# Using DNA/MVA/protein immunization of rhesus macaques to investigate how the background of the HIV-1 envelope and nature of the protein boost shape the genetic and functional antibody landscape.

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $1,037,744

## Abstract

Abstract (Project Summary/Abstract)
Despite a strong and lengthy effort focused on developing an HIV vaccine, immune correlates necessary to
achieve robust and sustained protection remain unknown. The discovery and characterization of numerous
broadly neutralizing antibodies (bnAbs) that neutralize genetically diverse viruses, and the observation that
bnAbs can passively protect against infection in nonhuman primates has generated optimism that strategically
selected envelope (Env) immunogens will induce neutralizing antibodies (nAbs) that are broadly protective.
Recent studies suggest that Env immunogens that (i) preserve features of the native trimer and (ii) are based
on variants from individuals that developed bnAbs are worthy pursuits. We propose to utilize patient-informed
Env immunogens delivered via DNA/modified vaccinia Ankara (MVA) immunization followed by protein boost
to determine how the natural history and presentation of the Envs shape the genetic and functional antibody
landscape in rhesus macaques (RM). The Env immunogen sets are derived from two HIV-1 infected
individuals, chosen due to the disparate nature of their early antibody responses, which can be mimicked by
vaccination, and subsequent development of ‘elite’ or ‘poor’ nAb breadth. Monoclonal antibodies derived from
these two individuals 7 months after infection display striking differences in germline usage, clonality, binding
affinity, and autologous neutralization. Thus, a detailed understanding of how antibody responses are
influenced and altered by the immunogen choice and presentation form will ensure that vaccine efforts can be
driven towards bnAbs, while simultaneously avoiding pathways that produce antibodies with limited function.
DNA/MVA, a vaccine platform that produces robust and durable Env-specific antibody responses in RM and
humans, and has provided protection against SIV challenge, will be used to deliver sequential patient-derived
Env immunogens. These immunizations will be followed by a protein boost consisting of either gp120 or ‘native
flexibly linked’ (NFL) gp140 stabilized trimers. Our ensuing multi-parametric analysis will include antibody
germline usage, somatic hypermutation, development and longevity of clonal lineages, binding affinity (KD),
and capacity to neutralize virus or facilitate Fc-mediated signaling, as well as post-immunization activation of
germinal center (GC) B cells and T follicular helper cells (Tfh). To achieve an unprecedented level of
resolution, our analysis will take place at the single B cell and monoclonal antibody level, examining
plasmablasts, memory B cells, and long lived plasma cells residing in the bone marrow. Based on the results
of these analyses, we will select individual B cells from immunized monkeys for RNA-Seq transcriptome
analysis to connect B cell biology with antibody functional capacity. Our overall hypothesis is that the
immunogens from the ‘elite’ neutralizer will elicit functional neutralizing antib...

## Key facts

- **NIH application ID:** 9941036
- **Project number:** 5R01AI128837-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Cynthia Ann Derdeyn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,037,744
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9941036

## Citation

> US National Institutes of Health, RePORTER application 9941036, Using DNA/MVA/protein immunization of rhesus macaques to investigate how the background of the HIV-1 envelope and nature of the protein boost shape the genetic and functional antibody landscape. (5R01AI128837-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9941036. Licensed CC0.

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