiyama K, and Ishii KJ
- Subjects
- Adjuvants, Immunologic administration & dosage, Animals, Durapatite administration & dosage, Female, Mice, Inbred C57BL, Nanoparticles administration & dosage, Vaccines administration & dosage, Adjuvants, Immunologic pharmacology, Chemical Phenomena, Durapatite pharmacology, Vaccines immunology
- Abstract
Various particles such as Alum or silica are known to act as an adjuvant if co-administered with vaccine antigens. Several reports have demonstrated that the adjuvanticity is strongly affected by the physicochemical properties of particles such as the size, shape and surface charge, although the required properties and its relationship to the adjuvanticity are still controversial. Hydroxyapatite particle (HAp) composed of calcium phosphate has been shown to work as adjuvant in mice. However, the properties of HAp required for the adjuvanticity have not been fully characterized yet. In this study, we examined the role of size or shape of HAps in the antibody responses after immunization with antigen. HAps whose diameter ranging between 100 and 400 nm provided significantly higher antibody responses than smaller or larger ones. By comparison between sphere and rod shaped HAps, rod shaped HAps induced stronger inflammasome-dependent IL-1β production than the sphere shaped ones in vitro. However, sphere- and rod-shaped HAp elicited comparable antibody response in WT mice. Vice versa, Nlrp3(-/-), Asc(-/-) or Caspase1(-/-) mice provided comparable level of antibody responses to HAp adjuvanted vaccination. Collectively, our results demonstrated that the size rather than shape is a more critical property, and IL-1β production via NLRP3 inflammasome is dispensable for the adjuvanticity of HAps in mice., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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16. Immunization with antigenic peptides complexed with β-glucan induces potent cytotoxic T-lymphocyte activity in combination with CpG-ODNs.
- Author
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Mochizuki S, Morishita H, Kobiyama K, Aoshi T, Ishii KJ, and Sakurai K
- Subjects
- Adjuvants, Immunologic pharmacokinetics, Animals, Antigen-Presenting Cells drug effects, Antigen-Presenting Cells immunology, Antigen-Presenting Cells metabolism, Cancer Vaccines immunology, Cancer Vaccines pharmacokinetics, Cells, Cultured, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Lymphocytes, Tumor-Infiltrating pathology, Mice, Inbred C57BL, Neoplasms immunology, Neoplasms metabolism, Neoplasms pathology, Oligodeoxyribonucleotides immunology, Oligodeoxyribonucleotides pharmacokinetics, Ovalbumin immunology, Ovalbumin pharmacokinetics, Peptide Fragments administration & dosage, Peptide Fragments immunology, Peptide Fragments pharmacokinetics, Sizofiran immunology, Sizofiran pharmacokinetics, Spleen drug effects, Spleen immunology, Spleen metabolism, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic metabolism, Tissue Distribution, Tumor Burden drug effects, Adjuvants, Immunologic administration & dosage, Cancer Vaccines administration & dosage, Immunization, Lymphocyte Activation drug effects, Lymphocytes, Tumor-Infiltrating drug effects, Neoplasms drug therapy, Oligodeoxyribonucleotides administration & dosage, Ovalbumin administration & dosage, Sizofiran administration & dosage, T-Lymphocytes, Cytotoxic drug effects
- Abstract
The induction of antigen-specific immune responses requires immunization with not only antigens, but also adjuvants. CpG oligonucleotides (CpG-ODNs) are well-known ligands for Toll-like receptor 9 and a potent adjuvant that induces both Th1-type humoral and cellular immune responses including cytotoxic T-lymphocyte responses. We previously demonstrated that β-glucan schizophyllan (SPG) can form complexes with CpG-ODNs with attached dA40 (CpG-dA/SPG), which can accumulate in macrophages in the draining inguinal lymph nodes and induce strong immune responses by co-administration of antigenic proteins, namely ovalbumin (OVA). Immunization with antigenic peptides, OVA257-264, did not induce these antigen-specific immune responses even in combination with CpG-dA/SPG, indicating that peptides require a carrier to antigen presenting cells. In this study, we prepared conjugates comprising OVA257-264 and dA40, and made complexes with SPG. Immunization with OVA257-264-dA/SPG induced peptide-specific immune responses in combination with CpG-dA regardless of complexation with SPG both in vitro and in vivo. When splenocytes from immunized mice were incubated with E.G7-OVA tumor model cells presenting OVA peptides, the number of cells drastically decreased after 24h. Furthermore, mice pre-immunized with OVA257-264-dA/SPG and CpG-ODNs exhibited a long delay in tumor growth after tumor inoculation. Therefore, these peptide-dA/SPG and CpG-dA/SPG complexes could be used as a potent vaccine for the treatment of cancers and infectious diseases., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
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17. Development of Nonaggregating Poly-A Tailed Immunostimulatory A/D Type CpG Oligodeoxynucleotides Applicable for Clinical Use.
- Author
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Aoshi T, Haseda Y, Kobiyama K, Narita H, Sato H, Nankai H, Mochizuki S, Sakurai K, Katakai Y, Yasutomi Y, Kuroda E, Coban C, and Ishii KJ
- Subjects
- Animals, Cytokines biosynthesis, Dose-Response Relationship, Drug, Dose-Response Relationship, Immunologic, Fatty Acids, Monounsaturated chemistry, Humans, Influenza Vaccines immunology, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Macaca fascicularis, Oligodeoxyribonucleotides administration & dosage, Oligodeoxyribonucleotides chemistry, Quaternary Ammonium Compounds chemistry, Solubility, Adjuvants, Immunologic, Oligodeoxyribonucleotides immunology, Poly A chemistry
- Abstract
Immunostimulatory CpG ODNs have been developed and utilized as TLR9-dependent innate immune activators and vaccine adjuvants. Four different types of immunostimulatory CpG ODNs (A/D, B/K, C, and P type) have been reported. A/D type ODNs are characterized by high IFN-α production but intrinsically form aggregates, hindering its good manufacturing practice grade preparation. In this study, we developed several D35-derived ODNs (a commonly used A/D type ODN), which were modified with the addition of a phosphorothioate polynucleotide tail (such as dAs40), and examined their physical properties, solubility in saline, immunostimulatory activity on human PBMCs, and vaccine adjuvant potential in monkeys. We found that two modified ODNs including D35-dAs40 and D35core-dAs40 were immunostimulatory, similar to original D35 in human PBMCs, resulting in high IFN-α secretion in a dose-dependent manner. Physical property analysis by dynamic light scattering revealed that both D35-dAs40 and D35core-dAs40 did not form aggregates in saline, which is currently impossible for the original D35. Furthermore, D35-dAs40 and D35core-dAs40 worked as better vaccine adjuvant in monkeys. These results suggested that D35-dAs40 and D35core-dAs40 are two promising prototypes of nonaggregating A/D type ODN with advantages of ease of drug preparation for clinical applications as vaccine adjuvants or IFN-α inducing immunomodifiers.
- Published
- 2015
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18. Hemozoin as a novel adjuvant for inactivated whole virion influenza vaccine.
- Author
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Uraki R, Das SC, Hatta M, Kiso M, Iwatsuki-Horimoto K, Ozawa M, Coban C, Ishii KJ, and Kawaoka Y
- Subjects
- Animals, Antibodies, Viral blood, Antibody Formation, Female, Hemagglutination Inhibition Tests, Influenza A Virus, H1N1 Subtype, Influenza A Virus, H5N1 Subtype, Mice, Inbred BALB C, Vaccines, Inactivated immunology, Adjuvants, Immunologic pharmacology, Hemeproteins pharmacology, Influenza Vaccines immunology, Orthomyxoviridae Infections prevention & control
- Abstract
Because vaccination is an effective means to protect humans from influenza viruses, extensive efforts have been made to develop not only new vaccines, but also for new adjuvants to enhance the efficacy of existing inactivated vaccines. Here, we examined the adjuvanticity of synthetic hemozoin, a synthetic version of the malarial by-product hemozoin, on the vaccine efficacy of inactivated whole influenza viruses in a mouse model. We found that mice immunized twice with hemozoin-adjuvanted inactivated A/California/04/2009 (H1N1pdm09) or A/Vietnam/1203/2004 (H5N1) virus elicited higher virus-specific antibody responses than did mice immunized with non-adjuvanted counterparts. Furthermore, mice immunized with hemozoin-adjuvanted inactivated viruses were better protected from lethal challenge with influenza viruses than were mice immunized with non-adjuvanted inactivated vaccines. Our results show that hemozoin improves the immunogenicity of inactivated influenza viruses, and is thus a promising adjuvant for inactivated whole virion influenza vaccines., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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19. Hemozoin is a potent adjuvant for hemagglutinin split vaccine without pyrogenicity in ferrets.
- Author
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Onishi M, Kitano M, Taniguchi K, Homma T, Kobayashi M, Sato A, Coban C, and Ishii KJ
- Subjects
- Animals, Antibodies, Viral blood, Body Temperature, Female, Ferrets, Hemagglutination Inhibition Tests, Influenza B virus, Adjuvants, Immunologic administration & dosage, Hemagglutinin Glycoproteins, Influenza Virus immunology, Hemeproteins administration & dosage, Influenza Vaccines immunology, Orthomyxoviridae Infections prevention & control
- Abstract
Background: Synthetic hemozoin (sHZ, also known as β-hematin) from monomeric heme is a particle adjuvant which activates antigen-presenting cells (APCs), such as dendritic cells and macrophages, and enhances humoral immune responses to several antigens, including ovalbumin, human serum albumin, and serine repeat antigen 36 of Plasmodium falciparum. In the present study, we evaluated the adjuvanticity and pyrogenicity of sHZ as an adjuvant for seasonal trivalent hemagglutinin split vaccine (SV) for humans using the experimental ferret model., Method: Ferrets were twice immunized with trivalent SV, SV with sHZ (SV/sHZ) or Fluad, composed of trivalent SV with MF59. Serum hemagglutination inhibition (HI) titers against three viral hemagglutinin (HA) antigens were measured at every week after the immunization. The pyrogenicity of SV/sHZ was examined by monitoring the body temperature of the immunized ferrets. To evaluate the protective efficacy of SV/sHZ, the immunized ferrets were challenged with influenza virus B infection, followed by measurement of viral titers in the nasal cavity and body temperature., Results: sHZ enhanced HI titers against three viral HA antigens in a dose-dependent manner, to an extent comparable to that of Fluad. The highest dose of sHZ (800 μg) immunized with SV conferred sterile protection against infection with heterologous Influenza B virus, without causing any pyrogenic reaction such as high fever., Conclusion: In the present study, sHZ enhanced the protective efficacy of SV against influenza infection without inducing pyrogenic reaction, suggesting sHZ to be a promising adjuvant candidate for human SV., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2014
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20. Particulate adjuvant and innate immunity: past achievements, present findings, and future prospects.
- Author
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Kuroda E, Coban C, and Ishii KJ
- Subjects
- Adjuvants, Immunologic therapeutic use, Alum Compounds therapeutic use, Animals, Asthma therapy, Humans, Immunity, Innate, Nanostructures therapeutic use, Particle Size, Particulate Matter chemistry, Particulate Matter immunology, Pneumonia therapy, Th2 Cells drug effects, Vaccines administration & dosage, Vaccines immunology, Adjuvants, Immunologic metabolism, Asthma immunology, Particulate Matter metabolism, Pneumonia immunology, Th2 Cells immunology
- Abstract
Particulates and crystals stimulate the immune system to induce inflammatory responses. Several nanometer- to micrometer-sized particulates, such as particle matter 2.5 (PM2.5), diesel particles, and sand dust, induce pulmonary inflammation and allergic asthma. Conversely, nanometer- to micrometer-sized crystal, sphere, and hydrogel forms of aluminum salts (referred to as "alum") have been used as vaccine adjuvants to enhance antibody responses in animals and humans. Although most of these particulates induce type-2 immune responses in vivo, the molecular and immunological mechanisms of action as a vaccine adjuvant are poorly understood. In this review, recent advances in particulate adjuvant research from the standpoint of innate immune responses are discussed.
- Published
- 2013
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21. TLR9 adjuvants enhance immunogenicity and protective efficacy of the SE36/AHG malaria vaccine in nonhuman primate models.
- Author
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Tougan T, Aoshi T, Coban C, Katakai Y, Kai C, Yasutomi Y, Ishii KJ, and Horii T
- Subjects
- Adjuvants, Immunologic administration & dosage, Animals, Antibodies, Protozoan blood, Disease Models, Animal, Hemeproteins administration & dosage, Immunoglobulin G blood, Leukocytes, Mononuclear immunology, Macaca fascicularis, Malaria Vaccines administration & dosage, Malaria, Falciparum immunology, Oligodeoxyribonucleotides administration & dosage, Parasitemia prevention & control, Saimiri, Adjuvants, Immunologic adverse effects, Hemeproteins adverse effects, Malaria Vaccines adverse effects, Malaria Vaccines immunology, Malaria, Falciparum prevention & control, Oligodeoxyribonucleotides adverse effects, Toll-Like Receptor 9 agonists
- Abstract
The SE36 antigen, derived from serine repeat antigen 5 (SERA5) of Plasmodium falciparum, is a promising blood stage malaria vaccine candidate. Ongoing clinical trials suggest the efficacy of the SE36 vaccine could be increased by the incorporation of more effective adjuvants into the vaccine formulation. In this study, we assessed the safety, immunogenicity and protective efficacy of SE36/AHG formulated with TLR9 ligand adjuvants K3 CpG oligodeoxyribonucleotides (CpG ODNs) (K3 ODN), D3 ODN or synthetic hemozoin, in two non-human primate models. SE36/AHG with or without each adjuvant was administrated to cynomolgus monkeys. A combination of TLR9 ligand adjuvant with SE36/AHG induced higher humoral and cellular immune response compared with SE36/AHG alone. Administration of a crude extract of P. falciparum parasite resulted in the induction of more SE36-specific IgG antibodies in monkeys vaccinated with a combination of SE36/AHG and adjuvant, as opposed to vaccination with SE36/AHG alone. The most effective TLR9 ligand, K3 ODN, was chosen for further vaccine trials in squirrel monkeys, in combination with SE36/AHG. All monkeys immunized with the combined SE36/AHG and K3 ODN formulation effectively suppressed parasitemia and symptoms of malaria following challenge infections. Furthermore, no serious adverse events were observed. Our results show that the novel vaccine formulation of K3 ODN with SE36/AHG demonstrates safety, potent immunogenicity and efficacy in nonhuman primates, and this vaccine formulation may form the basis of a more effective malaria vaccine.
- Published
- 2013
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22. The chemotherapeutic agent DMXAA as a unique IRF3-dependent type-2 vaccine adjuvant.
- Author
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Tang CK, Aoshi T, Jounai N, Ito J, Ohata K, Kobiyama K, Dessailly BH, Kuroda E, Akira S, Mizuguchi K, Coban C, and Ishii KJ
- Subjects
- Animals, Enzyme-Linked Immunosorbent Assay, Female, Immunity, Innate drug effects, Interferon Regulatory Factor-3 genetics, Interleukin-33, Interleukins genetics, Interleukins metabolism, Male, Mice, Mice, Knockout, Adjuvants, Immunologic therapeutic use, Interferon Regulatory Factor-3 metabolism, Xanthones therapeutic use
- Abstract
5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a potent type I interferon (IFN) inducer, was evaluated as a chemotherapeutic agent in mouse cancer models and proved to be well tolerated in human cancer clinical trials. Despite its multiple biological functions, DMXAA has not been fully characterized for the potential application as a vaccine adjuvant. In this report, we show that DMXAA does act as an adjuvant due to its unique property as a soluble innate immune activator. Using OVA as a model antigen, DMXAA was demonstrated to improve on the antigen specific immune responses and induce a preferential Th2 (Type-2) response. The adjuvant effect was directly dependent on the IRF3-mediated production of type-I-interferon, but not IL-33. DMXAA could also enhance the immunogenicity of influenza split vaccine which led to significant increase in protective responses against live influenza virus challenge in mice compared to split vaccine alone. We propose that DMXAA can be used as an adjuvant that targets a specific innate immune signaling pathway via IRF3 for potential applications including vaccines against influenza which requires a high safety profile.
- Published
- 2013
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23. Development and application of next generation SE36 malaria vaccine formulated with a novel adjuvant: approach to travelers' vaccine.
- Author
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Tougan T, Ishii KJ, and Horii T
- Subjects
- Animals, Humans, Malaria immunology, Malaria prevention & control, Adjuvants, Immunologic pharmacology, Antigens, Protozoan immunology, Malaria Vaccines immunology, Plasmodium falciparum immunology, Protozoan Proteins immunology
- Abstract
The SE36 antigen, derived from serine repeat antigen 5 (SERA5) of Plasmodium falciparum, is a promising blood stage malaria vaccine candidate. Previous clinical trials indicated the protective efficacy of BK-SE36 malaria vaccine that is constituted of SE36 recombinant protein and aluminum hydroxide gel. In this study, we assessed the safety, immunogenicity and protective efficacy of SE36/AHG formulated with TLR9 ligand adjuvants K3 CpG oligodeoxyribonucleotides (CpG ODNs) (K3 ODN), D3 ODN or synthetic hemozoin, in two non-human primate models. SE36/AHG with or without each adjuvant was administrated to cynomolgus monkeys. A combination of TLR9 ligand adjuvant with SE36/AHG induced higher humoral and cellular immune response compared with SE36/AHG alone. The most effective TLR9 ligand, K3 ODN, was chosen for further vaccine trials in squirrel monkeys, in combination with SE36/AHG. All monkeys immunized SE36/AHG with K3 ODN effectively suppressed parasitemia and symptoms of malaria following challenge infection. Furthermore, no serious adverse events were observed. Our results show that the novel vaccine formulation of K3 ODN with SE36/AHG is safety, potent immunogenicity and efficacy in nonhuman primates. We are conducting the first in human clinical trials with this formulation.
- Published
- 2013
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24. Alum-adjuvanted H5N1 whole virion inactivated vaccine (WIV) induced IgG1 and IgG4 antibody responses in young children.
- Author
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Nakayama T, Kumagai T, Ishii KJ, and Ihara T
- Subjects
- Adolescent, Age Factors, Child, Child, Preschool, Humans, Infant, Influenza Vaccines administration & dosage, Vaccines, Inactivated administration & dosage, Vaccines, Inactivated immunology, Adjuvants, Immunologic administration & dosage, Alum Compounds administration & dosage, Antibodies, Viral blood, Immunoglobulin G blood, Influenza A Virus, H5N1 Subtype immunology, Influenza Vaccines immunology
- Abstract
IgG subclass antibody responses are not fully understood. Alum-adjuvanted H5N1whole virion inactivated vaccine (WIV), a genetically reassortant vaccine seed strain originating from H5N1/A/Vietnam/1194/2004 and PR-8, induced significantly stronger antibody responses in neutralizing antibodies in children. In this report, IgG subclass antibody responses were investigated, and most serum samples were positive for IgG1 antibody before immunization. A significant response (more than 4-fold increase) of IgG1 antibody was observed in 67/193 (34.7%) and that of gG4 antibodies in 42/193(21.8%). Children <4 years of age showed a significant increase in IgG subclass antibodies but those ≥4 years showed lower responses. Alum- adjuvanted H5N1WIV induced an efficient immune response in young children especially <4 years., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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25. Adjuvants in influenza vaccines.
- Author
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Tetsutani K and Ishii KJ
- Subjects
- Alum Compounds pharmacology, Drug Combinations, Humans, Polysorbates pharmacology, Squalene pharmacology, Vaccines, Inactivated immunology, alpha-Tocopherol pharmacology, Adjuvants, Immunologic pharmacology, Influenza Vaccines immunology
- Abstract
The effectiveness of influenza vaccines is still controversial, and the role of adjuvants in such vaccines is briefly reviewed in this paper. Inactivated whole virus vaccines may include components that function as adjuvants, meaning that additive adjuvants are often not required. MF59 and AS03 showed higher adjuvanticity than aluminum salts in several clinical studies. Recent research has suggested that immune cell recruitment is the main mechanism underlying adjuvant actions in general, and that aluminum salts induce this recruitment via inflammation at the injected site. The aspect of how oil-based adjuvants, such as MF59 and AS03, recruit immune cells remains to be clarified., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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26. Alum-adjuvanted H5N1 whole virion inactivated vaccine (WIV) enhanced inflammatory cytokine productions.
- Author
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Nakayama T, Kashiwagi Y, Kawashima H, Kumagai T, Ishii KJ, and Ihara T
- Subjects
- Adolescent, Adult, Antibodies, Viral blood, Child, Child, Preschool, Drug-Related Side Effects and Adverse Reactions epidemiology, Female, Fever chemically induced, Humans, Infant, Influenza Vaccines administration & dosage, Influenza Vaccines adverse effects, Japan, Male, Middle Aged, Vaccines, Inactivated administration & dosage, Vaccines, Inactivated adverse effects, Vaccines, Inactivated immunology, Young Adult, Adjuvants, Immunologic administration & dosage, Alum Compounds administration & dosage, Cytokines metabolism, Influenza A Virus, H5N1 Subtype immunology, Influenza Vaccines immunology
- Abstract
Alum-adjuvanted H5 whole virion inactivated vaccine (WIV) was licensed for adults in Japan but induced marked febrile reactions with significantly stronger antibody responses in children. In this study, the mechanisms behind the different responses were investigated. Lymphocytes were obtained from 25 healthy subjects who were not immunized with H5 vaccine, to examine the innate immune impact of the various vaccine formulations, analyzing the cytokine production profile stimulated with alum adjuvant alone, alum-adjuvanted H5 WIIV, plain H5 WIV, and H5 split vaccine. Alum adjuvant did not induce cytokine production, but H5 split induced IFN-γ and TNF-α. H5 WIV induced IL-6, IL-17, TNF-α, MCP-1, IFN-γ, and IFN-α. An extremely low level of IL-1β was produced in response to H5 WIV, and alum-adjuvanted H5 WIV enhanced IL-1β production, with similar levels of other cytokines stimulated with H5 WIV. Enhanced production of cytokines induced by alum-adjuvanted H5 WIV may be related to the higher incidence of febrile reactions with stronger immune responses in children but it should be further investigated why efficient immune responses with febrile illness were observed only in young children., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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27. [Vaccine adjuvant].
- Author
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Aoshi T and Ishii KJ
- Subjects
- Adaptive Immunity physiology, Antigen Presentation physiology, Humans, Immunity, Innate physiology, Adjuvants, Immunologic pharmacology
- Abstract
Inducing adaptive immune responses with vaccination requires prior innate immune responses. Adjuvants have been used empirically to enhance and modulate the adaptive immune responses elicited by the vaccination. Advances in the innate immune system revealed that many adjuvants act through the innate immune receptors including TLRs, NLRs, RLRs, and CLRs. Recently it has been shown that some particulate adjuvants directly activate dendritic cells in a receptor-independent manner. In this review, we discuss how adjuvants activate dendritic cells, directing adaptive immune responses to Th1, Th2, and Th17 cells. We also discuss a differential requirement of adjvuant between priming and boosting administration of vaccine, and appropriate use of adjuvants to reduce the side effect of vaccine.
- Published
- 2011
28. DNA released from dying host cells mediates aluminum adjuvant activity.
- Author
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Marichal T, Ohata K, Bedoret D, Mesnil C, Sabatel C, Kobiyama K, Lekeux P, Coban C, Akira S, Ishii KJ, Bureau F, and Desmet CJ
- Subjects
- Adjuvants, Immunologic pharmacology, Alum Compounds pharmacology, Animals, Cell Death drug effects, Deoxyribonuclease I, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Glycoproteins genetics, Immunoglobulin E metabolism, Immunoglobulin G metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, RNA-Binding Proteins, Spectrophotometry, Toll-Like Receptor 9 genetics, Adjuvants, Immunologic metabolism, B-Lymphocytes immunology, DNA metabolism, Signal Transduction immunology, Th2 Cells immunology
- Abstract
Aluminum-based adjuvants (aluminum salts or alum) are widely used in human vaccination, although their mechanisms of action are poorly understood. Here we report that, in mice, alum causes cell death and the subsequent release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we propose that host DNA signaling differentially regulates IgE and IgG1 production after alum-adjuvanted immunization. We suggest that, on the one hand, host DNA induces primary B cell responses, including IgG1 production, through interferon response factor 3 (Irf3)-independent mechanisms. On the other hand, we suggest that host DNA also stimulates 'canonical' T helper type 2 (T(H)2) responses, associated with IgE isotype switching and peripheral effector responses, through Irf3-dependent mechanisms. The finding that host DNA released from dying cells acts as a damage-associated molecular pattern that mediates alum adjuvant activity may increase our understanding of the mechanisms of action of current vaccines and help in the design of new adjuvants.
- Published
- 2011
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29. Intranasal vaccination with pneumococcal surface protein A plus poly(I:C) protects against secondary pneumococcal pneumonia in mice.
- Author
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Ezoe H, Akeda Y, Piao Z, Aoshi T, Koyama S, Tanimoto T, Ishii KJ, and Oishi K
- Subjects
- Adjuvants, Immunologic therapeutic use, Administration, Intranasal, Animals, Humans, Immunization, Secondary methods, Influenza A Virus, H1N1 Subtype immunology, Influenza, Human complications, Influenza, Human immunology, Mice, Mice, Inbred C57BL, Pneumococcal Infections etiology, Pneumococcal Infections immunology, Pneumococcal Infections prevention & control, Pneumococcal Vaccines immunology, Pneumonia, Pneumococcal etiology, Pneumonia, Pneumococcal immunology, Poly I-C immunology, Poly I-C therapeutic use, Adjuvants, Immunologic administration & dosage, Bacterial Proteins administration & dosage, Bacterial Proteins immunology, Influenza, Human prevention & control, Pneumococcal Vaccines administration & dosage, Pneumonia, Pneumococcal prevention & control, Poly I-C administration & dosage, Secondary Prevention methods
- Abstract
Effective pneumococcal vaccines are required for preventing secondary bacterial pneumonia, a life-threatening condition, during epidemics of influenza. We examined whether nasal administration of a low dose of pneumococcal surface protein A (PspA) plus polyinosinic-polycytidylic acid (poly(I:C)) could protect against a fatal secondary pneumococcal pneumonia after influenza A virus infection in mice. PspA-specific IgG but not IgA level was higher in the airways and blood of mice nasally administered a low dose of PspA plus poly(I:C) than in mice nasally administered PspA alone or poly(I:C) alone. Binding of PspA-specific IgG increased C3 deposition on the bacterial surface. The survival rate during secondary infection was higher in mice immunized with PspA plus poly(I:C) than in mice immunized with poly(I:C) alone. The significant reduction in bacterial density in the lung and blood was associated with increased survival of immunized mice with secondary pneumonia. Passive transfer of sera from mice immunized with PspA plus poly(I:C) increased the survival of mice infected with secondary pneumonia. Our data suggest that an intranasal PspA vaccine has promising protective effects against secondary pneumonia after influenza and that PspA-specific IgG plays a critical role in this protection., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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30. TLR9 and endogenous adjuvants of the whole blood-stage malaria vaccine.
- Author
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Coban C, Horii T, Akira S, and Ishii KJ
- Subjects
- Humans, Malaria, Falciparum immunology, Adjuvants, Immunologic metabolism, Malaria Vaccines immunology, Malaria, Falciparum pathology, Malaria, Falciparum prevention & control, Plasmodium falciparum immunology, Toll-Like Receptor 9 immunology
- Abstract
Vaccination has been a successful tool in the protection against many infectious diseases, and recent advances in biotechnology have created new techniques and strategies to produce safe and efficacious vaccines for human use. However, developing a protective vaccine against malaria has been a challenge. In this article, we focus on an old approach with some new modifications, the so-called whole-parasite vaccination strategy against blood-stage Plasmodium falciparum, the deadliest human malarial agent. In addition, we discuss recent developments in our understanding of how the endogenous adjuvant activity in the parasites, which functions via Toll-like receptor 9, acts as a double-edged sword between protective vaccination and pathological responses against malaria infection.
- Published
- 2010
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31. Immunogenicity of whole-parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9.
- Author
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Coban C, Igari Y, Yagi M, Reimer T, Koyama S, Aoshi T, Ohata K, Tsukui T, Takeshita F, Sakurai K, Ikegami T, Nakagawa A, Horii T, Nuñez G, Ishii KJ, and Akira S
- Subjects
- Animals, Antibodies, Protozoan blood, Carrier Proteins genetics, Carrier Proteins immunology, Hypersensitivity prevention & control, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88 deficiency, Myeloid Differentiation Factor 88 immunology, NLR Family, Pyrin Domain-Containing 3 Protein, Ovalbumin immunology, Protein Binding, Protein Conformation, Toll-Like Receptor 9 deficiency, Adjuvants, Immunologic pharmacology, Hemeproteins pharmacology, Malaria Vaccines immunology, Malaria, Falciparum prevention & control, Plasmodium falciparum immunology, Toll-Like Receptor 9 agonists
- Abstract
Although whole-parasite vaccine strategies for malaria infection have regained attention, their immunological mechanisms of action remain unclear. We find that immunization of mice with a crude blood stage extract of the malaria parasite Plasmodium falciparum elicits parasite antigen-specific immune responses via Toll-like receptor (TLR) 9 and that the malarial heme-detoxification byproduct, hemozoin (HZ), but not malarial DNA, produces a potent adjuvant effect. Malarial and synthetic (s)HZ bound TLR9 directly to induce conformational changes in the receptor. The adjuvant effect of sHZ depended on its method of synthesis and particle size. Although natural HZ acts as a TLR9 ligand, the adjuvant effects of synthetic HZ are independent of TLR9 or the NLRP3-inflammasome but are dependent on MyD88. The adjuvant function of sHZ was further validated in a canine antiallergen vaccine model. Thus, HZ can influence adaptive immune responses to malaria infection and may have therapeutic value in vaccine adjuvant development., (2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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32. A signaling polypeptide derived from an innate immune adaptor molecule can be harnessed as a new class of vaccine adjuvant.
- Author
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Kobiyama K, Takeshita F, Ishii KJ, Koyama S, Aoshi T, Akira S, Sakaue-Sawano A, Miyawaki A, Yamanaka Y, Hirano H, Suzuki K, and Okuda K
- Subjects
- Adaptor Proteins, Signal Transducing administration & dosage, Adaptor Proteins, Signal Transducing genetics, Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic genetics, Animals, Carcinoma, Lewis Lung genetics, Carcinoma, Lewis Lung immunology, Carcinoma, Lewis Lung prevention & control, Caspases administration & dosage, Caspases genetics, Cell Line, Cells, Cultured, Female, HeLa Cells, Humans, Influenza A Virus, H1N1 Subtype genetics, Influenza A Virus, H1N1 Subtype immunology, Influenza Vaccines administration & dosage, Influenza Vaccines genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Moths, Oligodeoxyribonucleotides administration & dosage, Oligodeoxyribonucleotides genetics, Oligodeoxyribonucleotides immunology, Peptide Fragments administration & dosage, Peptide Fragments genetics, Protein Structure, Tertiary genetics, Protein Transport immunology, Signal Transduction genetics, Vaccines, DNA administration & dosage, Vaccines, DNA genetics, Adaptor Proteins, Signal Transducing immunology, Adjuvants, Immunologic classification, Caspases immunology, Immunity, Innate genetics, Influenza Vaccines immunology, Peptide Fragments immunology, Signal Transduction immunology, Vaccines, DNA immunology
- Abstract
Modulation of intracellular signaling using cell-permeable polypeptides is a promising technology for future clinical applications. To develop a novel approach to activate innate immune signaling by synthetic polypeptides, we characterized several different polypeptides derived from the caspase recruitment domain (CARD) of IFN-beta promoter stimulator 1, each of which localizes to a different subcellular compartment. Of particular interest was, N'-CARD, which consisted of the nuclear localization signal of histone H2B and the IFN-beta promoter stimulator 1CARD and which localized to the nucleus. This polypeptide led to a strong production of type I IFNs and molecular and genetic analyses showed that nuclear DNA helicase II is critically involved in this response. N'-CARD polypeptide fused to a protein transduction domain (N'-CARD-PTD) readily transmigrated from the outside to the inside of the cell and triggered innate immune signaling. Administration of N'-CARD-PTD polypeptide elicited production of type I IFNs, maturation of bone marrow-derived dendritic cells, and promotion of vaccine immunogenicity by enhancing Ag-specific Th1-type immune responses, thereby protecting mice from lethal influenza infection and from outgrowth of transplanted tumors in vivo. Thus, our results indicate that the N'-CARD-PTD polypeptide belongs to a new class of vaccine adjuvant that directly triggers intracellular signal transduction by a distinct mechanism from those engaged by conventional vaccine adjuvants, such as TLR ligands.
- Published
- 2009
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33. Cutting edge: cooperation of IPS-1- and TRIF-dependent pathways in poly IC-enhanced antibody production and cytotoxic T cell responses.
- Author
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Kumar H, Koyama S, Ishii KJ, Kawai T, and Akira S
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Vesicular Transport genetics, Animals, Antibody Formation genetics, Mice, Mice, Knockout, Poly I-C immunology, RNA Helicases metabolism, T-Lymphocytes, Cytotoxic immunology, Toll-Like Receptor 3 agonists, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Vesicular Transport metabolism, Adjuvants, Immunologic pharmacology, Antibody Formation drug effects, Poly I-C pharmacology, T-Lymphocytes, Cytotoxic drug effects
- Abstract
Double-stranded RNA, polyriboinosinic-polyribocytidylic acid (poly IC), acts as an adjuvant that enhances adaptive immune responses. The recognition of poly IC is mediated by endosomal TLR3 and cytoplasmic RNA helicase melanoma differentiation-associated gene 5 (Mda5), which signal through the adaptors Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF) and IFN-beta promoter stimulator-1 (IPS-1), respectively. However, the contribution of these pathways to the adjuvant effects of poly IC remains unclear. In this study, we found that poly IC-enhanced, Ag-specific Ab production was severely decreased in IPS-1-deficient mice but not in TRIF-deficient mice. However, the double deficiency resulted in a complete loss of Ab production. Furthermore, Ag-specific CD8+ T cell expansion was reduced in both IPS-1-deficient and TRIF-deficient mice and entirely abrogated in the doubly deficient mice. Taken together, these results demonstrate that the adjuvant effects of poly IC require a cooperative activation of TLR and cytoplasmic RNA helicase pathways.
- Published
- 2008
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34. Toll or toll-free adjuvant path toward the optimal vaccine development.
- Author
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Ishii KJ and Akira S
- Subjects
- Humans, Immunity, Innate drug effects, Immunization, Signal Transduction immunology, Toll-Like Receptors immunology, Adjuvants, Immunologic, Toll-Like Receptors physiology, Vaccines pharmacology
- Abstract
Successful vaccines contain an adjuvant component that activates the innate immune system, thereby eliciting antigen-specific immune responses. Many adjuvants appear to be ligands for toll-like receptors (TLR), which are thus promising targets for the development of novel adjuvants to elicit vaccine immunogenicity. However, recent evidence suggests that some adjuvants activate the innate immune system in a TLR-independent manner possibly through other pattern recognition receptors and signaling machinery. In particular, newly identified intracellular retinoic-acid-inducible gene (RIG)-like receptors, NOD-like receptors, or even as yet unknown recognition machinery for the adjuvant may regulate TLR-independent vaccine immunogenicity. To develop optimal vaccines, it will be critical to understand how TLR-dependent and TLR-independent innate immune activation, by various adjuvants, control the consequent adaptive immune responses to vaccine.
- Published
- 2007
- Full Text
- View/download PDF
35. Synthesis and in vitro characterization of antigen-conjugated polysaccharide as a CpG DNA carrier.
- Author
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Shimada N, Ishii KJ, Takeda Y, Coban C, Torii Y, Shinkai S, Akira S, and Sakurai K
- Subjects
- Adjuvants, Immunologic chemistry, Adjuvants, Immunologic metabolism, Animals, Cell Line, Circular Dichroism, Macromolecular Substances, Models, Molecular, Ovalbumin metabolism, Protein Binding, Sizofiran chemistry, Sizofiran metabolism, Adjuvants, Immunologic chemical synthesis, CpG Islands immunology, Ovalbumin chemistry, Sizofiran chemical synthesis
- Abstract
Oligodeoxynucleotides containing unmethylated CpG sequences (CpG DNAs) are known as an immune adjuvant. CpG DNAs coupled with a particular antigen enabling both CpG DNA and antigen delivery to the same antigen-presenting cell have been shown to be more effective. Based on our previous finding that beta-(1-->3)-D-glucan schizophyllan (SPG) can be used as a CpG DNA carrier, here we present the synthesis of an antigen-conjugated SPG and the characterization of the conjugate. Ovalbumin (OVA, 43 kDa) was used as a model antigen, and two OVA were conjugated to one SPG molecule (M(w) = 150,000), denoted by OVA-SPG. Circular dichroism and gel electrophoresis showed that OVA-SPG could form a complex with a (dA)(40)-tailed CpG DNA at the 3' end (1,668-(dA)(40)). When OVA-SPG was added to macrophages (J774.A1), the amount of the ingested OVA-SPG was increased compared with that of OVA itself, suggesting that Dectin-1 (proinflammatory nonopsonic receptor for beta-glucans) is involved to ingest OVA-SPG. Furthermore, the complex of the conjugate and DNA was co-localized in the same vesicles, implying that OVA (antigen) and CpG DNA (adjuvant) were ingested into the cell at the same time. This paper shows that OVA-SPG can be used as a CpG DNA carrier to induce antigen-specific immune responses.
- Published
- 2006
- Full Text
- View/download PDF
36. Toll-like receptor adaptor molecules enhance DNA-raised adaptive immune responses against influenza and tumors through activation of innate immunity.
- Author
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Takeshita F, Tanaka T, Matsuda T, Tozuka M, Kobiyama K, Saha S, Matsui K, Ishii KJ, Coban C, Akira S, Ishii N, Suzuki K, Klinman DM, Okuda K, and Sasaki S
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Vesicular Transport genetics, Animals, Antigens, Viral genetics, Antigens, Viral immunology, Cancer Vaccines genetics, Female, Humans, Immunization, Influenza Vaccines genetics, Influenza, Human genetics, Influenza, Human immunology, Influenza, Human prevention & control, Mice, Mice, Inbred BALB C, Myeloid Differentiation Factor 88, Neoplasms genetics, Neoplasms immunology, Neoplasms therapy, Papillomavirus E7 Proteins genetics, Papillomavirus E7 Proteins immunology, Plasmids genetics, Plasmids immunology, Promoter Regions, Genetic genetics, Promoter Regions, Genetic immunology, Vaccines, DNA genetics, Adaptor Proteins, Signal Transducing immunology, Adaptor Proteins, Vesicular Transport immunology, Adjuvants, Immunologic genetics, Cancer Vaccines immunology, Immunity, Innate genetics, Influenza Vaccines immunology, Vaccines, DNA immunology
- Abstract
Toll-like receptors (TLRs) recognize microbial components and trigger the signaling cascade that activates the innate and adaptive immunity. TLR adaptor molecules play a central role in this cascade; thus, we hypothesized that overexpression of TLR adaptor molecules could mimic infection without any microbial components. Dual-promoter plasmids that carry an antigen and a TLR adaptor molecule such as the Toll-interleukin-1 receptor domain-containing adaptor-inducing beta interferon (TRIF) or myeloid differentiation factor 88 (MyD88) were constructed and administered to mice to determine if these molecules can act as an adjuvant. A DNA vaccine incorporated with the MyD88 genetic adjuvant enhanced antigen-specific humoral immune responses, whereas that with the TRIF genetic adjuvant enhanced cellular immune responses. Incorporating the TRIF genetic adjuvant in a DNA vaccine targeting the influenza HA antigen or the tumor-associated antigen E7 conferred superior protection. These results indicate that TLR adaptor molecules can bridge innate and adaptive immunity and potentiate the effects of DNA vaccines against virus infection and tumors.
- Published
- 2006
- Full Text
- View/download PDF
37. Contribution of nitric oxide to CpG-mediated protection against Listeria monocytogenes.
- Author
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Ito S, Ishii KJ, Ihata A, and Klinman DM
- Subjects
- Animals, Interferon-gamma physiology, Mice, Mice, Inbred C57BL, Adjuvants, Immunologic therapeutic use, Listeriosis immunology, Nitric Oxide physiology, Oligodeoxyribonucleotides therapeutic use
- Abstract
Immunostimulatory CpG oligodeoxynucleotides (ODN) improve host resistance to listeriae. CpG ODN trigger immune cells to produce gamma interferon and "prime" host cells to secrete nitric oxide in response to bacterial exposure. CpG treatment does not protect inducible nitric oxide synthase 2 knockout mice, indicating that NO is critical to CpG-mediated protection against listeriae.
- Published
- 2005
- Full Text
- View/download PDF
38. CpG RNA: identification of novel single-stranded RNA that stimulates human CD14+CD11c+ monocytes.
- Author
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Sugiyama T, Gursel M, Takeshita F, Coban C, Conover J, Kaisho T, Akira S, Klinman DM, and Ishii KJ
- Subjects
- 3' Untranslated Regions chemistry, 3' Untranslated Regions metabolism, Adjuvants, Immunologic chemical synthesis, Humans, Monocytes enzymology, NF-kappa B metabolism, Oligodeoxyribonucleotides chemical synthesis, Oligoribonucleotides chemical synthesis, Oligoribonucleotides pharmacology, Poly G chemistry, Poly G metabolism, RNA chemical synthesis, p38 Mitogen-Activated Protein Kinases metabolism, Adjuvants, Immunologic pharmacology, CD11c Antigen biosynthesis, CpG Islands immunology, Lipopolysaccharide Receptors biosynthesis, Monocytes immunology, Monocytes metabolism, Oligodeoxyribonucleotides pharmacology, RNA pharmacology
- Abstract
Synthetic immunostimulatory nucleic acids such as CpG DNA are being harnessed therapeutically as vaccine adjuvants, anticancer or antiallergic agents. Efforts to identify nucleic acid-based agents capable of more specifically modulating the immune system are being developed. The current study identifies a novel class of single-stranded oligoribonucleotides (ORN) containing unmethylated CpG motifs and a poly(G) run at the 3' end (CpG ORN) that directly stimulate human CD14+CD11c+ monocytes but not dendritic cells or B cells. CpG ORN activate NF-kappaB and p38 MAPK, resulting in IL-6 and IL-12 production and costimulatory molecule up-regulation but not IFNalpha. Methylation of cytosine at the 5' portion in core CpG motif abrogates such activation. TLR3, 7, 8, or 9 alone did not confer response to CpG ORN, in contrast to previously reported respective nucleic acid ligands. These data suggest that CpG ORN represent a novel class of synthetic immunostimulatory nucleic acids with distinct target cells, receptors, and functions from that of previously known immunomodulatory nucleic acids.
- Published
- 2005
- Full Text
- View/download PDF
39. CpG oligodeoxynucleotides enhance neonatal resistance to Listeria infection.
- Author
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Ito S, Ishii KJ, Gursel M, Shirotra H, Ihata A, and Klinman DM
- Subjects
- Adjuvants, Immunologic administration & dosage, Age Factors, Animals, Animals, Newborn growth & development, Bacterial Toxins immunology, Cells, Cultured, Epitopes, T-Lymphocyte immunology, Heat-Shock Proteins immunology, Hemolysin Proteins, Immunity, Innate immunology, Immunophenotyping, Kinetics, Listeria monocytogenes growth & development, Listeria monocytogenes immunology, Listeriosis microbiology, Listeriosis mortality, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Oligodeoxyribonucleotides administration & dosage, Spleen cytology, Spleen immunology, Spleen metabolism, Spleen microbiology, Survival Analysis, Adjuvants, Immunologic pharmacology, Animals, Newborn immunology, Animals, Newborn microbiology, Listeriosis immunology, Listeriosis prevention & control, Oligodeoxyribonucleotides pharmacology
- Abstract
Infection by Listeria monocytogenes causes serious morbidity and mortality during the neonatal period. Previous studies established that immunostimulatory CpG oligodeoxynucleotides (ODN) can increased the resistance of adult mice to many infectious pathogens, including Listeria. This work examines the capacity of CpG ODN to stimulate a protective immune response in newborns. Results indicate that dendritic cells, macrophages, and B cells from 3-day-old mice respond to CpG stimulation by secreting IFN-gamma, IL-12, and/or TNF-alpha. Spleen cells from CpG-treated neonates produce large amounts of cytokine and NO when exposed to bacteria in vitro. Newborns treated with CpG ODN are protected from lethal Listeria challenge and generate Ag-specific CD4 and CD8 T cells that afford long-term protection against subsequent infection. These results demonstrate that cellular elements of the neonatal immune system respond to stimulation by CpG ODN, thereby reducing host susceptibility to infectious pathogens.
- Published
- 2005
- Full Text
- View/download PDF
40. CpG oligodeoxynucleotides improve the survival of pregnant and fetal mice following Listeria monocytogenes infection.
- Author
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Ito S, Ishii KJ, Shirota H, and Klinman DM
- Subjects
- Animals, Female, Immunity, Innate, Infectious Disease Transmission, Vertical prevention & control, Listeriosis drug therapy, Listeriosis microbiology, Mice, Mice, Inbred BALB C, Oligodeoxyribonucleotides immunology, Pregnancy, Pregnancy Complications, Infectious drug therapy, Pregnancy Complications, Infectious microbiology, Adjuvants, Immunologic administration & dosage, CpG Islands immunology, Listeria monocytogenes pathogenicity, Listeriosis mortality, Oligodeoxyribonucleotides administration & dosage, Pregnancy Complications, Infectious mortality
- Abstract
Listeria infection during pregnancy can cause the death of both mother and fetus. Previous studies established that immunostimulatory CpG oligodeoxynucleotides (ODN) increase the resistance of healthy adult mice to many infectious pathogens, including Listeria monocytogenes. This study examines whether the innate immune response elicited by CpG ODN can reduce the susceptibility of pregnant mice to lethal listeria challenge. The results indicate that CpG ODN treatment significantly improves maternal survival and reduces pathogen transmission to offspring. CpG ODN administered during pregnancy did not induce abortion, birth defects, or reduce the size or health of litters. These findings suggest that CpG ODN may provide a safe and effective means of improving the health of mothers and fetuses during pregnancy.
- Published
- 2004
- Full Text
- View/download PDF
41. Effect of CpG oligodeoxynucleotides on the immunogenicity of Pfs25, a Plasmodium falciparum transmission-blocking vaccine antigen.
- Author
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Coban C, Ishii KJ, Stowers AW, Keister DB, Klinman DM, and Kumar N
- Subjects
- Alum Compounds, Animals, Antibodies, Protozoan blood, Antibody Affinity, Immunization, Immunization, Secondary, Malaria Vaccines administration & dosage, Malaria, Falciparum prevention & control, Mice, Mice, Inbred BALB C, Oligodeoxyribonucleotides administration & dosage, Protozoan Proteins genetics, Adjuvants, Immunologic, Malaria Vaccines immunology, Malaria, Falciparum transmission, Oligodeoxyribonucleotides immunology, Plasmodium falciparum immunology, Protozoan Proteins immunology
- Abstract
Antibodies directed against Pfs25, a protein present on the surface of zygotes and ookinetes of Plasmodium falciparum, completely block pathogen transmission. We evaluated the immunomodulatory effect of CpG oligodeoxynucleotides (ODN) on the immunogenicity of recombinant Pfs25 (rPfs25) formulated in alum (Al). Immunization of mice with rPfs25 plus CpG ODN improved both the antibody titer (a 30-fold-higher antibody response than that with rPfs25-Al alone) and avidity. Coadministration of CpG ODN dramatically enhanced the titer of immunoglobulin G2A (IgG2a) compared to the titer of the IgG1-dominant response caused by rPfs25-Al alone, and the sera from the CpG ODN-coadministered group completely blocked the transmission of P. falciparum parasites to mosquitoes, as determined by membrane feeding assays. However, transmission-blocking experiments revealed that blocking efficacy was dependent on high-titer antibody levels, independent of isotypes. These results suggest that CpG ODN can be used as an adjuvant to enhance the immunogenicity of rPfs25 as a malaria transmission-blocking vaccine.
- Published
- 2004
- Full Text
- View/download PDF
42. Influence of stimulatory and suppressive DNA motifs on host susceptibility to inflammatory arthritis.
- Author
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Zeuner RA, Verthelyi D, Gursel M, Ishii KJ, and Klinman DM
- Subjects
- Adoptive Transfer, Animals, Arthritis, Experimental pathology, Arthritis, Reactive pathology, Cell Transplantation, Disease Models, Animal, Dose-Response Relationship, Drug, Hindlimb, Injections, Intra-Articular, Joints pathology, Mice, Mice, Inbred BALB C, Oligonucleotides administration & dosage, Spleen cytology, Spleen immunology, Spleen metabolism, Tumor Necrosis Factor-alpha metabolism, Adjuvants, Immunologic, Arthritis, Experimental immunology, Arthritis, Reactive immunology, CpG Islands immunology, Disease Susceptibility immunology, Oligonucleotides immunology
- Abstract
Objective: To examine whether systemic administration of immunostimulatory and immunosuppressive oligodeoxynucleotides (ODNs) alter host susceptibility to inflammatory arthritis., Methods: Normal BALB/c mice were treated systemically with CpG ODNs or suppressive ODNs, and then challenged intraarticularly with CpG DNA. The onset and magnitude of the resulting inflammatory response was monitored., Results: Systemic delivery of CpG ODNs significantly increased susceptibility to local inflammation, whereas systemic treatment with suppressive ODNs reduced this susceptibility. CD11c+ cells played a key role in mediating host sensitivity to arthritis. These cells were the dominant source of tumor necrosis factor alpha production in CpG-stimulated animals and transferred resistance to arthritis from mice treated with suppressive ODNs., Conclusion: Systemic exposure to immunostimulatory and immunosuppressive DNA influences host susceptibility to local inflammatory challenge. Current findings raise the possibility that suppressive ODNs may be useful in the prevention/treatment of proinflammatory diseases.
- Published
- 2003
- Full Text
- View/download PDF
43. Effect of suppressive DNA on CpG-induced immune activation.
- Author
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Yamada H, Gursel I, Takeshita F, Conover J, Ishii KJ, Gursel M, Takeshita S, and Klinman DM
- Subjects
- Adjuvants, Immunologic metabolism, Animals, Female, Flow Cytometry, Immunosuppressive Agents metabolism, Interferon-gamma biosynthesis, Interleukin-12 biosynthesis, Interleukin-6 biosynthesis, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Oligodeoxyribonucleotides metabolism, Spleen cytology, Spleen drug effects, Spleen immunology, Spleen metabolism, Suppressor Factors, Immunologic biosynthesis, Adjuvants, Immunologic pharmacology, CpG Islands immunology, DNA pharmacology, Immunosuppressive Agents pharmacology, Lymphocyte Activation drug effects, Oligodeoxyribonucleotides pharmacology
- Abstract
Bacterial DNA and synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs stimulate a strong innate immune response. This stimulation can be abrogated by either removing the CpG DNA or adding inhibitory/suppressive motifs. Suppression is dominant over stimulation and is specific for CpG-induced immune responses (having no effect on LPS- or Con A-induced activation). Individual cells noncompetitively internalize both stimulatory and suppressive ODN. Studies using ODN composed of both stimulatory and suppressive motifs indicate that sequence recognition proceeds in a 5'-->3' direction, and that a 5' motif can block recognition of immediately 3' sequences. These findings contribute to our understanding of the immunomodulatory activity of DNA-based products and the rules that govern immune recognition of stimulatory and suppressive motifs.
- Published
- 2002
- Full Text
- View/download PDF
44. Purified malaria pigment (hemozoin) enhances dendritic cell maturation and modulates the isotype of antibodies induced by a DNA vaccine.
- Author
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Coban C, Ishii KJ, Sullivan DJ, and Kumar N
- Subjects
- Animals, Antigens, Protozoan genetics, Cell Differentiation, Cells, Cultured, Dendritic Cells cytology, Dendritic Cells immunology, Female, Hemeproteins isolation & purification, Humans, Interleukin-12 biosynthesis, Malaria immunology, Malaria prevention & control, Mice, Mice, Inbred BALB C, Monocytes cytology, Monocytes drug effects, Monocytes immunology, Pigments, Biological, Protozoan Proteins genetics, Adjuvants, Immunologic, Antibodies, Protozoan biosynthesis, Antigens, Protozoan immunology, Dendritic Cells drug effects, Hemeproteins pharmacology, Immunoglobulin Isotypes biosynthesis, Malaria Vaccines immunology, Protozoan Proteins immunology, Vaccines, DNA immunology
- Abstract
Hemozoin (malaria pigment) has been implicated in the modulation of immune responses during malaria infection. This study was designed to evaluate the effect of purified hemozoin on the in vitro activation of myeloid dendritic cells. Our study also revealed that in addition to enhancing the maturation of dendritic cells, hemozoin also greatly promotes immunoglobulin G2a antibody responses when coadministered with a DNA vaccine plasmid encoding Pfs25, a Plasmodium falciparum transmission-blocking antigen.
- Published
- 2002
- Full Text
- View/download PDF
45. Differential and competitive activation of human immune cells by distinct classes of CpG oligodeoxynucleotide.
- Author
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Gürsel M, Verthelyi D, Gürsel I, Ishii KJ, and Klinman DM
- Subjects
- B-Lymphocytes drug effects, B-Lymphocytes immunology, Cells, Cultured, Endocytosis, Humans, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Lymphocyte Activation, Monocytes drug effects, Monocytes immunology, Oligodeoxyribonucleotides classification, Oligodeoxyribonucleotides metabolism, Adjuvants, Immunologic pharmacology, Leukocytes, Mononuclear drug effects, Oligodeoxyribonucleotides pharmacology
- Abstract
Synthetic oligodeoxynucleotides (ODN) expressing "CpG motifs" show promise as immune adjuvants, antiallergens, anticancer, and immunoprotective agents. Two structurally distinct classes of CpG ODN have been identified that stimulate human PBMC. This work establishes that both types of ODN bind to and are internalized by the same individual B cells, NK cells, and monocytes. However, the intracellular localization of "D" and "K" ODN differs, as does their functional activity: "K" type ODN trigger monocytes and B cells to proliferate and secrete IL-6 and IgM, whereas "D" type ODN induce NK cells to produce IFN-gamma and monocytes to differentiate into CD83(+)/CD86(+) dendritic cells. In monocytes, these two types of ODN (which differ in backbone composition and CpG motif) cross-inhibit one another's activity. Thus, different types of CpG ODN have distinct and in some cases incompatible effects on the same cells, a finding with important implications for the therapeutic use of these agents.
- Published
- 2002
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