The Notch Pathway in Antigen Design

Document text

Principal Investigator: David M Allman
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $207,772
Funding agency: National Institute of Allergy and Infectious Diseases

Project summary
There is an urgent need to develop new vaccination strategies that induce antibodies that
target relevant epitopes on complex microbes. Moreover, approaches that allow control of
the number and fine specificity repertoire of responding naïve or memory B cells would
fuel new vaccine designs for a variety of mutating viruses. This project centers on the
hypothesis that co-engagement of the B cell receptor (BCR) for antigen with the Notch2
receptor will amplify responses by naïve and memory B cells. This hypothesis builds on
preliminary data showing that BCR+Notch2 co-stimulation increases both number of B
cells that respond and the number of proliferative events experienced by these cells. To
test our hypothesis, we will generate unique mosaic nanoparticles based on immunogenic
and sub-immunogenic variants of the HIV envelop (Env) antigen. We will answer the
following questions: 1) Does BCR+Notch2 co-engagement prime naïve clones to target
native-like Env variants?, and 2) Does BCR+Notch2 co-engagement on memory B cells
increase their contribution to GC and PC pools? These studies will provide unique and
needed insights into the potential exploitation of BCR signaling thresholds in emerging
vaccine design.

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