Therapeutic vaccine induced plasma cell differentiation is defective upon persistent HBsAg stimulation [bulkRNA]

Background & Aims: The precise mechanism underlying the attenuation of the antigen-specific B cell response induced by therapeutic vaccination during chronic HBV infection remains unclear. The development of vaccines or strategies targeting this impediment through rational design could potentially result in significant advancements in the treatment of chronic hepatitis B. Methods: A mouse model with a knock-in of a B cell receptor specific to the hepatitis B virus surface antigen was generated under the name E6F6-B. This model was utilized to investigate the temporal and spatial patterns of humoral responses induced by therapeutic vaccination in the presence of persistent antigen stimulation. Through the use of multiple transcriptome sequencing techniques, the differentiation trajectory of HBsAg-specific B cells post therapeutic vaccination during chronic hepatitis B infection was elucidated. Results: In light of the E6F6-B transfer model, a significant reduction in antibody secreting cells were observed two weeks after vaccination. Additionally, an atypical pre-plasma cell population (BLIMP-1+ IRF4+ CD40- CD138-) was identified as a consequence of persistent BCR signaling in the absence of CD40 co-stimulation. A therapeutic antibody-induced suppression of BCR signaling revitalized the HBsAg-specific B cell response.