The Project Management Team has provided continuous support to the project and faced the necessity of providing a third amendment process to the project (delay related to the COVID-19 crisis). Partners’ compliance to the Consortium Agreement and H2020 financial and GA rules has been continuously monitored. Regarding the PoC clinical trial (WP2), the first participant was randomised in France on March 1st, 2022, and the inclusion period has been extended by 3 months, bringing the end of the inclusion period to March 31st, 2024. In total, 73 participants have been screened and 51 randomised. 9 participating centers were active in recruiting participants for the trial. In WP3, the preclinical HBV immune therapy platform supports the design and the study of innovative HBV therapeutic vaccines, evaluates the effects of an immunotherapeutic TLR8 agonist GS-9688 in humanized mice, and performs mechanistic studies in HBV infected hepatocyte cultures. Innovative DC-targeting anti-HBV vaccines have been designed and produced, which are currently being evaluated for immunogenicity in humanized mice. A relevant humanized mouse model has been established to study the immune-modulator TLR8 agonist (GS9688/Selgantolimod) in vivo, and the optimal dosage and frequency of treatment have been determined. The immunocompetent humanized mouse model chronically infected with HBV, used as a platform to assess anti-HBV adaptive immune responses, has also been validated. A precision cut liver slices model for HBV infection has been established to study the liver microenvironment and its response to host targeting agents. A focus has been made on further validation of the IP-cure-B standard operating procedures for liver fine needle aspirates (WP4). Extensive tests on the HBcrAg and circulating HBV RNAs biomarkers in real life cohorts of untreated and NUC-treated chronically HBV infected patients and in CHB patients co-infected with HDV and HIV have also been developed. Further development, validation and harmonization of experimental set ups to monitor changes of innate and adaptive immune responses in patients with chronic hepatitis B undergoing new anti-HBV therapies (WP5). Careful set up of conventional as well as novel explorative signalling, metabolic and transcriptional parameters in blood and liver has successfully been completed. HBV-specific B-cells have been detected in all samples tested, differently from virus-specific T-cell responses showing a very low frequency for some patients and time points. A data spreadsheet for immunological analysis of the adaptive response is in progress, as is the optimization of a HBV-specific CD4 T cell analysis panel. The humanized mouse model will allow the teams to investigate the ability of novel immunotherapeutic treatments to restore antigen specific immune responses, following chronic HBV infections. The data science platform (WP6) will be launched at a later stage when the clinical data will be made available by the partners and transferred for analysis to the datawarehouse. These data should allow gathering information from double humanized mice for liver and immune system. These are expected to consolidate the basic elements specific to the HBV infection pathway to adapt the mechanistic within host model already developed by our team. A first ODE mechanistic system is ready to be fit with the human data, once the data will be completely produced. In WP7, conceptual improvement was made on the structure of the economic model and led to a simplified representation of the progression of chronic hepatitis B. The structure of the CHB model for the representative population of the clinical trial is finalized. The communication team (WP8) has worked to expand visibility to the IP-cure-B project. IP-cure-B visibility is ensured by a dedicated website, X and LinkedIn accounts. In November 2022, the 1st laymen event took place with patient communities throughout Europe. A myth-busters campaign has been set up with the PIs of the project, and short videos were recorded during the IP-cure-B annual meeting in April 2024. The videos have been available on YouTube since July 2024 and have been shared on social media.
