scholarly journals The mucosal adjuvant cyclic di-GMP enhances antigen uptake and selectively activates pinocytosis-efficient cells in vivo

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Steven M Blaauboer ◽  
Samira Mansouri ◽  
Heidi R Tucker ◽  
Hatti L Wang ◽  
Vincent D Gabrielle ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Cyclic Gmp ◽  
Mucosal Vaccine ◽  
Vaccine Adjuvant ◽  
Vaccine Response ◽  
Antigen Uptake ◽  
Mucosal Adjuvant ◽  
Adjuvanted Vaccine

Effective mucosal adjuvants enhance the magnitude and quality of the vaccine response. Cyclic di-GMP (CDG) is a promising mucosal vaccine adjuvant. However, its in vivo mechanisms are unclear. Here, we showed, in mice, that CDG elicits stronger Ab and TH responses than the mammalian 2′3′-cyclic GMP-AMP (cGAMP), and generated better protection against Streptococcus pneumoniae infection than 2′3′-cGAMP adjuvanted vaccine. We identified two in vivo mechanisms of CDG. First, intranasally administered CDG greatly enhances Ag uptake, including pinocytosis and receptor-mediated endocytosis in vivo. The enhancement depends on MPYS (STING, MITA) expression in CD11C+ cells. Second, we found that CDG selectively activated pinocytosis-efficient-DCs, leading to TH polarizing cytokines IL-12p70, IFNγ, IL-5, IL-13, IL-23, and IL-6 production in vivo. Notably, CDG induces IFNλ, but not IFNβ, in vivo. Our study revealed previously unrecognized in vivo functions of MPYS and advanced our understanding of CDG as a mucosal vaccine adjuvant.

scholarly journals Essential Role of Host Double-Stranded DNA Released from Dying Cells by Cationic Liposomes for Mucosal Adjuvanticity

Vaccines ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 8
Author(s):  
Rui Tada ◽  
Akihiro Ohshima ◽  
Yuya Tanazawa ◽  
Akari Ohmi ◽  
Saeko Takahashi ◽  
...  
Keyword(s):  
Essential Role ◽  
Cationic Liposome ◽  
Cationic Liposomes ◽  
Mucosal Vaccine ◽  
Nasal Administration ◽  
Adjuvant Activity ◽  
Mucosal Adjuvant ◽  
Double Stranded Dna ◽  
Dying Cells

Infectious disease remains a substantial cause of death. To overcome this issue, mucosal vaccine systems are considered to be a promising strategy. Yet, none are approved for clinical use, except for live-attenuated mucosal vaccines, mainly owing to the lack of effective and safe systems to induce antigen-specific immune responses in the mucosal compartment. We have reported that intranasal vaccination of an antigenic protein, with cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium-propane and 3β-[N-(N′,N′-dimethylaminoethane)-carbamoyl], induced antigen-specific mucosal and systemic antibody responses in mice. However, precise molecular mechanism(s) underlying the mucosal adjuvant effects of cationic liposomes remain to be uncovered. Here, we show that a host double-stranded DNA (dsDNA), released at the site of cationic liposome injection, plays an essential role for the mucosal adjuvanticity of the cationic liposome. Namely, we found that nasal administration of the cationic liposomes induced localized cell death, at the site of injection, resulting in extracellular leakage of host dsDNA. Additionally, in vivo DNase I treatment markedly impaired OVA-specific mucosal and systemic antibody production exerted by cationic liposomes. Our report reveals that host dsDNA, released from local dying cells, acts as a damage-associated molecular pattern that mediates the mucosal adjuvant activity of cationic liposomes.

scholarly journals Cholesteryl Pullulan Encapsulated TNF-αNanoparticles Are an Effective Mucosal Vaccine Adjuvant against Influenza Virus

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Daiki Nagatomo ◽  
Madoka Taniai ◽  
Harumi Ariyasu ◽  
Mutsuko Taniguchi ◽  
Miho Aga ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Virus Infection ◽  
Repeated Administration ◽  
Mucosal Vaccine ◽  
Nasal Administration ◽  
Vaccine Adjuvant ◽  
Severe Toxicity ◽  
Lethal Challenge ◽  
Antigen Uptake ◽  
Humoral And Cellular Immunity

We encapsulated tumor necrosis factor-α(TNF-α), a major proinflammatory cytokine, into cholesteryl pullulan (CHP) to prepare TNF/CHP nanoparticles. In this report, we describe the immune-enhancing capability of the nanoparticles to act as a vaccine adjuvant. TNF/CHP nanoparticles showed excellent storage stability and enhanced host immune responses to external immunogens. The nanoparticles were effective via the nasal route of administration for inducing systemic IgG1as well as mucosal IgA. We applied the nanoparticles in a model experimental influenza virus infection to investigate their adjuvant ability. TNF/CHP nanoparticles combined with a conventional split vaccine protected mice via nasal administration against a lethal challenge of A/PR/8/34 (H1N1) influenza virus. Mechanistic studies showed that the nanoparticles enhanced antigen uptake by dendritic cells (DCs) and moderately induced the expression of inflammation-related genes in nasopharynx lymphoid tissue (NALT), leading to the activation of both B and T cells. Preliminary safety study revealed no severe toxicity to TNF/CHP nanoparticles. Slight-to-moderate influences in nasal mucosa were observed only in the repeated administration and they seemed to be reversible. Our data show that TNF/CHP nanoparticles effectively enhance both humoral and cellular immunity and could be a potential adjuvant for vaccines against infectious diseases, especially in the mucosa.

scholarly journals PMA Induces Vaccine Adjuvant Activity by the Modulation of TLR Signaling Pathway

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Dool-Ri Oh ◽  
Hu Won Kang ◽  
Jong-Ro Kim ◽  
Sunoh Kim ◽  
In-Kyu Park ◽  
...  
Keyword(s):  
Active Component ◽  
Mucosal Vaccine ◽  
Vaccine Adjuvant ◽  
Vaccine Adjuvants ◽  
Adjuvant Activity ◽  
Independent Manner ◽  
Etoh Extract ◽  
Croton Tiglium ◽  
Fractionation Column

Toll-like receptor (TLR) ligands are being developed for use as vaccine adjuvants and as immunomodulators because of their ability to stimulate innate and adaptive immune responses. Flagellin, a TLR5 ligand, was reported to show potent mucosal vaccine adjuvant activity. To identify ligands that potentiate the adjuvant activity of flagellin, we screened a plant library using HEK293T cells transiently cotransfected with phTLR5 and pNF-κB-SEAP plasmids. The 90% EtOH extract fromCroton tigliumshowed significant NF-κB transactivation in a TLR5-independent manner along with the increase of a flagellin activity. We have studied to characterize an active component fromCroton tigliumand to elucidate the action mechanisms. Phorbol 12-myristate 13-acetate (PMA) was isolated as an active component ofCroton tigliumby activity-guided fractionation, column chromatography, HPLC, NMR, and MS. PMA at a range of nM induced PKC-dependent NF-κB activation and IL-8 production in both TLR5− and TLR5+ assay systems. In in vivo mouse vaccination model, PMA induced antigen-specific IgG and IgA antibody responses and increased IL-12 production corresponding to T cell responses in spleen lymphocytes. These results suggest that PMA would serve as an efficacious mucosal vaccine adjuvant.

scholarly journals Vaccine Inoculation Route Modulates Early Immunity and Consequently Antigen-Specific Immune Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Pierre Rosenbaum ◽  
Nicolas Tchitchek ◽  
Candie Joly ◽  
André Rodriguez Pozo ◽  
Lev Stimmer ◽  
...  
Keyword(s):  
Immune Response ◽  
Adaptive Response ◽  
Neutralizing Antibodies ◽  
Route Of Administration ◽  
Public Healthcare ◽  
Vaccine Response ◽  
Major Interest ◽  
Subcutaneous Immunization

Vaccination is one of the most efficient public healthcare measures to fight infectious diseases. Nevertheless, the immune mechanisms induced in vivo by vaccination are still unclear. The route of administration, an important vaccination parameter, can substantially modify the quality of the response. How the route of administration affects the generation and profile of immune responses is of major interest. Here, we aimed to extensively characterize the profiles of the innate and adaptive response to vaccination induced after intradermal, subcutaneous, or intramuscular administration with a modified vaccinia virus Ankara model vaccine in non-human primates. The adaptive response following subcutaneous immunization was clearly different from that following intradermal or intramuscular immunization. The subcutaneous route induced a higher level of neutralizing antibodies than the intradermal and intramuscular vaccination routes. In contrast, polyfunctional CD8+ T-cell responses were preferentially induced after intradermal or intramuscular injection. We observed the same dichotomy when analyzing the early molecular and cellular immune events, highlighting the recruitment of cell populations, such as CD8+ T lymphocytes and myeloid-derived suppressive cells, and the activation of key immunomodulatory gene pathways. These results demonstrate that the quality of the vaccine response induced by an attenuated vaccine is shaped by early and subtle modifications of the innate immune response. In this immunization context, the route of administration must be tailored to the desired type of protective immune response. This will be achieved through systems vaccinology and mathematical modeling, which will be critical for predicting the efficacy of the vaccination route for personalized medicine.

scholarly journals Development of Safe and Non-Self-Immunogenic Mucosal Adjuvant by Recombinant Fusion of Cholera Toxin A1 Subunit with Protein Transduction Domain

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Byoung-Shik Shim ◽  
In Su Cheon ◽  
Eugene Lee ◽  
Sung-Moo Park ◽  
Youngjoo Choi ◽  
...  
Keyword(s):  
Cholera Toxin ◽  
Cytotoxic T Lymphocyte ◽  
Antibody Responses ◽  
Mucosal Vaccine ◽  
Protein Transduction ◽  
Protein Transduction Domain ◽  
Igg Antibody ◽  
Mucosal Adjuvant ◽  
Virus Challenge

Potential use of cholera toxin (CT) as a mucosal vaccine adjuvant has been documented in a variety of animal models. However, native CT is highly toxic to be used as a mucosal adjuvant in humans. Here, we demonstrate a new approach to generate a mucosal adjuvant by replacing the B subunit of CT with HIV-1 Tat protein transduction domain (PTD), which efficiently delivers fusion proteins into the cell cytoplasm by unspecific binding to cell surface. We compared the adjuvanticity and toxicity of Tat PTD-CTA1-Tat PTD (TCTA1T) with those of CT. Our results indicate that intranasal (i.n.) delivery of ovalbumin (OVA) with TCTA1T significantly augments the OVA-specific systemic and mucosal antibody responses to levels comparable to those seen with CT adjuvant. Moreover,in vivocytotoxic T lymphocyte activity elicited by TCTA1T was significantly higher than that elicited by a mutant TCTA1T (TmCTA1T) lacking ADP-ribosyltransferase function. In addition, coadministration of influenza M2 protein with TCTA1T conferred near complete protection against lethal influenza virus challenge. Importantly, TCTA1T, in contrast to CT, did not induce serum IgG antibody responses to itself and was shown to be nontoxic. These results suggest that TCTA1T may be a safe and effective adjuvant when given by mucosal routes.

CAF01 liposomes as a mucosal vaccine adjuvant: In vitro and in vivo investigations

2010 ◽  
Vol 390 (1) ◽  
pp. 19-24 ◽  
Author(s):  
Dennis Christensen ◽  
Camilla Foged ◽  
Ida Rosenkrands ◽  
Carina Vingsbo Lundberg ◽  
Peter Andersen ◽  
...  
Keyword(s):  
Mucosal Vaccine ◽  
Vaccine Adjuvant

scholarly journals Polymeric Caffeic Acid Acts as a Nasal Vaccine Formulation against Streptococcus pneumoniae Infections in Mice

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 585
Author(s):  
Rui Tada ◽  
Hidehiko Suzuki ◽  
Miki Ogasawara ◽  
Daisuke Yamanaka ◽  
Yoshiyuki Adachi ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Caffeic Acid ◽  
Pathogenic Bacteria ◽  
Protein A ◽  
Surface Protein ◽  
Mucosal Vaccine ◽  
Vaccine Formulation ◽  
Protective Effects ◽  
Mucosal Adjuvant ◽  
Nasal Vaccine

Infectious diseases are the second leading cause of death worldwide, highlighting the importance of the development of a novel and improved strategy for fighting pathogenic microbes. Streptococcus pneumoniae is a highly pathogenic bacteria that causes pneumonia with high mortality rates, especially in children and elderly individuals. To solve these issues, a mucosal vaccine system would be the best solution for the prevention and treatment of these diseases. We have recently reported that enzymatically polymerized caffeic acid (pCA) acts as a mucosal adjuvant when co-administered with antigenic proteins via the nasal route. Moreover, the sources of caffeic acid and horseradish peroxidase are ingredients found commonly in coffee beans and horseradish, respectively. In this study, we aimed to develop a pneumococcal nasal vaccine comprising pneumococcal surface protein A (PspA) and pCA as the mucosal adjuvant. Intranasal immunization with PspA and pCA induced the production of PspA-specific antibody responses in the mucosal and systemic compartments. Furthermore, the protective effects were tested in a murine model of S. pneumoniae infection. Intranasal vaccination conferred antigen-dependent protective immunity against a lethal infection of S. pneumoniae. In conclusion, pCA is useful as a serotype-independent universal nasal pneumococcal vaccine formulation.

scholarly journals 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

2020 ◽  
Vol 8 (8) ◽  
pp. 1102
Author(s):  
Ken Yoshii ◽  
Koji Hosomi ◽  
Atsushi Shimoyama ◽  
Yunru Wang ◽  
Haruki Yamaura ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mucosal Immunity ◽  
Lipid A ◽  
Biologically Active ◽  
Mucosal Vaccine ◽  
Vaccine Antigen ◽  
Vaccine Adjuvant ◽  
Vaccine Adjuvants ◽  
Cervical Lymph Nodes ◽  
Nasal Vaccine

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.

scholarly journals Author response: The mucosal adjuvant cyclic di-GMP enhances antigen uptake and selectively activates pinocytosis-efficient cells in vivo

2015 ◽  
Author(s):  
Steven M Blaauboer ◽  
Samira Mansouri ◽  
Heidi R Tucker ◽  
Hatti L Wang ◽  
Vincent D Gabrielle ◽  
...  
Keyword(s):  
Author Response ◽  
Antigen Uptake ◽  
Mucosal Adjuvant
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