# Flipped Germinal Centers

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $740,268

## Abstract

PROJECT SUMMARY
Developing universal vaccines to influenza and HIV-1 is an urgent global goal. A critical challenge is that
immune responses to native HIV-1 envelope (Env) and influenza hemagglutinin (HA) are dominated by non-
neutralizing and highly strain-specific antibodies. Discoveries that some individuals produce broadly
neutralizing antibodies (bnAbs) invigorated hope that, while not naturally dominant, broadly protective antibody
responses are possible. Antibodies mature during through somatic hypermutation (SHM) and affinity-based
selection in germinal centers (GCs) in competition with other antibodies that recognize different parts of the
same virus. It is widely believed that a prime and boost vaccine tactic can effectively elicit bnAb precursors and
strategically guide SHM trajectory can produce bnAbs. Challenges to this process are that native envelope
proteins may not bind well to the bnAb precursor antibodies and may be poorly represented in the antibody
repertoire. A strategic prime and boost strategy requires generation of designer viral envelope variants that
bind well to bnAb ancestor antibodies acting as a primer, followed by modified variants to function as boosting
immunogen(s) to shepherd bnAb maturation. This promising approach is hindered by time and effort required
to identify Env or HA variants as immunogens, which traditionally require mutation library generation, in vitro
static selection, cloning, expression, and validation testing. This extensive hands-on trial and error process
greatly hinders the pace of progress. Here a new technology is proposed with power to explosively accelerate
the pace of immunogen discovery by creatively harnessing the full spectrum of automated mutation and
selection inherent in one of nature’s innovations in hyperevolution—namely the GC SHM and affinity
maturation system—an automated in vivo dynamic mutation process coupled to parallel selection activity that
dynamically shuttles superior binding variants back for further diversification and selection. In addition to
dramatically improving binding affinity, the GC system can be engineered to generate new recognition. The
objective is to create flipped GC systems in which antibody genes are replaced with viral envelope proteins—
and deploy them for immunogen design. In contrast to dynamic antibody evolution to viral envelop protein in
normal GCs, flipped GCs dynamically evolve viral envelop protein toward user-defined antibodies (e.g. select
bnAb precursors and intermediates). The overall hypothesis is that, in the context of key modifications, the
GC/affinity maturation system is sufficiently flexible to permit bioengineered viral envelope proteins to affinity
mature toward user-defined bnAb precursors and intermediates. The objective will be pursued with two aims:
1) to establish parameters to engineer GCs as a platform for non-Ig protein evolution. And 2) to generate HIV-1
and influenza envelop variants from flipped GC mice. Completion...

## Key facts

- **NIH application ID:** 10273598
- **Project number:** 1R01AI169619-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Duane R. Wesemann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $740,268
- **Award type:** 1
- **Project period:** 2021-09-17 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10273598

## Citation

> US National Institutes of Health, RePORTER application 10273598, Flipped Germinal Centers (1R01AI169619-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10273598. Licensed CC0.

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