Preclinical evaluation of therapeutic vaccines for chronic hepatitis B that stimulate antiviral activities of T cells and NKT cells

Mooney, Anna H.; Draper, Sarah L.; Burn, Olivia K.; Anderson, Regan J.; Compton, Benjamin J.; Tang, Chingwen; Farrand, Kathryn J.; Di Lucia, Pietro; Ravà, Micol; Fumagalli, Valeria; Giustini, Leonardo; Bono, Elisa; Godfrey, Dale I.; Heath, William R.; Yuan, Weiming; Chisari, Francis V.; Guidotti, Luca G.; Iannacone, Matteo; Sidney, John; Sette, Alessandro; Gulab, Shivali A.; Painter, Gavin F.; Hermans, Ian F.

doi:10.1016/j.jhepr.2024.101038

JHEP Reports

2024

DOI: 10.1016/j.jhepr.2024.101038

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Preclinical evaluation of therapeutic vaccines for chronic hepatitis B that stimulate antiviral activities of T cells and NKT cells

Anna H. Mooney,

Sarah L. Draper,

Olivia K. Burn

et al.

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2024

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Cited by 3 publications

References 94 publications

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Developing an On‐Resin Synthesis of α‐Galactosylceramide‐Peptide Conjugate Vaccines

Meijlink,

Chan,

Farrand

et al. 2024

ChemistryEurope

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The covalent attachment of peptide antigens to the NKT cell agonist, α‐galactosylceramide (αGalCer), generates self‐adjuvanting vaccines that prevent and/or eliminate disease in animal models of cancer and infectious disease. To date, the manufacture of these glycolipid‐peptide (GLP) conjugate vaccines utilises an automated solid‐phase process to produce the peptide followed by a manual ‘wet chemistry’ conjugation step. To expedite GLP vaccine manufacture, we sought to develop methodology that enables the attachment of resin‐bound peptide antigen to αGalCer via an amide bond thereby avoiding the need to carry out a separate chemoselective conjugation step. To facilitate this approach, novel analogues of αGalCer incorporating an activated ester spaced by an acid‐resistant, protease‐sensitive linker from either the 6′′‐position or the N‐acyl lipid were synthesised. Reacting these with resin‐bound peptide afforded the conjugate vaccines in good to excellent yields and purity. In vivo testing showed that vaccines incorporating peptide antigen attached via the galactosyl head group induced strong antigen specific CD8+ T cell responses compared to those with antigen attached via the lipid tail and control vaccine manufactured in a stepwise manner.

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Developing an On‐Resin Synthesis of α‐Galactosylceramide‐Peptide Conjugate Vaccines

Meijlink,

Chan,

Farrand

et al. 2024

ChemistryEurope

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CCR2+TREM-1+ monocytes promote natural killer T cell dysfunction contributing towards HBV disease progression

Wu,

Zhao,

Miao

et al. 2024

Immunol Res

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Natural killer T (NKT) cells are amongst the most important innate immune cells against Hepatitis B virus (HBV) infection. Moreover, previous studies have shown that HBV infection induced TREM-1 + expression in monocyte and secretion of in ammatory cytokines. Thus, this prompted us to elucidate the role of TREM-1 + monocytes in regulating the function of NKT cells. Ninety patients and 20 healthy participants were enrolled in the study. The percentage and phenotype of iNKT cells and TREM-1 + monocytes were measured in the peripheral blood of healthy controls (HC), patients with chronic HBV infection (CHB), HBV-related liver cirrhosis (LC), and HBV-related acute-on-chronic liver failure (ACLF) via ow cytometry. Moreover, co-culture experiments with NKT cells and TREM-1 overexpressing THP-1 cells were performed to determine the role of TREM-1 in regulation of NKT cell function. We observed that the percentage of NKT cells and CD4-NKT cells gradually decreased, whereas percentage of CCR2 + TREM-1 + monocytes increased with the progression of the disease. In addition, activation of the TREM-1 signaling pathway induced the secretion of in ammatory cytokines leading to pyroptosis of NKT cells and secretion of IL-17 contributing towards disease progression. Therefore, this study suggests that blocking the activation of TREM-1 in monocytes could promote the elimination of HBV by inhibiting pyroptosis of NKT cells and restoring their function. However, further studies are required to validate these results that would help in developing new treatment strategies for patients with HBV infections.

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The surveillance of viral infections by the unconventional Type I NKT cell

Rajashekar,

Stern,

Almeida

et al. 2024

Front. Immunol.

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Type I NKT cells, also known as Invariant Natural Killer T (iNKT) cells, are a subpopulation of unconventional, innate-like T (ILT) cells which can proficiently influence downstream immune effector functions. Type I NKT cells express a semi-invariant αβ T cell receptor (TCR) that recognises lipid-based ligands specifically presented by the non-classical cluster of differentiation (CD1) protein d (CD1d) molecule. Due to their potent immunomodulatory functional capacity, type I NKT cells are being increasingly considered in prophylactic and therapeutic approaches towards various diseases, including as vaccine-adjuvants. As viruses do not encode lipid synthesis, it is surprising that many studies have shown that some viruses can directly impede type I NKT activation through downregulating CD1d expression. Therefore, in order to harness type I NKT cells for potential anti-viral therapeutic uses, it is critical that we fully appreciate how the CD1d-iNKT cell axis interacts with viral immunity. In this review, we examine clinical findings that underpin the importance of type I NKT cell function in viral infections. This review also explores how certain viruses employ immunoevasive mechanisms and directly encode functions to target CD1d expression and type I NKT cell function. Overall, we suggest that the CD1d-iNKT cell axis may hold greater gravity within viral infections than what was previously appreciated.

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Preclinical evaluation of therapeutic vaccines for chronic hepatitis B that stimulate antiviral activities of T cells and NKT cells

Cited by 3 publications

References 94 publications

Developing an On‐Resin Synthesis of α‐Galactosylceramide‐Peptide Conjugate Vaccines

Developing an On‐Resin Synthesis of α‐Galactosylceramide‐Peptide Conjugate Vaccines

CCR2+TREM-1+ monocytes promote natural killer T cell dysfunction contributing towards HBV disease progression

The surveillance of viral infections by the unconventional Type I NKT cell

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