Natural STING Agonist as an “Ideal” Adjuvant for Cutaneous Vaccination

Wang, Ji; Li, Peiyu; Wu, Minxian

doi:10.1016/j.jid.2016.05.105

Cited by 76 publications

(100 citation statements)

References 33 publications

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“…The unadjuvanted vaccine was not protective: only 22% of vaccinated animals survived the challenge. ID-delivered cGAMP was previously reported to induce a strong Th-1 response in adult mice via activation of the STING pathway (29,30). However, in our experiments all aged mice immunized ID with the vaccine supplemented with 5 µg cGAMP succumbed to infection upon challenge (Figures 1A,B).…”

Section: Results Cgamp and Quil-a As Individual Adjuvants In Aged Micementioning

confidence: 58%

“…Saponin was selected because in addition to enhancing membrane permeability for small molecules (51,52) it is an effective adjuvant that stimulates production of proinflammatory cytokines and promotes cellular immune response to protein antigens. Separate studies with cGAMP (30) or Quil-A-containing adjuvants (53) were each reported to stimulate Th1 responses to influenza vaccines in adult mice. The rapid increase in the IgG2a antibody isotype in cGAMP/Quil-A adjuvanted groups that we observed was also consistent with a Th-1 bias of adjuvant action mode (54).…”

Section: Discussionmentioning

confidence: 99%

“…The signaling cascade triggered by activation of STING (24,25) leads to production of IFN-β and other cytokines important for innate immunity (26)(27)(28) without causing adverse reactions attributed to Toll-like receptor agonists or Alum (22). However, rather high amounts of cGAMP or other cyclic di-nucleotides have been required for adjuvant activity (22,29,30). We hypothesized that improving the availability of the cGAMP ligand to the STING receptor in the interior of the immunocompetent cells of aged subjects will increase its adjuvant efficiency.…”

Section: Introductionmentioning

confidence: 99%

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Combination of STING Pathway Agonist With Saponin Is an Effective Adjuvant in Immunosenescent Mice

2019

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There is an urgent need to improve protective responses to influenza vaccination in the elderly population, which is at especially high risk for adverse outcomes from influenza infection. Currently available inactivated vaccines provide limited protection, even when a 4-fold higher dose of the vaccine is administered. Adjuvants are often added to vaccines to boost protective efficacy. Here we describe a novel combination of an activator of the STING pathway, 2 ′ ,3 ′ -cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) with a saponin adjuvant, that we found to be highly effective in boosting protective immunity from vaccination in an aged mouse model. Using this combination with a subunit influenza vaccine, we observed that survival of vaccinated 20 month-old mice after lethal challenge increased from 0 to 20% with unadjuvanted vaccine to 80-100%, depending on the vaccination route. Compared to unadjuvanted vaccine, the levels of vaccine-specific IgG and IgG2a increased by almost two orders of magnitude as early as 2 weeks after a single immunization with the adjuvanted formulation. By analyzing phosphorylation of interferon regulatory factor 3 (IRF3) in cell culture, we provide evidence that the saponin component increases access of exogenous cGAMP to the intracellular STING pathway. Our findings suggest that combining a STING activator with a saponin-based adjuvant increases the effectiveness of influenza vaccine in aged hosts, without having to increase dose or perform additional vaccinations. This study reports a novel adjuvant combination that (a) is more effective than current methods of boosting vaccine efficacy, (b) can be used to enhance efficacy of licensed influenza vaccines, and (c) results in effective protection using a single vaccine dose.

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Section: Results Cgamp and Quil-a As Individual Adjuvants In Aged Micementioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combination of STING Pathway Agonist With Saponin Is an Effective Adjuvant in Immunosenescent Mice

2019

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“…). Moreover, 2′3′‐cGAMP also acts as an effective adjuvant boosting antigen‐specific T‐cell activation .…”

Section: Identification and Characterization Of The Cgas‐cgamp‐sting mentioning

confidence: 99%

cGAS‐cGAMP‐STING: The three musketeers of cytosolic DNA sensing and signaling

2016

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Innate immunity is the first line of host defense against invading pathogens. The detection of aberrant nucleic acids which represent some conserved PAMPs triggers robust type I IFNmediated innate immune responses. Host-or pathogen-derived cytosolic DNA binds and activates the DNA sensor cGAS, which synthesizes the second messenger 2 0 3 0 -cGAMP and triggers STING-dependent downstream signaling. Here, we highlight recent progress in cGAS-cGAMP-STING, the Three Musketeers of cytosolic DNA sensing and signaling, and their essential roles in infection, autoimmune diseases, and cancer. We also focus on the regulation of these critical signal components by variant host/pathogen proteins and update our understanding of this indispensable pathway to provide new insights for drug discovery.

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“…In particular, 94 cyclic dinucleotides (CDNs) that activate stimulator of interferon genes (STING, also known 95 as TMEM173, MPYS, ERIS and MITA) and induce a type I interferon (IFN-I) response as 96 well as production of pro-inflammatory cytokines are being developed as adjuvants (Cai et Pyrophosphatase/Phosphodiesterase 1 (ENPP1), an enzyme degrading extracellular ATP and 107 cGAMP (Carozza et al, 2019;Li et al, 2014). Indeed, when injected intra-muscularly, the 108 concentration of cGAMP at the inoculation site decreases rapidly, resulting in a sub-optimal 109 adjuvant effect (Wang et al, 2016). 110…”

Section: Introduction 40mentioning

confidence: 99%

cGAMP loading enhances the immunogenicity of VLP vaccines

Chauveau

Bridgeman

Tan

et al. 2020

Preprint

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23Cyclic GMP-AMP (cGAMP) is an immunostimulatory second messenger produced by cGAS 24 that activates STING. Soluble cGAMP acts as an adjuvant when administered with antigens. 25 cGAMP is also incorporated into enveloped virus particles during budding. We hypothesised 26 that inclusion of the adjuvant cGAMP within viral vaccine vectors would promote adaptive 27 immunity against vector antigens. We immunised mice with virus-like particles (VLPs) 28 containing the HIV-1 Gag protein and VSV-G. Inclusion of cGAMP within these VLPs 29 augmented splenic VLP-specific CD4 and CD8 T cell responses. It also increased VLP-and 30 VSV-G-specific serum antibody titres and enhanced in vitro virus neutralisation. The superior 31 antibody response was accompanied by increased numbers of T follicular helper cells in 32 draining lymph nodes. Vaccination with cGAMP-loaded VLPs containing haemagglutinin 33 induced high titres of influenza A virus neutralising antibodies and conferred protection 34 following subsequent influenza A virus challenge. Together, these results show that 35 incorporating cGAMP into VLPs enhances their immunogenicity, making cGAMP-VLPs an 36 attractive platform for novel vaccination strategies. 37 38 Running title: Immunogenicity of cGAMP-loaded VLP vaccines 39 GCs; and by supporting the generation of long-lived plasma cells and memory B cells (Crotty, 66 2019). In contrast, CD4 Tfr cells are involved in limiting GC reactions to prevent autoantibody 67 formation. Therefore, the Tfh/Tfr ratio is important for regulation of GC responses (Sage et al., 68 2013). 69 Virus-specific cytotoxic T cell (CTL) responses mediate clearance of infected cells to prevent 70 virus spread and eradicate infection. If sterilising immunity is not conferred by antibodies, 71 CTLs can make a key contribution to prophylactic vaccine efficacy (Hansen et al., 2011), and 72 they are critical for the control of persistent infection with viruses such as hepatitis B virus, 73 hepatitis C virus, cytomegalovirus and HIV (Panagioti et al., 2018). CTLs exert their activity 74 by triggering destruction of infected cells via release of perforins and granzymes; by ligation 75 of death-domain containing receptors and/or secretion of TNFa; and by producing "curative" 76 cytokines such as IFNg. Both the magnitude, i.e. the number of activated cells, and 77polyfunctionality of the T cell response, i.e. the capacity to mediate a breadth of effector 78 activities including production of multiple cytokines, are important determinants of CD8 T 79 cell-based vaccine efficacy (Panagioti et al., 2018). 80 Initiation of virus-specific CD4 and CD8 T cell responses requires presentation of viral 81antigens to naïve T cells by professional antigen-presenting cells (APCs), principally dendritic 82 cells (DCs). T cells need to receive three signals for activation: T cell receptor (TCR) triggering 83 by contact with peptide-major histocompatibility complexes (MHC) (signal 1); costimulatory 84 signals (signal 2); and inflammatory cytokines (signal 3) (Joffre et al.,...

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Natural STING Agonist as an “Ideal” Adjuvant for Cutaneous Vaccination

Cited by 76 publications

References 33 publications

Combination of STING Pathway Agonist With Saponin Is an Effective Adjuvant in Immunosenescent Mice

Combination of STING Pathway Agonist With Saponin Is an Effective Adjuvant in Immunosenescent Mice

cGAS‐cGAMP‐STING: The three musketeers of cytosolic DNA sensing and signaling

cGAMP loading enhances the immunogenicity of VLP vaccines

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