Induction of humoral and cellular immune response to HBV vaccine can be up-regulated by STING ligand

Ito, Hiroyasu; Kanbe, Ayumu; Hara, Akira; Ishikawa, Tetsuya

doi:10.1016/j.virol.2019.03.013

Cited by 18 publications

(16 citation statements)

References 36 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). However, rather high amounts of cGAMP or other cyclic di-nucleotides have been required for adjuvant activity (22,29,30).…”

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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“…The antigen‐specific cellular immune response was assessed using the enzyme‐linked immunosorbent spot (ELISPOT) assay as described previously 5 13 . Single cell suspensions were prepared from the whole spleen at 2, 6, 8, and 20 weeks after transplantation.…”

Section: Methodsmentioning

confidence: 99%

Novel hepatitis B virus infection mouse model using herpes simplex virus type 1 thymidine kinase transgenic mice

Kanbe

Ishikawa

Hara

et al. 2020

J of Gastro and Hepatol

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Background and Aim The chronicity of hepatitis B virus (HBV) infection is the result of impaired HBV‐specific immune responses that cannot eliminate or cure the infected hepatocytes efficiently. Previous studies have used immunodeficient mice such as herpes simplex virus type 1 thymidine kinase NOD/Scid/IL2Rrnull (HSV‐TK‐NOG) mice. However, it is difficult to analyze the immune response in the previous models. In the present study, we established a novel HBV infection model using herpes simplex virus type 1 thymidine kinase (HSV‐TK) mice in which the host immune system was not impaired. Methods Herpes simplex virus type 1 thymidine kinase mice were injected intraperitoneally with ganciclovir (GCV). Seven days after GCV injection, GCV‐treated mice were transplanted with 1 × 106 hepatocytes from HBV‐transgenic (HBV‐Tg) mice. Results Serum alanine aminotransferase levels in HSV‐TK mice increased 1 and 2 weeks after GCV injection. The number and viability of hepatocytes from the whole liver of HBV‐Tg mice significantly increased using digestion medium containing liberase. Hepatitis B surface antigen (HBsAg)‐positive areas in the liver tissue were observed for at least 20 weeks after HBsAg‐positive hepatocyte transplantation. In addition, we measured HBsAg in the serum after transplantation. HBsAg levels in HBV‐Tg hepatocyte‐replaced mice increased 4 weeks after transplantation. Furthermore, we examined the immune response in HSV‐TK mice. The increase in hepatitis B surface antibody levels in replaced mice was maintained for 20 weeks. Also, interferon‐γ‐producing cells were increased in non‐replaced mice. Conclusions A novel HBV infection mouse model will help to understand the mechanisms of HBV tolerance similar to human chronic HBV‐infected patients and can be used to develop a new strategy to treat chronic HBV infection.

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“…cGAMP, as an effective ligand for STING, greatly enhances the immune response to HBV vaccines when applied as a vaccine adjuvant. 112 (Fig. 3b) Compared with TLR agonists, STING agonists not only induce a more potent antiviral response but also lead to less severe inflammation and tissue damage by reducing proinflammatory cytokine responses.…”

Section: Cgas-sting Signaling: a Potential Therapeutic Targetmentioning

confidence: 99%

The role of cGAS-STING signalling in liver diseases

Chen

Zhu

et al. 2021

JHEP Reports

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Induction of humoral and cellular immune response to HBV vaccine can be up-regulated by STING ligand

Cited by 18 publications

References 36 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

Novel hepatitis B virus infection mouse model using herpes simplex virus type 1 thymidine kinase transgenic mice

The role of cGAS-STING signalling in liver diseases

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