ABSTRACT
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.