# Structural biology and immunogen design

> **NIH NIH P01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $1,198,558

## Abstract

Abstract, Project 3
A premise of current research on vaccines for rapidly evolving pathogens (e.g., influenza virus
and HIV) is that better understanding of molecular events during antibody affinity maturation can
lead to more "rational" vaccine design. The goals of Project 3 are to interpret, in biophysical and
structural terms, the findings from immunization studies with humans, non-human primates, and
mice in Projects 1 and 2; to define, with quantitative experimental results, concepts such as
immunodominance and epitopic distance; to provide "molecular movies" of specific affinity
maturation trajectories; and to design new immunogens, as tests for the hypotheses explored
and generated in the Program Project as a whole. We concentrate on antibodies that target the
receptor-binding site (RBS). (1) We will generate a structural epitope map of the naïve
response to a single HA subtype, to provide an epitope "language" for the rest of the project.
We will then seek structural explanations for any heterosubtypic antibodies in the naïve
response (human, macaque) to a multivalent vaccine. (2) Can we use a set of HAs with defined
similarity at a particular epitope ("epitopic distance") to determine the extent to which a primary
exposure will dominate a subsequent, heterologous humoral response? We propose an
operational definition of epitopic distance and outline experiments to test and modify it. We will
relate epitopic distance to structural features, with the long-term goal of enabling computational
estimates from knowledge of a single-Fab:single-HA-variant structure. This approach to the HA
RBS, an extremely well characterized epitope, will establish benchmarks and concepts to apply
more broadly to design of immunogens and vaccination regimens. (3) Building on (1) and (2),
we will test directly and critically the concept of B-cell lineage-based immunogen design, while
also testing the outcomes, in mice and macaques (Projects 2 and 1, respectively), of particular
immunization protocols with particular designed immunogens.

## Key facts

- **NIH application ID:** 10229504
- **Project number:** 5P01AI089618-10
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** STEPHEN COPLAN HARRISON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,198,558
- **Award type:** 5
- **Project period:** 2011-08-01 → 2023-04-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229504

## Citation

> US National Institutes of Health, RePORTER application 10229504, Structural biology and immunogen design (5P01AI089618-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10229504. Licensed CC0.

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