Roles of vaccine perturbations on germinal center dynamics

The National Institute of Allergy and Infectious Diseases awarded the University of California, San Diego $202,889 on December 5, 2025, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate how vaccine formulations alter germinal center dynamics in the context of HIV vaccine design.

The work examines how sequential immunization strategies influence antibody-secreting cell and memory B cell differentiation by remodeling the germinal center microenvironment. The research uses mouse models with sequential immunization regimens designed to track antigen-specific germinal center B cells and stromal cells, employing multiparameter flow cytometry, high-resolution microscopy, RNA sequencing, ELISA, and ELISPOT techniques. The investigation focuses on the stromal network underlying germinal center microenvironment as a mechanism for generating broadly neutralizing antibodies—a key challenge in HIV vaccine development. Results are intended to inform formulation strategies for HIV vaccines capable of sustaining long-term B cell retention within germinal centers to produce broadly neutralizing antibodies.

Performance occurs in La Jolla, California, with a completion date of February 3, 2028.

Abstract

Human immunodeficiency virus (HIV) lacks a vaccine despite being a global priority. HIV poses a unique challenge to vaccine design, as many characterized broadly neutralizing antibodies (bnabs) possess unusually high frequencies of somatic hypermutations. To generate potential bnabs, b cells must undergo iterative rounds of affinity maturation and selection within germinal centers (GCS). Our lab and collaborators have made significant contributions to the HIV vaccine field. These contributions include sequential immunization strategies to efficiently prime bnab-precursor b cells to enter GCS and to increase the diversity and length of the GC. Despite our success with these regimens in preclinical models, our understanding of sequential immunization strategies impacts to the GC microenvironment is lacking. We hypothesize that the formulation of an immunization regimen i) can directly influence antibody-secreting and memory b cell differentiation and II) this is driven by the remodeling of the GC microenvironment. These hypotheses will be tested using different mouse models with sequential immunization strategies designed to track antigen-specific GC b cells and stromal cells. A combination of multiparameter flow cytometry, high resolution microscopy, RNA-sequencing, elisa, and elispot techniques will be used throughout the proposed work. These investigations including the studies of the stromal network underlying the GC microenvironment is a largely underappreciated facet for the generation of adaptive immunity. This work has the potential to reveal novel considerations for the formulation of HIV vaccines with the capacity for long-term retention of b cells within GCS to generate bnabs.