We propose that the features of germinal center biology important for developing high affinity B cells to a very difficult epitope, such as a tier 2 nAb epitope on HIV Env trimer, are very different than the well characterized features of GC biology for conventional antigens, such as haptens. We have demonstrated that slow delivery immunization changes fundamental aspects of the immune response, which can result in dramatic improvements in nAb responses (Cell 2019). Conventional immunization strategies will likely be insufficient for the development of a bnAb vaccine to HIV or other difficult pathogens due to the immunological hurdles posed, including B cell immunodominance and GC quantity and quality. We found that two independent methods of slow delivery immunization of RMs resulted in more robust Tfh cells and more GC B cells with Env-binding, tracked by longitudinal lymph node (LN) fine needle aspirates (FNA) 1. Improved GCs correlated with the development of > 20-fold higher titers of autologous tier 2 neutralizing Abs (nAbs). BCR sequencing and Ab mapping demonstrated targeting of immunodominant non-neutralizing (nnAb) epitopes by conventional bolus immunized animals, while slow delivery immunized animals targeted a more diverse set of epitopes, including multiple tier 2 nAb epitopes. We will continue these groundbreaking studies to use novel slow release technologies to probe the biology of germinal centers relevant to affinity maturation against a difficult HIV trimer immunogen in non-human primates (NHP, rhesus macaques).
A broadly neutralizing antibody (bnAb)-directed HIV vaccine is possible in concept, but exceptional immunological hurdles must be overcome to reach that goal. Major limitations in our understanding of the biology of GCs to difficult antigens include (1) ?Is immunodominance in GC responses preventing development of bnAbs to conventional immunizations??, and 2) ?Is sustained exposure to antigen in GCs necessary for the extensive somatic hypermutation (SHM) associated with the generation of bnAbs?? We will explore these questions in the context of a candidate HIV vaccine.