T cell help is a limiting factor for rare anti-influenza memory B cells to reenter germinal centers and generate potent broadly neutralizing antibodies

Abstract Development of vaccines eliciting broadly neutralizing influenza antibodies (bnAbs) is an extraordinary challenge. One hypothetical proposal is that CD4+ T cell help to rare immuno-subdominant bnAb class memory B cells is one critical factor to cause these B cells to reenter secondary germinal centers (GCs) and generate potent bnAbs. In this regard, we previously showed that the prototypic hemagglutinin stem vaccine does not contain the dominant CD4+ T cell epitope. Here, to test the above hypothesis, we examined the effects of adding a single influenza T cell epitope to the stem vaccine in an influenza pre-infected booster mouse model. We found that this fused booster vaccine efficiently recruited anti-stem memory B cells with prior GC experience into the secondary GCs in draining lymph nodes. Furthermore, these secondary GC-experienced cells evolved, thereby contributing to generation of more potent neutralizing activity towards variant viruses. Thus, our results suggest the importance of T cell help in generating potent bnAbs by recruiting rare subdominant memory B cells into secondary GCs, and have implications for vaccine design.