The Experts below are selected from a list of 6132 Experts worldwide ranked by ideXlab platform
Hiroshi Kiyono - One of the best experts on this subject based on the ideXlab platform.
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Chemically Synthesized Alcaligenes Lipid A Shows a Potent and Safe Nasal Vaccine Adjuvant Activity for the Induction of Streptococcus pneumoniae-Specific IgA and Th17 Mediated Protective Immunity
Microorganisms, 2020Co-Authors: Ken Yoshii, Hiroshi Kiyono, Hidehiko Suzuki, Takahiro Nagatake, Huangwenxian Lan, Koji Hosomi, Atsushi Shimoyama, Yunru Wang, Haruki Yamaura, Koichi FukaseAbstract:Effective and safe Vaccine adjuvants are needed to appropriately augment mucosal Vaccine effects. Our previous study demonstrated that lipopolysaccharide (LPS) from Peyer's patch resident Alcaligenes stimulated dendritic cells to promote the production of mucosal immunity-enhancing cytokines (e.g., IL-6 and BAFF), thus enhancing antigen-specific immune responses (including IgA production and Th17 responses) without excessive inflammation. Here, we chemically synthesized Alcaligenes lipid A, the biologically active part of LPS, and examined its efficacy as a Nasal Vaccine adjuvant for the induction of protectively immunity against Streptococcus pneumoniae infection. Mice were Nasally immunized with pneumococcal surface protein A (PspA) as a Vaccine antigen for S. pneumoniae, together with Alcaligenes lipid A. Alcaligenes lipid A supported the generation of high levels of PspA-specific IgA and IgG responses through the augmentation of germinal center formation in the nasopharynx-associated lymphoid tissue and cervical lymph nodes (CLNs). Moreover, Alcaligenes lipid A promoted PspA-specific CD4+ Th17 responses in the CLNs and spleen. Furthermore, neutrophils were recruited to infection sites upon Nasal infection and synchronized with the antigen-specific T and B cell responses, resulting in the protection against S. pneumoniae infection. Taken together, Alcaligenes lipid A could be applied to the prospective adjuvant to enhance Nasal Vaccine efficacy by means of augmenting both the innate and acquired arms of mucosal immunity against respiratory bacterial infection.
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Cationic pullulan nanogel as a safe and effective Nasal Vaccine delivery system for respiratory infectious diseases.
Human vaccines & immunotherapeutics, 2018Co-Authors: Rika Nakahashi-ouchida, Yoshikazu Yuki, Hiroshi KiyonoAbstract:The mucosal surfaces of the respiratory and gastrointestinal tracts are continuously exposed to countless beneficial and pathologic antigens. These mucosal surfaces are thus equipped with an immune system that is unique from those elsewhere in the body; this unique system provides the first line of immune surveillance and defense against pathogen invasion. The sophisticated immune induction machinery in the aero-digestive tract involves mucosa-associated lymphoid tissues, including nasopharyngeal- and gut-associated lymphoid tissues, for the generation of antigen-specific humoral and cellular immune responses. Consequently, Nasal or oral immunization with an appropriate Vaccine delivery vehicle prompts the induction of protective immunity in both the mucosal and systemic compartments, leading to a double layer of protection against pathogens. To harness the benefits of mucosal Vaccines, various mucosal antigen delivery vehicles are under development, and a cationic cholesteryl-group-bearing pullulan nanogel (cCHP nanogel) has emerged as a potent Nasal Vaccine delivery system for the induction of protective immunity against respiratory infections.
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Nasal vaccination with pneumococcal surface protein A in combination with cationic liposomes consisting of DOTAP and DC-chol confers antigen-mediated protective immunity against Streptococcus pneumoniae infections in mice.
International immunopharmacology, 2018Co-Authors: Rui Tada, Hiroshi Kiyono, Hidehiko Suzuki, Jun Kunisawa, Saeko Takahashi, Yoichi Negishi, Yukihiko AramakiAbstract:Infectious diseases are the second leading cause of death worldwide, suggesting that there is still a need for the development of new and improved strategies for combating pathogens effectively. Streptococcus pneumoniae is the most virulent bacteria causing pneumonia with high mortality, especially in children and the elderly. Because of the emergence of antibiotic resistance in S. pneumoniae, employing a serotype-independent mucosal Vaccine would be the best approach to prevent and treat the diseases caused by S. pneumoniae. In this study, we have developed a pneumococcal Nasal Vaccine, consisting of pneumococcal surface protein A (PspA) and cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and cholesteryl 3β-N-(dimethylaminoethyl)-carbamate (DC-chol) (DOTAP/DC-chol liposome). The efficiency of this cationic liposome-based PspA Nasal Vaccine was examined in a murine model of S. pneumoniae infection. IntraNasal vaccination with PspA and DOTAP/DC-chol liposomes conferred protective immunity against lethal inhalation of S. pneumoniae, improving the survival rate of infected mice. Moreover, intraNasal immunization with PspA and DOTAP/DC-chol liposomes not only induced the production of PspA-specific IgA and IgG by both mucosal and systemic compartments but also elicited PspA-specific Th17 responses, which play a pivotal role in controlling S. pneumoniae infection by host innate immune response. We further demonstrated that DOTAP/DC-chol liposomes enhanced PspA uptake by Nasal dendritic cells (DCs), which might be a mechanism for the induction of protective immune responses to S. pneumoniae infection. These results show that DOTAP/DC-chol liposome would be an efficient mucosal Vaccine system for a serotype-independent universal Nasal Vaccine against pneumococcal infection.
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Impaired airway mucociliary function reduces antigen-specific IgA immune response to immunization with a claudin-4-targeting Nasal Vaccine in mice.
Scientific reports, 2018Co-Authors: Hidehiko Suzuki, Hiroshi Kiyono, Takahiro Nagatake, Ayaka Nasu, Huangwenxian Lan, Koji Ikegami, Mitsutoshi Setou, Yoko Hamazaki, Kiyohito Yagi, Masuo KondohAbstract:Vaccine delivery is an essential element for the development of mucosal Vaccine, but it remains to be investigated how physical barriers such as mucus and cilia affect Vaccine delivery efficacy. Previously, we reported that C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) targeted claudin-4, which is expressed by the epithelium associated with nasopharynx-associated lymphoid tissue (NALT), and could be effective as a Nasal Vaccine delivery. Mice lacking tubulin tyrosine ligase-like family, member 1 (Ttll1-KO mice) showed mucus accumulation in Nasal cavity due to the impaired motility of respiratory cilia. Ttll1-KO mice Nasally immunized with C-CPE fused to pneumococcal surface protein A (PspA-C-CPE) showed reduced PspA-specific Nasal IgA responses, impaired germinal center formation, and decreased germinal center B-cells and follicular helper T cells in the NALT. Although there was no change in the expression of claudin-4 in the NALT epithelium in Ttll1-KO mice, the epithelium was covered by a dense mucus that prevented the binding of PspA-C-CPE to NALT. However, administration of expectorant N-acetylcysteine removed the mucus and rescued the PspA-specific Nasal IgA response. These results show that the accumulation of mucus caused by impaired respiratory cilia function is an interfering factor in the C-CPE-based claudin-4-targeting Nasal Vaccine.
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Development of a nanogel-based Nasal Vaccine as a novel antigen delivery system
Expert review of vaccines, 2017Co-Authors: Rika Nakahashi-ouchida, Yoshikazu Yuki, Hiroshi KiyonoAbstract:ABSTRACTIntroduction: Nasal vaccination is one of the most effective immunization methods because it can induce effective antigen-specific immune responses not only at the mucosal site of administration but also at distant mucosal surfaces, as well as in the systemic compartment. Based on this advantage, many Nasal Vaccines are being developed and some have been licensed and marketed for clinical use. However, some have been withdrawn because of unacceptable adverse events such as inactivated influenza Vaccine administrated with a heat-labile enterotoxin of Escherichia coli as an adjuvant. Thus, it is important to consider both the efficacy and safety of Nasal Vaccines.Areas covered: This review describes the benefits of cholesteryl group–bearing pullulan (CHP) nanogels for Nasal Vaccine delivery and Vaccine development identified on Pubmed database with the term ‘Nanogel-based Nasal Vaccine’.Expert commentary: CHP nanogels have been developed as novel drug delivery system, and a cationic CHP nanogels hav...
Yoshikazu Yuki - One of the best experts on this subject based on the ideXlab platform.
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Cationic pullulan nanogel as a safe and effective Nasal Vaccine delivery system for respiratory infectious diseases.
Human vaccines & immunotherapeutics, 2018Co-Authors: Rika Nakahashi-ouchida, Yoshikazu Yuki, Hiroshi KiyonoAbstract:The mucosal surfaces of the respiratory and gastrointestinal tracts are continuously exposed to countless beneficial and pathologic antigens. These mucosal surfaces are thus equipped with an immune system that is unique from those elsewhere in the body; this unique system provides the first line of immune surveillance and defense against pathogen invasion. The sophisticated immune induction machinery in the aero-digestive tract involves mucosa-associated lymphoid tissues, including nasopharyngeal- and gut-associated lymphoid tissues, for the generation of antigen-specific humoral and cellular immune responses. Consequently, Nasal or oral immunization with an appropriate Vaccine delivery vehicle prompts the induction of protective immunity in both the mucosal and systemic compartments, leading to a double layer of protection against pathogens. To harness the benefits of mucosal Vaccines, various mucosal antigen delivery vehicles are under development, and a cationic cholesteryl-group-bearing pullulan nanogel (cCHP nanogel) has emerged as a potent Nasal Vaccine delivery system for the induction of protective immunity against respiratory infections.
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Development of a nanogel-based Nasal Vaccine as a novel antigen delivery system
Expert review of vaccines, 2017Co-Authors: Rika Nakahashi-ouchida, Yoshikazu Yuki, Hiroshi KiyonoAbstract:ABSTRACTIntroduction: Nasal vaccination is one of the most effective immunization methods because it can induce effective antigen-specific immune responses not only at the mucosal site of administration but also at distant mucosal surfaces, as well as in the systemic compartment. Based on this advantage, many Nasal Vaccines are being developed and some have been licensed and marketed for clinical use. However, some have been withdrawn because of unacceptable adverse events such as inactivated influenza Vaccine administrated with a heat-labile enterotoxin of Escherichia coli as an adjuvant. Thus, it is important to consider both the efficacy and safety of Nasal Vaccines.Areas covered: This review describes the benefits of cholesteryl group–bearing pullulan (CHP) nanogels for Nasal Vaccine delivery and Vaccine development identified on Pubmed database with the term ‘Nanogel-based Nasal Vaccine’.Expert commentary: CHP nanogels have been developed as novel drug delivery system, and a cationic CHP nanogels hav...
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Nanogel-based Nasal ghrelin Vaccine prevents obesity
Mucosal Immunology, 2017Co-Authors: Tatsuhiko Azegami, Mio Mejima, Kumiko Ishige, Shin-ichi Sawada, Kazunari Akiyoshi, Yoshikazu Yuki, Hiroshi Itoh, Hiroshi KiyonoAbstract:Obesity is associated with multiple comorbidities such as cardiovascular diseases and has a huge economic impact on the health-care system. However, the treatment of obesity remains insufficient in terms of efficacy, tolerability, and safety. Here we created a Nasal Vaccine against obesity for the first time. To avoid the injectable administration-caused pain and skin-related adverse event, we focused on the intraNasal route of antigen delivery. We developed a Vaccine antigen (ghrelin–PspA (pneumococcal surface protein A)), which is a recombinant fusion protein incorporating ghrelin, a hormone that stimulates food intake and decreases energy expenditure, and PspA, a candidate of pneumococcal Vaccine as a carrier protein. Ghrelin–PspA antigen was mixed with cyclic di-GMP adjuvant to enhance the immunogenicity and incorporated within a nanometer-sized hydrogel for the effective antigen delivery. IntraNasal immunization with ghrelin–PspA Vaccine elicited serum immunoglobulin G antibodies against ghrelin and attenuated body weight gain in diet-induced obesity mice. This obesity-attenuating effect was caused by a decrease in fat accumulation and an increase in energy expenditure that was partially due to an increase in the expression of mitochondrial uncoupling protein 1 in brown adipose tissue. The development of this Nasal Vaccine provides a new strategy for the prevention and treatment of obesity.
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Nanogel-based pneumococcal surface protein A Nasal Vaccine induces microRNA-associated Th17 cell responses with neutralizing antibodies against Streptococcus pneumoniae in macaques
Mucosal immunology, 2015Co-Authors: Yoshiko Fukuyama, Norihiro Harada, Yuko Katakai, Mio Mejima, Shiho Kurokawa, Yoshikazu Yuki, Haruko Takahashi, Shigeo Takeda, Sunyi Joo, Shin-ichi SawadaAbstract:We previously established a nanosized Nasal Vaccine delivery system by using a cationic cholesteryl group-bearing pullulan nanogel (cCHP nanogel), which is a universal protein-based antigen-delivery vehicle for adjuvant-free Nasal vaccination. In the present study, we examined the central nervous system safety and efficacy of Nasal vaccination with our developed cCHP nanogel containing pneumococcal surface protein A (PspA-nanogel) against pneumococcal infection in nonhuman primates. When [18F]-labeled PspA-nanogel was Nasally administered to a rhesus macaque (Macaca mulatta), longer-term retention of PspA was noted in the Nasal cavity when compared with administration of PspA alone. Of importance, no deposition of [18F]-PspA was seen in the olfactory bulbs or brain. Nasal PspA-nanogel vaccination effectively induced PspA-specific serum IgG with protective activity and mucosal secretory IgA (SIgA) Ab responses in cynomolgus macaques (Macaca fascicularis). Nasal PspA-nanogel-induced immune responses were mediated through T-helper (Th) 2 and Th17 cytokine responses concomitantly with marked increases in the levels of miR-181a and miR-326 in the serum and respiratory tract tissues, respectively, of the macaques. These results demonstrate that Nasal PspA-nanogel vaccination is a safe and effective strategy for the development of a Nasal Vaccine for the prevention of pneumonia in humans.
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Nanogel-based PspA Nasal Vaccine induces microRNA-associated protective immunity in nonhuman primates (MUC4P.834)
Journal of Immunology, 2014Co-Authors: Yoshiko Fukuyama, Yuko Katakai, Shin-ichi Sawada, Kazunari Akiyoshi, Yoshikazu Yuki, Haruko Takahashi, Sunyi Joo, Eun Jeong Park, Hiroshi KiyonoAbstract:We previously demonstrated a cationic type of cholesteryl group-bearing pullulan based nanogel containing pneumococcal surface protein A (PspA-nanogel) induced both protective Th2-mediated Ag-specific systemic and mucosal antibody (Ab) responses and Th17 cell-mediated immunity. In this study, we examined whether PspA-nanogel Nasal Vaccine could induce PspA-specific protective immunity and cytokines-related miRNA expression in nonhuman primates. When cynomolgus macaques were Nasally immunized with 25 μg of PspA-nanogel/dose, increased levels of Th2 cell dependent PspA-specific serum and broncho alveolar lavage fluid (BALF) IgG, and Nasal wash (NW) secretory IgA (SIgA) Ab responses with elevated Th17 cell immunity were seen when compared with control macaques Nasally immunized with 25 μg of PspA alone or PBS. MicroRNA (miRNA) analysis of serum and Nasal tissues from these PspA-nanogel immunized macaques revealed specific elevation of miR-181a and miR-326 which have been shown to corresponding to Th2 and Th17 responses, respectively. These results suggest that these two miRNAs are also associated with non-human primate Th2 and Th17 cell responses after Nasal vaccination with PspA-nanogel Vaccine which accounted for the induction of protective immunity against pneumonia.
Paola Neri - One of the best experts on this subject based on the ideXlab platform.
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a Nasal Vaccine comprising b subunit derivative of shiga toxin 2 for cross protection against shiga toxin types 1 and 2
Vaccine, 2008Co-Authors: Takao Tsuji, Takeshi Shimizu, Keiko Sasaki, Kentaro Tsukamoto, Hideyuki Arimitsu, Sadayuki Ochi, Koki Taniguchi, Toshiyasu Shimizu, Masatoshi Noda, Paola NeriAbstract:Enterohemorrhagic Escherichia coli (EHEC) produces Stx1 and Stx2 causing severe diseases. Their B-subunits (StxBs) exhibit low immunogenicity and the anti-StxB antibodies neutralizing both Stxs has not been prepared yet. By intraNasal vaccination with His-tagged-StxB (Stx1B-His or Stx2B-His) plus a mutant heat-labile enterotoxin (mLT) in mice, their serum and lung fluid reacted with appropriate StxB. Mice vaccinated with Stx2B-His plus mLT had antibodies reacting Stx1B and showed the resistance to toxemia of Stx1 and Stx2. This is the first demonstration to get anti-Stx2B serum neutralizing both Stxs. These suggest that the Nasal vaccination with Stx2B-His and mLT is effective for preventing toxemias by EHEC.
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Protection of mice from Shiga toxin-2 toxemia by mucosal Vaccine of Shiga toxin 2B-His with Escherichia coli enterotoxin
Vaccine, 2007Co-Authors: Takao Tsuji, Takeshi Shimizu, Keiko Sasaki, Yoshiyasu Shimizu, Kentaro Tsukamoto, Hideyuki Arimitsu, Sadayuki Ochi, Satoshi Sugiyama, Koki Taniguchi, Paola NeriAbstract:Escherichia coli O157:H7 produces Stx1 and Stx2 causing severe diseases. Their B subunits (StxBs) are useful for a Vaccine but exhibit low immunogenicity, especially Stx2B. Nasal vaccination with StxBs plus cholera toxin induces only serum anti-Stx1B antibodies in mice. However, Nasal administration of a mutant of E. coli enterotoxin and His-tagged Stx2B induced serum antibodies neutralizing Stx2 in vitro or in vivo and mucosal IgA antibodies in lungs. As His-tagged Stx2B showed five or three polymers in gel filtration chromatography, His-tagged Stx2B forms smaller tertiary structure than the native one and is effective for preventing Stx2 toxemia as a Nasal Vaccine.
Herman F Staats - One of the best experts on this subject based on the ideXlab platform.
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development of a novel adjuvanted Nasal Vaccine c48 80 associated with chitosan nanoparticles as a path to enhance mucosal immunity
European Journal of Pharmaceutics and Biopharmaceutics, 2015Co-Authors: Dulce Bento, Herman F Staats, Teresa Goncalves, Olga BorgesAbstract:Abstract In a time in which mucosal Vaccines development has been delayed by the lack of safe and effective mucosal adjuvants, the combination of adjuvants has started to be explored as a strategy to obtain potent Vaccine formulations. This study describes a novel adjuvant combination as an effective approach for a Nasal Vaccine – the association of the mast cell activator compound 48/80 with chitosan based nanoparticles. It was hypothesized that mucoadhesive nanoparticles would promote the cellular uptake and prolong the antigen residence time on Nasal cavity. Simultaneously, mast cell activation would promote a local microenvironment favorable to the development of an immune response. To test this hypothesis, two different C48/80 loaded nanoparticles (NPs) were prepared: Chitosan-C48/80 NP (Chi-C48/80 NP) and Chitosan/Alginate-C48/80 NP (Chi/Alg-C48/80 NP). The potential as a Vaccine adjuvant of the two delivery systems was evaluated and directly compared. Both formulations had a mean size near 500 nm and a positive charge; however, Chi-C48/80 NP was a more effective adjuvant delivery system when compared with Chi/Alg-C48/80 NP or C48/80 alone. Chi-C48/80 NP activated mast cells at a greater extent, were better internalized by antigen presenting cells than Chi/Alg-C48/80 NP and successfully enhanced the Nasal residence time of a model antigen. Superiority of Chi-C48/80 NP as adjuvant was also observed in vivo. Therefore, Nasal immunization of mice with Bacillus anthracis protective antigen (PA) adsorbed on Chi-C48/80 NP elicited high levels of serum anti-PA neutralizing antibodies and a more balanced Th1/Th2 profile than C48/80 in solution or Chi/Alg-C48/80 NP. The incorporation of C48/80 within Chi NP also promoted a mucosal immunity greater than all the other adjuvanted groups tested, showing that the combination of a mast cell activator and chitosan NP could be a promising strategy for Nasal immunization.
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Development of a novel adjuvanted Nasal Vaccine: C48/80 associated with chitosan nanoparticles as a path to enhance mucosal immunity.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2015Co-Authors: Dulce Bento, Herman F Staats, Teresa Goncalves, Olga BorgesAbstract:Abstract In a time in which mucosal Vaccines development has been delayed by the lack of safe and effective mucosal adjuvants, the combination of adjuvants has started to be explored as a strategy to obtain potent Vaccine formulations. This study describes a novel adjuvant combination as an effective approach for a Nasal Vaccine – the association of the mast cell activator compound 48/80 with chitosan based nanoparticles. It was hypothesized that mucoadhesive nanoparticles would promote the cellular uptake and prolong the antigen residence time on Nasal cavity. Simultaneously, mast cell activation would promote a local microenvironment favorable to the development of an immune response. To test this hypothesis, two different C48/80 loaded nanoparticles (NPs) were prepared: Chitosan-C48/80 NP (Chi-C48/80 NP) and Chitosan/Alginate-C48/80 NP (Chi/Alg-C48/80 NP). The potential as a Vaccine adjuvant of the two delivery systems was evaluated and directly compared. Both formulations had a mean size near 500 nm and a positive charge; however, Chi-C48/80 NP was a more effective adjuvant delivery system when compared with Chi/Alg-C48/80 NP or C48/80 alone. Chi-C48/80 NP activated mast cells at a greater extent, were better internalized by antigen presenting cells than Chi/Alg-C48/80 NP and successfully enhanced the Nasal residence time of a model antigen. Superiority of Chi-C48/80 NP as adjuvant was also observed in vivo. Therefore, Nasal immunization of mice with Bacillus anthracis protective antigen (PA) adsorbed on Chi-C48/80 NP elicited high levels of serum anti-PA neutralizing antibodies and a more balanced Th1/Th2 profile than C48/80 in solution or Chi/Alg-C48/80 NP. The incorporation of C48/80 within Chi NP also promoted a mucosal immunity greater than all the other adjuvanted groups tested, showing that the combination of a mast cell activator and chitosan NP could be a promising strategy for Nasal immunization.
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a comparison of non toxin Vaccine adjuvants for their ability to enhance the immunogenicity of Nasally administered anthrax recombinant protective antigen
Vaccine, 2013Co-Authors: William M Gwinn, Brandi T Johnson, Shaun M Kirwan, Ashley E Sobel, Michael D Gunn, Soman N. Abraham, Herman F StaatsAbstract:Abstract Development of Nasal immunization for human use is hindered by the lack of acceptable adjuvants. Although CT is an effective adjuvant, its toxicity will likely prevent its use in Nasal Vaccines. This study compared non-toxin adjuvants to CT for their ability to induce protective antibody responses with Nasal immunization. C3H/HeN and C57BL/6 mice were immunized with rPA formulated with the following adjuvants: CT, IL-1α, LPS, CpG, Pam3CSK4, 3M-019, resiquimod/R848 or c48/80. Serum and Nasal wash cytokine concentrations were monitored 6 h post-vaccination as biomarkers for acute activation of the innate immune system. Not all of the adjuvants induced significant changes in innate serum or Nasal wash cytokines, but when changes were observed, the cytokine signatures were unique for each adjuvant. All adjuvants except Pam3CSK4 induced significantly increased anti-rPA serum IgG titers in both strains of mice, while only IL-1α, c48/80 and CpG enhanced mucosal anti-rPA IgA. Pam3CSK4 was the only adjuvant unable to enhance the induction of serum LeTx-neutralizing antibodies in C3H/HeN mice while c48/80 was the only adjuvant to induce increased serum LeTx-neutralizing antibodies in C57BL/6 mice. Only CT enhanced total serum IgE in C3H/HeN mice while IL-1α enhanced total serum IgE in C57BL/6 mice. The adjuvant influenced antigen-specific serum IgG subclass and T cell cytokine profiles, but these responses did not correlate with the induction of LeTx-neutralizing activity. Our results demonstrate the induction of diverse innate and adaptive immune responses by non-toxin Nasal Vaccine adjuvants that lead to protective humoral immunity comparable to CT and that these responses may be influenced by the host strain.
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Cytokines: The Future of IntraNasal Vaccine Adjuvants
Clinical & developmental immunology, 2011Co-Authors: Afton L. Thompson, Herman F StaatsAbstract:Due to its potential as an effective, needle-free route of immunization for use with subunit Vaccines, Nasal immunization continues to be evaluated as a route of immunization in both research and clinical studies. However, as with other vaccination routes, subunit Vaccines often require the addition of adjuvants to induce potent immune responses. Unfortunately, many commonly used experimental Vaccine adjuvants, such as cholera toxin and E. coli heat-labile toxin, are too toxic for use in humans. Because new adjuvants are needed, cytokines have been evaluated for their ability to provide effective adjuvant activity when delivered by the Nasal route in both animal models and in limited human studies. It is the purpose of this paper to discuss the potential of cytokines as Nasal Vaccine adjuvants.
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Novel dry powder preparations of whole inactivated influenza virus for Nasal vaccination
AAPS PharmSciTech, 2007Co-Authors: Robert J. Garmise, Herman F Staats, Anthony J. HickeyAbstract:The purpose of these studies was to enhance mucosal and systemic antibody production in response to increased local residence time of a whole inactivated influenza virus administered as a dry powder Nasal Vaccine formulation. Spray-freeze-drying (SFD) particles suitable for Nasal delivery were characterized for physico-chemical properties and stability. Mucoadhesive compounds (MA) were characterized for their effects on Nasal residence time of Vaccine powders in rats compared with published in vitro data and elicited immune responses. SFD particles (D_50=26.9µm) were spherical with a specific surface area of 1.25 m^2/g. Thermal analysis indicated SFD powders were amorphous and demonstrated improved stability with respect to liquid formulations under various storage conditions. In vitro physico-chemical studies and in vivo scintigraphic imaging experiments indicated sodium alginate (SA) and carboxymethylcellulose-high molecular weight (CMC-HMW) powder formulations most significantly increased residence time in Brown Norway rats. Intramuscular delivery provided equivalent serum antibody titers to intraNasal (IN) powder without MA, in the presence of CMC-HMW, SA, and hydroxypropyl methylcellulose (HPMC-HMW) after initial dosing and all formulations except IN powder with chitosan after boosting. IN liquid provided equivalent serum antibody titers to all IN powders after the initial vaccination and significantly greater serum antibody titers than IN powder with chitosan after boosting. Trends were consistent between residence time studies and immune response; however, no statistically significant differences between powder and liquid formulations were observed. It was concluded that enhanced serum and mucosal antibody responses were elicited by a dry powder Nasal Vaccine, specifically, administered in the presence of sodium alginate.
Jun Kunisawa - One of the best experts on this subject based on the ideXlab platform.
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Impaired mucociliary motility enhances antigen-specific Nasal IgA immune responses to a cholera toxin-based Nasal Vaccine
International immunology, 2020Co-Authors: Huangwenxian Lan, Hidehiko Suzuki, Takahiro Nagatake, Koji Ikegami, Mitsutoshi Setou, Koji Hosomi, Jun KunisawaAbstract:Nasal mucosal tissues are equipped with physical barriers, mucus and cilia, on their surface. The mucus layer captures inhaled materials, and the cilia remove the inhaled materials from the epithelial layer by asymmetrical beating. The effect of Nasal physical barriers on the Vaccine efficacy remains to be investigated. Tubulin tyrosine ligase-like family, member 1 (Ttll1) is an essential enzyme for appropriate movement of the cilia on respiratory epithelium, and its deficiency (Ttll1-KO) leads to mucus accumulation in the Nasal cavity. Here, when mice were intra-Nasally immunized with pneumococcal surface protein A (PspA, as Vaccine antigen) together with cholera toxin (CT, as mucosal adjuvant), Ttll1-KO mice showed higher levels of PspA-specific IgA in the Nasal wash and increased numbers of PspA-specific IgA-producing plasma cells in the Nasal passages when compared with Ttll1 hetero (He) mice. Mucus removal by N-acetylcysteine did not affect the enhanced immune responses in Ttll1-KO mice versus Ttll1-He mice. Immunohistological and flow cytometry analyses revealed that retention time of PspA in the Nasal cavity in Ttll1-KO mice was longer than that in Ttll1-He mice. Consistently, uptake of PspA by dendritic cells was higher in the nasopharynx-associated lymphoid tissue (NALT) of Ttll1-KO mice than that of Ttll1-He mice. These results indicate that the ciliary function of removing Vaccine antigen from the NALT epithelial layer is a critical determinant of the efficacy of Nasal Vaccine.
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Clostridium perfringens enterotoxin-based protein engineering for the Vaccine design and delivery system.
Vaccine, 2019Co-Authors: Huangwenxian Lan, Koji Hosomi, Jun KunisawaAbstract:Clostridium perfringens is a major cause of food poisoning worldwide, with its enterotoxin (CPE) being the major virulence factor. The C-terminus of CPE (C-CPE) is non-toxic and is the part of the toxin that binds to epithelial cells via the claudins in tight junctions; however, C-CPE has low antigenicity. To address this issue, we have used protein engineering technology to augment the antigenicity of C-CPE and have developed a C-CPE-based Vaccine against C. perfringens-mediated food poisoning. Moreover, C-CPE has properties that make it potentially useful for the development of Vaccines against other bacterial toxins that cause food poisoning. For example, we hypothesized that the ability of C-CPE to bind to claudins could be harnessed to deliver Vaccine antigens directly to mucosa-associated lymphoid tissues, and we successfully developed a Nasally administered C-CPE-based Vaccine delivery system that promotes antigen-specific mucosal and systemic immune responses. In addition, our group has revealed the roles that the Nasal mucus plays in lowering the efficacy of C-CPE-based Nasal Vaccines. Here, we review recent advances in the development of C-CPE-based Vaccines against the major bacterial toxins that cause food poisoning and discuss our C-CPE-based Nasal Vaccine delivery system.
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Nasal vaccination with pneumococcal surface protein A in combination with cationic liposomes consisting of DOTAP and DC-chol confers antigen-mediated protective immunity against Streptococcus pneumoniae infections in mice.
International immunopharmacology, 2018Co-Authors: Rui Tada, Hiroshi Kiyono, Hidehiko Suzuki, Jun Kunisawa, Saeko Takahashi, Yoichi Negishi, Yukihiko AramakiAbstract:Infectious diseases are the second leading cause of death worldwide, suggesting that there is still a need for the development of new and improved strategies for combating pathogens effectively. Streptococcus pneumoniae is the most virulent bacteria causing pneumonia with high mortality, especially in children and the elderly. Because of the emergence of antibiotic resistance in S. pneumoniae, employing a serotype-independent mucosal Vaccine would be the best approach to prevent and treat the diseases caused by S. pneumoniae. In this study, we have developed a pneumococcal Nasal Vaccine, consisting of pneumococcal surface protein A (PspA) and cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and cholesteryl 3β-N-(dimethylaminoethyl)-carbamate (DC-chol) (DOTAP/DC-chol liposome). The efficiency of this cationic liposome-based PspA Nasal Vaccine was examined in a murine model of S. pneumoniae infection. IntraNasal vaccination with PspA and DOTAP/DC-chol liposomes conferred protective immunity against lethal inhalation of S. pneumoniae, improving the survival rate of infected mice. Moreover, intraNasal immunization with PspA and DOTAP/DC-chol liposomes not only induced the production of PspA-specific IgA and IgG by both mucosal and systemic compartments but also elicited PspA-specific Th17 responses, which play a pivotal role in controlling S. pneumoniae infection by host innate immune response. We further demonstrated that DOTAP/DC-chol liposomes enhanced PspA uptake by Nasal dendritic cells (DCs), which might be a mechanism for the induction of protective immune responses to S. pneumoniae infection. These results show that DOTAP/DC-chol liposome would be an efficient mucosal Vaccine system for a serotype-independent universal Nasal Vaccine against pneumococcal infection.
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Attachment of class B CpG ODN onto DOTAP/DC-chol liposome in Nasal Vaccine formulations augments antigen-specific immune responses in mice
BMC research notes, 2017Co-Authors: Rui Tada, Hiroshi Kiyono, Jun Kunisawa, Shoko Muto, Tomoko Iwata, Akira Hidaka, Yukihiko AramakiAbstract:To overcome infectious diseases, the development of mucosal Vaccines would be an effective strategy, since mucosal surfaces are the entry site for most pathogens. In general, protein antigens show inherently poor immunogenicity when administered by the mucosal route. Therefore, co-administration of an appropriate mucosal adjuvant is required to exert immune responses toward pathogen-derived antigens effectively. However, the development of a safe and effective mucosal adjuvant system is still challenging. Although, recent studies reported that oligodeoxynucleotides (ODNs) containing immunostimulatory CpG motifs (CpG ODNs) act as potent mucosal adjuvants and are useful in the formulation of Nasal Vaccines, there are some disadvantages. For instance, the administration of phosphorothioate (PS)-modified CpG ODNs can induce adverse systemic effects, such as splenomegaly, in a dose-dependent manner. Therefore, a reduced dose of CpG ODN might be crucial when used as Vaccine adjuvant for clinical purposes. Therefore, we prepared a CpG ODN-loaded cationic liposome, and evaluated its mucosal adjuvant activity. We prepared a CpG ODN-loaded DOTAP/DC-chol liposome that was stable during our experiments, by mixing CpG ODNs and liposomes at an N/P ratio of 4. Further, we demonstrated that the attachment of class B CpG ODN to the DOTAP/DC-chol liposomes synergistically enhanced antigen-specific IgA production in the Nasal area than that induced by CpG ODN and DOTAP/DC-chol liposomes alone. The endpoint titers were more than tenfolds higher than that induced by either single CpG ODN or single DOTAP/DC-chol liposomes. Additionally, although serum IgG1 responses (indicated as a Th2 response) remained unchanged for DOTAP/DC-chol liposomes and CpG ODN-loaded DOTAP/DC-chol liposomes, the CpG ODN-loaded DOTAP/DC-chol liposomes synergistically induced the production of serum IgG2a (indicated as a Th1 response) than that by the individual liposomes. We conclude that the advantage of using DOTAP/DC-chol liposome harboring CpG ODN is it induces both antigen-specific mucosal IgA responses and balanced Th1/Th2 responses. Therefore, such a combination enables us to resolve the adverse effects of using CpG ODNs (as a mucosal adjuvant) by reducing the overall dose of CpG ODNs. Further, the biodegradable and essentially non-antigenic nature of the liposomes makes it superior than the other existing mucosal adjuvants.
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attachment of class b cpg odn onto dotap dc chol liposome in Nasal Vaccine formulations augments antigen specific immune responses in mice
BMC Research Notes, 2017Co-Authors: Rui Tada, Hiroshi Kiyono, Jun Kunisawa, Shoko Muto, Tomoko Iwata, Akira Hidaka, Yukihiko AramakiAbstract:To overcome infectious diseases, the development of mucosal Vaccines would be an effective strategy, since mucosal surfaces are the entry site for most pathogens. In general, protein antigens show inherently poor immunogenicity when administered by the mucosal route. Therefore, co-administration of an appropriate mucosal adjuvant is required to exert immune responses toward pathogen-derived antigens effectively. However, the development of a safe and effective mucosal adjuvant system is still challenging. Although, recent studies reported that oligodeoxynucleotides (ODNs) containing immunostimulatory CpG motifs (CpG ODNs) act as potent mucosal adjuvants and are useful in the formulation of Nasal Vaccines, there are some disadvantages. For instance, the administration of phosphorothioate (PS)-modified CpG ODNs can induce adverse systemic effects, such as splenomegaly, in a dose-dependent manner. Therefore, a reduced dose of CpG ODN might be crucial when used as Vaccine adjuvant for clinical purposes. Therefore, we prepared a CpG ODN-loaded cationic liposome, and evaluated its mucosal adjuvant activity. We prepared a CpG ODN-loaded DOTAP/DC-chol liposome that was stable during our experiments, by mixing CpG ODNs and liposomes at an N/P ratio of 4. Further, we demonstrated that the attachment of class B CpG ODN to the DOTAP/DC-chol liposomes synergistically enhanced antigen-specific IgA production in the Nasal area than that induced by CpG ODN and DOTAP/DC-chol liposomes alone. The endpoint titers were more than tenfolds higher than that induced by either single CpG ODN or single DOTAP/DC-chol liposomes. Additionally, although serum IgG1 responses (indicated as a Th2 response) remained unchanged for DOTAP/DC-chol liposomes and CpG ODN-loaded DOTAP/DC-chol liposomes, the CpG ODN-loaded DOTAP/DC-chol liposomes synergistically induced the production of serum IgG2a (indicated as a Th1 response) than that by the individual liposomes. We conclude that the advantage of using DOTAP/DC-chol liposome harboring CpG ODN is it induces both antigen-specific mucosal IgA responses and balanced Th1/Th2 responses. Therefore, such a combination enables us to resolve the adverse effects of using CpG ODNs (as a mucosal adjuvant) by reducing the overall dose of CpG ODNs. Further, the biodegradable and essentially non-antigenic nature of the liposomes makes it superior than the other existing mucosal adjuvants.
