Understanding Memory B Cell Responses To A Chimeric-Based Universal Influenza Virus Vaccine Candidate

Abstract A universal influenza virus vaccine candidate trial was recently conducted that utilized novel influenza viruses expressing chimeric hemagglutinin (HA) proteins. The chimeric HAs present in the vaccines are composed of a typical stalk domain (from an H1 HA) paired with an exotic head from a strain to which humans are naive (avian H5 or H8). Given the conserved nature of the HA-stalk region, broadly neutralizing antibodies that target this region would confer protection against a wide range of influenza virus strains. The major objective of the trial is to determine whether the human immune response to influenza virus can be re-programmed to target universally conserved stalk epitopes. In this study, we collected antigen-specific memory B cells at day 28 post-vaccination at prime, boost and 1-year time points, and subsequently characterized both the transcriptome by single cell RNA-seq and antibody specificity by generating monoclonal antibodies (mAbs) from the sequenced immunoglobulin genes of the same B cells. Our research has suggested HA stalk-reactive B cells were selected after the boost time point. In addition, we have identified clonal expansions within an individual (referred to as private clones) and across multiple individuals (referred to as public clones) that have neutralizing capability and are able to bind divergent influenza strains. Furthermore, we have identified different memory B cell subsets induced by universal influenza virus vaccination at the single-cell level.