{"doi":"10.1016/j.jhepr.2024.101038","title":"Preclinical evaluation of therapeutic vaccines for chronic hepatitis B that stimulate antiviral activities of T cells and NKT cells","abstract":"Background & Aims: Liver diseases resulting from chronic HBV infection are a significant cause of morbidity and mortality. Vaccines that elicit T-cell responses capable of controlling the virus represent a treatment strategy with potential for long-term effects. Here, we evaluated vaccines that induce the activity of type I natural killer T (NKT) cells to limit viral replication and license stimulation of conventional antiviral T-cells. Methods: Vaccines were prepared by conjugating peptide epitopes to an NKT-cell agonist to promote co-delivery to antigen-presenting cells, encouraging NKT-cell licensing and stimulation of T cells. Activity of the conjugate vaccines was assessed in transgenic mice expressing the complete HBV genome, administered intravenously to maximise access to NKT cell-rich tissues. Results: T cells into the transgenic mice, which typically results in specific T-cell dysfunction without virus control, vaccines containing the targeted HBcAg epitope induced prolonged antiviral activity because of qualitatively improved T-cell stimulation. In a step towards a clinical product, vaccines were prepared using synthetic long peptides covering clusters of known HLA-binding epitopes and shown to be immunogenic in HLA transgenic mice. Predictions based on HLA distribution suggest a product containing three selected SLP-based vaccines could give >90 % worldwide coverage, with an average of 3.38 epitopes targeted per individual. Conclusions: The novel vaccines described show promise for further clinical development as a treatment for chronic hepatitis B. Impact and Implications: Although there are effective prophylactic vaccines for HBV infection, it is estimated that 350-400 million people worldwide have chronic hepatitis B, putting these individuals at significant risk of life-threatening liver diseases. Therapeutic vaccination aimed at activating or boosting HBV-specific T-cell responses holds potential as a strategy for treating chronic infection, but has so far met with limited success. Here, we show that a glycolipid-peptide conjugate vaccine designed to coordinate activity of type I NKT cells alongside conventional antiviral T cells has antiviral activity in a mouse model of chronic infection. It is anticipated that a product based on a combination of three such conjugates, each prepared using long peptides covering clusters of known HLA-binding epitopes, could be developed further as a treatment for chronic hepatitis B with broad global HLA coverage.","journal":"JHEP Reports","year":2024,"id":444167,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1259307,"name":"Sarah L. Draper","orcid":"0000-0001-8330-121X","position":1,"is_corresponding":false},{"id":1259308,"name":"Olivia K. Burn","orcid":"0000-0003-1130-0220","position":2,"is_corresponding":false},{"id":711471,"name":"R. J. Anderson","orcid":"0000-0003-3467-9202","position":3,"is_corresponding":false},{"id":527179,"name":"Benjamin J. Compton","orcid":"0000-0002-5245-9767","position":4,"is_corresponding":false},{"id":1259712,"name":"Ching‐Wen Tang","orcid":null,"position":5,"is_corresponding":false},{"id":988601,"name":"Kathryn J. Farrand","orcid":"0000-0001-6320-6960","position":6,"is_corresponding":false},{"id":814552,"name":"Pietro Di Lucia","orcid":"0000-0002-0726-1532","position":7,"is_corresponding":false},{"id":814550,"name":"Micol Ravà","orcid":"0000-0001-7606-8368","position":8,"is_corresponding":false},{"id":814551,"name":"Valeria Fumagalli","orcid":"0000-0003-2583-2498","position":9,"is_corresponding":false},{"id":1206382,"name":"Leonardo Giustini","orcid":null,"position":10,"is_corresponding":false},{"id":1205490,"name":"Elisa Bono","orcid":"0000-0002-5212-3446","position":11,"is_corresponding":false},{"id":675832,"name":"Dale I. Godfrey","orcid":"0000-0002-3009-5472","position":12,"is_corresponding":false},{"id":242756,"name":"William R. Heath","orcid":"0000-0001-9670-259X","position":13,"is_corresponding":false},{"id":248983,"name":"Weiming Yuan","orcid":"0000-0002-4780-7157","position":14,"is_corresponding":false},{"id":1259309,"name":"Francis V. Chisari","orcid":"0000-0002-4832-1044","position":15,"is_corresponding":false},{"id":1205500,"name":"Luca G. Guidotti","orcid":"0000-0002-0205-2678","position":16,"is_corresponding":false},{"id":52959,"name":"Matteo Iannacone","orcid":"0000-0002-9370-2671","position":17,"is_corresponding":false},{"id":55666,"name":"John Sidney","orcid":"0000-0002-0987-405X","position":18,"is_corresponding":false},{"id":55670,"name":"Alessandro Sette","orcid":"0000-0001-7013-2250","position":19,"is_corresponding":false},{"id":1259310,"name":"Shivali A. Gulab","orcid":"0000-0003-2992-4533","position":20,"is_corresponding":false},{"id":527178,"name":"Gavin F. Painter","orcid":"0000-0002-1310-7769","position":21,"is_corresponding":false},{"id":711473,"name":"Ian F. Hermans","orcid":"0000-0002-7584-887X","position":22,"is_corresponding":false},{"id":1259306,"name":"Anna Mooney","orcid":"0000-0001-7044-7017","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T02:01:33.526738Z","pmid":"38694959","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}