# Activation of HIV-1 specific B cell precursors using novel vaccine approaches

> **NIH NIH P01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $508,500

## Abstract

Project Summary
According to the World Health Organization, approximately 36 million people worldwide were living with HIV-1
at the end of 2015 and 1.1 million people died from this disease during the same year. Vaccination is the most
effective strategy to prevent infectious diseases, and successful vaccines are usually protective because they
elicit antibodies that neutralize the pathogen (1). Although there is no protective vaccine against HIV-1, broadly
neutralizing antibodies (bNAbs) isolated from infected patients are protective in animal models of infection even
at relatively low concentrations. These antibodies are potent neutralizers that recognize conserved features of
the virus envelope spike (Env) that are shared among diverse strains of the virus, and it is generally agreed that
a vaccine that elicits bNAbs would be protective against HIV-1 infection. However, with the exception of llamas
and genetically engineered mice, bNAbs have not been elicited by vaccination (2). The experiments in genetically
engineered knock-in mice showed that bNAb development required germline-targeting Env-antigens that were
specifically designed to activate B cells expressing the germline precursor antibodies that correspond to bNAbs
(3-5). In addition, singular antigens were not sufficient, and bNAb development required a sequence of specific
immunogens delivered in order (5-8). However, the immunization schemes devised in knock-in mice could not
be extended to wild type (wt) mice or other animals in part because of lack of understanding of the relationship
between germline antigen affinity and bNAb precursor B cell frequency in initiating a productive immune
response in the presence of competing polyclonal B cells. The objects of the proposed research are to: 1. define
the precise relationship between precursor B cell frequency and affinity to cognate antigen, in recruiting bNAb
precursors into the germinal center; 2. test the idea that pre-expansion of specific precursors using anti-idiotypic
antibodies will facilitate the development of anti-CD4bs antibodies. The relationship between affinity and
precursor B cell frequency will be defined in adoptive transfer experiments using antigens provided by Drs.
Stamatatos and McGuire. New vaccination approaches using anti-idiotypic antibodies to expand bNAb
precursor frequency before vaccination will be tested in three different mouse models with variable levels of
polyclonality: I) In HC only knock-in mice which have the lowest level of polyclonality due to variable mouse light
chains II) adoptive transfer of variable numbers of knock-in B cells expressing a single Env-specific BCR into wt
mice and III) fully polyclonal mice expressing human germline Ig genes. The information obtained by these
experiments will advance our understanding of how to approach the problem of how to develop a protective
vaccine against HIV-1.

## Key facts

- **NIH application ID:** 10062819
- **Project number:** 5P01AI138212-03
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Michel C Nussenzweig
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $508,500
- **Award type:** 5
- **Project period:** 2018-12-06 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062819

## Citation

> US National Institutes of Health, RePORTER application 10062819, Activation of HIV-1 specific B cell precursors using novel vaccine approaches (5P01AI138212-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10062819. Licensed CC0.

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