# Manipulating Epitope Immunodominance and Tracking B-cell-Antigen Interactions for Vaccine Design.

> **NIH NIH DP2** · WISTAR INSTITUTE · 2022 · $1,616,010

## Abstract

PROJECT SUMMARY/ ABSTRACT
Infectious diseases are serious and recurrent health threats. Particularly concerning are viruses with the capacity
to mutate and generate de novo diversity in short periods of time. These viruses adapt to new hosts and
environments, and continuously escape from the host anti-viral immune response. Preventative vaccines are
highly desirable; however, no defined guidelines exist for the design of efficacious vaccines against rapidly
mutating viruses such as HIV-1, influenza, or the current SARS-CoV2, with multiple different circulating variants.
Despite their high diversity, viral variants present conserved regions that are essential for viral fitness and
infectivity. These conserved epitopes are their Achilles heels, and the focus of antibody-based vaccine design
efforts. A vaccine against a highly mutating virus should elicit an antibody response that specifically targets the
conserved regions of the virus, as it would recognize and neutralize the broad diversity of its variants.
Significant efforts in the field have focused on engineering viral immunogens to make their conserved epitopes
more available for antibody recognition. Unfortunately, targeting antibody responses to specific conserved
epitopes of interest is incredibly challenging. Complex antigens, such as viral spike proteins, elicit polyclonal
responses dominated by antibodies to non-conserved epitopes. These antibodies have no potential to broadly
neutralize the virus, and also interfere with the maturation of broadly protective antibodies in the germinal centers.
Aiming to elicit broadly neutralizing antibodies (bNAbs) against a conserved epitope of HIV-1, we recently
designed and evaluated a new HIV-1 Envelope (Env)-based priming immunogen, which elicited bNAb-like
antibodies against a conserved epitope of Env in wild type mice and macaques; despite this achievement, these
antibodies showed no neutralization activity against HIV-1, suggesting that additional immunization would be
required to induce bNAbs. Nevertheless, further immunization in macaques elicited a polyclonal antibody
response of only limited potency and breadth, dominated by antibodies to non-conserved epitopes of Env.
Based on these observations, I hypothesize that reducing interfering antibody responses to non-conserved viral
epitopes, and tracking the antibody responses with potential to become bNAbs, will pave the path towards bNAb
development and inform vaccine design efforts. In this proposal, we will design and evaluate a novel
strategy to modulate epitope immunodominance, which in addition, will allow us to record and track the
history of antigen-B-cell interactions in vivo. The proposed technology will be used to customize the
immunodominance properties of complex antigens in order to direct the antibody response to the epitopes of
interest. In addition, we will use our new technology to barcode B cells responding to multiple immunizations,
track their fates and record their histor...

## Key facts

- **NIH application ID:** 10468492
- **Project number:** 1DP2AI175470-01
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Amelia Escolano
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,616,010
- **Award type:** 1
- **Project period:** 2022-09-08 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468492

## Citation

> US National Institutes of Health, RePORTER application 10468492, Manipulating Epitope Immunodominance and Tracking B-cell-Antigen Interactions for Vaccine Design. (1DP2AI175470-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10468492. Licensed CC0.

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