# Multivalent nanoparticle platforms for elicitation of broadly neutralizing HIV-1 antibodies

> **NIH NIH R21** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $255,000

## Abstract

Project Summary
Efforts in recent years have led to a number of breakthroughs in our understanding of how the immune system
recognizes HIV-1, and this has brought optimism that we are at, or at least close to, one threshold of success –
the elicitation of broadly neutralizing antibodies (bNAbs) in response to vaccination. Substantial focus of late
has shifted toward the design of (SOSIP) immunogens that aim at mimicking the trimeric prefusion closed
conformation of Env, since this is a conformation recognized preferentially by bNAbs, but not by weakly and
non-neutralizing antibodies. These efforts have resulted in primarily autologous neutralization against the
specific immunogen strain. However, when multiple strains are used in the immunization strategy, either as a
cocktail or sequentially, some (generally sporadic) heterologous Tier-2 neutralization has been observed.
These results serve as a strong indicator that incorporating strain sequence diversity within the immunization
strategy will be a critical step toward the design of a vaccine that can elicit truly broadly neutralizing antibody
responses. In addition, recent epitope-focused efforts that rely on a prime-boost strategy involving a fusion
epitope-peptide as a prime and SOSIP trimer as a boost have led to arguably the strongest elicitation of
heterologous bNAb responses to date. While the elicited neutralization breadth was virtually unprecedented, it
was still primarily limited to strains that matched the sequence of the immunogen construct that was used in
the immunization. Together, these results strongly motivate exploring the premise that the incorporation of
strain sequence diversity will be critical for the elicitation of truly broadly neutralizing antibody responses.
 There are a number of different ways in which strain sequence diversity can be incorporated into the
immunization strategy, with immunogen cocktails and sequential immunization being two standard examples.
Here, we propose to develop a new technology that will allow the incorporation of multiple diverse antigens
onto the surface of a self-assembling nanoparticle. The hypothesis here is that placing antigens from diverse
strains in spatial proximity onto the same particle will engage B cells that can simultaneously recognize the
sequence-diverse, spatially proximal, spikes. In this application, we propose to develop such multivalent
nanoparticles in two contexts: for displaying trimeric Env (Specific Aim 1) and for displaying epitope-peptides
(Specific Aim 2) from diverse HIV-1 strains. For both aims, nanoparticles will be designed using computational
technology and validated experimentally using a variety of techniques. Top-ranked nanoparticles will be used
for immunization in rabbits, to evaluate their ability to elicit robust heterologous bNAb responses.
 If successful, this proposal will not only generate new lead HIV-1 immunogen candidates, but will also
result in the development of novel multivalent nanopar...

## Key facts

- **NIH application ID:** 9968008
- **Project number:** 5R21AI147768-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Ivelin Georgiev
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $255,000
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968008

## Citation

> US National Institutes of Health, RePORTER application 9968008, Multivalent nanoparticle platforms for elicitation of broadly neutralizing HIV-1 antibodies (5R21AI147768-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9968008. Licensed CC0.

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