Intranasal Delivery of Influenza rNP Adjuvanted with c-di-AMP Induces Strong Humoral and Cellular Immune Responses and Provides Protection against Virus Challenge

Sánchez, María Victoria; Ebensen, Thomas; Schulze, Kai; Cargnelutti, Diego Esteban; Błażejewska, Paulina; Scodeller, Eduardo A.; Guzmán, Carlos A.

doi:10.1371/journal.pone.0104824

Cited by 45 publications

(43 citation statements)

References 65 publications

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“…Surprisingly, none of the tested formulations following TF immunization promoted the elicitation of IgG2c antibodies (Fig.5C). This is in contrast to our previous study where mice were immunized via TF route using chitosan conjugated PLGA NPs, which stimulated production of IgG2c antibodies [13], as well as previous vaccination studies in which c-di-nucleotides were used as adjuvants for soluble antigens ( [15,[17][18][19][20]). Results are expressed as the last dilution (end point dilution, e.p.d.)…”

Section: Adjuvanted Imsg Nps Stimulate Efficient Humoral Immune Respocontrasting

confidence: 85%

“…This adjuvant belongs to a new group of natural compounds, the cyclic di-nucleotides, which exhibit strong immune stimulating properties [15,17,19,20]. The c-di-AMP enhances dendritic cells (DC) activation, resulting in increase of both antigen-specific humoral and cellular immune responses, which confer protection against infections [15,17,18]. STING (stimulator of IFN genes) was identified as an innate sensor of cyclic di-nucleotides.…”

Section: Discussionmentioning

confidence: 99%

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Inverse micellar sugar glass (IMSG) nanoparticles for transfollicular vaccination

Mittal

Schulze

Ebensen

et al. 2015

Journal of Controlled Release

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Transfollicular antigen delivery through the intact skin is an interesting new avenue for needle-free vaccination. The aim of this work was to evaluate the potential of surfactant based inverse micellar sugar glass nanoparticles (IMSG NPs) as a delivery system for such purpose. To this end, we evaluated the strength and type of immune response elicited after administration of IMSG NPs containing the model antigen ovalbumin (OVA) by intranasal, transfollicular or intradermal route. Furthermore, we explored the possibility of improving the immune response elicited by co-encapsulating the adjuvant bis-(3',5')-cyclic dimeric adenosine monophosphate (c-di-AMP) and OVA within one particulate carrier system. The study showed enhanced stability and encapsulation efficacy of the antigen when encapsulated in IMSG NPs in comparison to polylactic-co-glycolic acid (PLGA) and chitosan-PLGA NPs. Moreover, by transfollicular delivery, IMSG NPs showed enhanced follicular uptake in comparison to OVA solution or OVA-loaded chitosan-PLGA NPs. While the immune response stimulated after intranasal administration was negligible, significant humoral and cellular responses were observed after immunization via transfollicular and intradermal route. This holds particularly true when OVA and c-di-AMP were co-encapsulated in IMSG NPs, as compared to OVA±c-di-AMP solution or OVA-loaded IMSG NPs without adjuvantation. The results of this study underscore not only the potential of transfollicular vaccination, but also the need for optimized nanocarriers and adjuvants.

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Section: Adjuvanted Imsg Nps Stimulate Efficient Humoral Immune Respocontrasting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Inverse micellar sugar glass (IMSG) nanoparticles for transfollicular vaccination

Mittal

Schulze

Ebensen

et al. 2015

Journal of Controlled Release

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“…For example, STING ligands of bacterial origin, including 3′3′-cGAMP, c-di-AMP, and c-di-GMP, effectively elicited mucosal and systemic immune responses following intranasal administration [33–35]. We now show that targeting STING with 3′3′-cGAMP is an effective strategy for enhancing the magnitude of immune responses induced by sublingual vaccines.…”

Section: Discussionmentioning

confidence: 80%

Sublingual targeting of STING with 3′3′-cGAMP promotes systemic and mucosal immunity against anthrax toxins

Martin

Jee

Kim

et al. 2017

Vaccine

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Anthrax is caused by Bacillus anthracis, a zoonotic bacterial pathogen affecting humans and livestock worldwide. The current human anthrax vaccine, anthrax vaccine adsorbed (AVA), is an injected vaccine with a cumbersome administration schedule and fails to promote mucosal immunity. Bacterial enterotoxins, which stimulate production of the cyclic nucleotide cAMP are effective experimental mucosal vaccine adjuvants, but their inherent toxicity has precluded their use in humans. We investigated whether cyclic dinucleotides that target Stimulator of Interferon Gamma Genes (STING) in mammalian cells could represent an alternative to bacterial enterotoxins as adjuvant for sublingual immunization and promotion of mucosal immunity and secretory IgA responses in addition to systemic immunity. We found that sublingual immunization of mice with Bacillus anthracis protective antigen (PA) and the STING ligand 3′3′-cGAMP promotes PA-specific serum IgG Ab responses of the same magnitude as those induced after immunization with PA and the experimental adjuvants cholera toxin (CT). Interestingly, this STING ligand also promoted serum anti-PA IgA and IgA-producing cells in the bone marrow. Furthermore, the saliva of mice immunized with the STING ligand exhibited similar levels of PA-specific IgA Abs as groups immunized with CT as adjuvant. The adjuvant activity of 3′3′-cGAMP was associated with mixed Th1, Th2, and Th17 responses. This STING ligand also induced rapid IFN-β and IL-10 responses in sublingual tissues and cervical lymph nodes, and TGF-β responses in the cervical lymph nodes, which could contribute to promoting IgA responses after sublingual immunization.

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“…Cyclic di-nucleotides that bind Stimulator of Interferon Gamma Genes (STING) were recently shown to be potential alternatives to cAMP-inducing bacterial toxins and derivatives as vaccine adjuvants. For example, STING ligands of bacterial origin, including 3′3′-cGAMP, c-di-AMP, and c-di-GMP, have been shown to effectively elicit mucosal and systemic immune responses following intranasal administration (64–66). More recently, targeting STING with 3′3′-cGAMP was found to be an effective strategy for enhancing the magnitude of immune responses and promoting IgA by sublingual immunization (67).…”

Section: Vaccine Adjuvants and Delivery Systems For Induction Of Mmentioning

confidence: 99%

Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems

Boyaka

2017

The Journal of Immunology

185

165

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Mucosal IgA or secretory IgA (SIgA) are structurally equipped to resist chemical degradation in the harsh environment of mucosal surfaces and the enzymes of host or microbial origin. Production of SIgA is finely regulated and distinct T-independent and T-dependent mechanisms orchestrate immunoglobulin heavy chain α class switching and SIgA responses against commensal and pathogenic microbes. Most infectious pathogens enter the host via mucosal surfaces. To provide a first line of protection at these entry ports, vaccines are being developed to induce pathogen-specific SIgA in addition to systemic immunity achieved by injected vaccines. Mucosal or epicutaneous delivery of vaccines helps target the inductive sites for IgA responses. The efficacy of such vaccines relies on the identification/engineering of vaccine adjuvants capable of supporting the development of SIgA alongside systemic immunity and delivery systems that improve vaccine delivery to the targeted anatomic sites and immune cells.

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Intranasal Delivery of Influenza rNP Adjuvanted with c-di-AMP Induces Strong Humoral and Cellular Immune Responses and Provides Protection against Virus Challenge

Cited by 45 publications

References 65 publications

Inverse micellar sugar glass (IMSG) nanoparticles for transfollicular vaccination

Inverse micellar sugar glass (IMSG) nanoparticles for transfollicular vaccination

Sublingual targeting of STING with 3′3′-cGAMP promotes systemic and mucosal immunity against anthrax toxins

Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems

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