The STING ligand cGAMP potentiates the efficacy of vaccine-induced CD8+ T cells

Gutjahr, Alice; Papagno, Laura; Nicoli, Francesco; Kanuma, Tomohiro; Kuse, Nozomi; Cabral-Piccin, Mariela Pires; Rochereau, Nicolas; Gostick, Emma; Lioux, Thierry; Pérouzel, Éric; Price, David A.; Takiguchi, Masafumi; Verrier, Bernard; Yamamoto, Takuya; Paul, Stéphane; Appay, Victor

doi:10.1172/jci.insight.125107

Cited by 68 publications

(67 citation statements)

References 34 publications

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“…An agonist of the intracellular stimulator of interferon genes (STING) pathway, cyclic di-nucleotide a 2 ′ 3 ′ -cGAMP, is an experimental vaccine adjuvant (20)(21)(22)(23). 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).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

2019

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“…To investigate the potential utility of CpG ODN 2006 (TLR9L) as a vaccine adjuvant, we used a previously optimized in vitro model that allows direct quantification of priming efficacy via the measurement of antigen-driven CD8 + T-cell expansion originating from naive precursors specific for Melan-A 26–35/A27L (EV10) restricted by HLA-A*02:01 (abbreviated from hereon as HLA-A2), which are readily accessible in standard preparations of peripheral blood mononuclear cells (PBMCs) 12 , 13 . Healthy donors were recruited for this study to minimize the likelihood of naturally occurring memory responses to EV10.…”

Section: Resultsmentioning

confidence: 99%

“…3 A–C). Although direct signaling via the STING pathway can inhibit cell proliferation, the priming efficacy of 2′3′-cGAMP relates primarily to the induction of type I IFNs via effects on DCs 13 . This latter process was likely impeded by TLR9L.…”

Section: Resultsmentioning

confidence: 99%

The TLR9 ligand CpG ODN 2006 is a poor adjuvant for the induction of de novo CD8+ T-cell responses in vitro

Papagno

Kuse

Lissina

et al. 2020

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Toll-like receptor 9 (TLR9) agonists have gained traction in recent years as potential adjuvants for the induction of adaptive immune responses. It has nonetheless remained unclear to what extent such ligands can facilitate the priming events that generate antigen-specific effector and/or memory CD8 + T-cell populations. We used an established in vitro model to prime naive precursors from human peripheral blood mononuclear cells in the presence of various adjuvants, including CpG ODN 2006, a synthetic oligonucleotide TLR9 ligand (TLR9L). Unexpectedly, we found that TLR9L induced a suboptimal inflammatory milieu and promoted the antigen-driven expansion and functional maturation of naive CD8 + T cells ineffectively compared with either ssRNA40 or 2′3′-cGAMP, which activate other pattern recognition receptors (PRRs). TLR9L also inhibited the priming efficacy of 2′3′-cGAMP. Collectively, these results suggest that TLR9L is unlikely to be a good candidate for the optimal induction of de novo CD8 + T-cell responses, in contrast to adjuvants that operate via discrete PRRs.

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“…Insufficient strength of the vaccine-induced immune responses provides a plausible reason for these differences. Other promising approaches, therefore, include formulated mRNA-based vaccines 39,162 or effective new adjuvants, such as those targeting STING 163 . We are currently working on the clinical development of a new synthetic Toll-like receptor 1/2 agonist, termed XS15, that thus far seems to be a strong adjuvant, at least in one human volunteer 164 .…”

Section: Selection the Selection And Identification Of Targetablementioning

confidence: 99%

Towards new horizons: characterization, classification and implications of the tumour antigenic repertoire

et al. 2020

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Immunologically recognizable cell-surface structures. Antigen-aware therapy (AaT). An active immunotherapy leading to the activation of and/or constituting antigenspecific cells designed to target known and/or well-defined antigens. Antigen-unaware therapy (AuT). An active immunotherapy leading to the activation of and/or constituting antigenspecific cells designed to targeting uncharacterized antigens.

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The STING ligand cGAMP potentiates the efficacy of vaccine-induced CD8+ T cells

Cited by 68 publications

References 34 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

The TLR9 ligand CpG ODN 2006 is a poor adjuvant for the induction of de novo CD8+ T-cell responses in vitro

Towards new horizons: characterization, classification and implications of the tumour antigenic repertoire

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