Vaccines are one of the most successful public health interventions over the past century. Of the 28 licensed vaccines, nearly all of them work by induction of protective antibodies capable of neutralizing the pathogen. However, our understanding of the cellular dynamics of immune responses to vaccines, particularly the biology surrounding B cell competition within germinal centers (GC) and memory B cell biology to complex vaccine antigens, has remained limited. This lack of fundamental understanding of these biological processes may be a contributor to the failure to develop an effective HIV vaccine, despite nearly 30 years of research. The fact that a small population of HIV+ individuals develop broadly neutralizing antibodies (bnAbs) gives renewed hope that an HIV vaccine is indeed possible. Recent work has found that many HIV negative healthy human donors have VRC01-class precursor B cells. However, work from these studies revealed that these potential bnAb precursor B cells are found at an unusually rare frequency, suggesting that following immunization these B cells would be outcompeted by more frequent non-neutralizing B cells. To answer immunological questions surrounding this problem, I developed a model system utilizing mice containing human genes for the germline- reverted VRC01 bnAb (VRC01gHL), together with teams from the labs of Dr. David Nemazee and Dr. William Schief. Through this B cell transfer model, we found that antigen affinity, avidity, and precursor frequency all played interdependent roles in competitive success of rare VRC01gHL B cells in GCs. Critically, we found that rare VRC01gHL B cells with physiological affinities could be primed to successfully compete within GCs and form memory. In this K99/R00 proposal I will build on these findings. I will explore how precursor frequency and affinity affect the balanced output of memory B cell and long lived plasma cells from GCs, and how Tfh help can modulate these processes. I will assess how these parameters affect recall and competitive success of VRC01gHL memory B cells. Moreover, I will investigate if different metabolic pathways are involved in successful recruitment of memory VRC01gHL B cells to and within secondary GCs. I will further my training by developing a co-T cell transfer method to specifically study the impact of different Tfh pathways in competitive success of VRC01gHL B cells. The K99 phase will be conducted in the laboratory of Dr. Shane Crotty at the La Jolla Institute (LJI). Dr. Crotty is an ideal mentor as he has a highly successful history in studying vaccine biology, particularly T follicular helper (Tfh) biology. He has also explored this biology related to HIV vaccines. I will additionally receive formal training in antibody characterization through coursework and further develop real world training in immunogen production and design in the laboratory of Dr. William Schief as a visiting scientist. During the R00 phase, I will take my experimental models with me and investigate multiple parameters affecting memory cell biology. These will include studying the roles of circulating antibody, memory Tfh, and ?metabolic memory? of B cells.
HIV remains a global pandemic in which there has been no vaccine despite three decades of research. The fact that a small subset of HIV infected individuals develop antibodies capable of neutralizing 98% of HIV viruses gives substantial promise that an HIV vaccine is possible, however there has been a lack of understanding the fundamental multi-step process of vaccine biology to mimic this. We have developed a novel mouse model system using transgenic cells expressing the genes responsible for producing this HIV- neutralizing antibody response in order to study the relevant biology necessary to understand to produce an effective HIV vaccine.
