# Development of a single-dose rabies virus vaccine

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $390,000

## Abstract

Abstract
A person, usually a child, dies of rabies every nine minutes globally. Current rabies virus (RABV) post-
exposure prophylaxis (PEP) remains complicated and costly, requiring four to five doses of inactivated RABV-
based vaccine plus rabies immune globulin (RIG). A single-dose vaccine that does not require expensive and
often unavailable RIG would greatly increase the efficacy of RABV vaccination, reduce the cost associated with
rabies prevention, and save lives. However, there is a gap in our understanding of how B cells are activated in
response to RABV-based vaccination. For the last 35 years, B cells secreting IgG (but not IgM) were thought to
be solely responsible for vaccine-induced protection against RABV infection via T cell-dependent responses in
post-exposure settings. Furthermore, mechanisms by which B cells acquire RABV antigen were not previously
known. Our laboratory has begun to unravel key attributes of rabies-specific B cell responses that contribute to
the rapid induction of vaccine-induced virus neutralizing antibodies (VNAs). We showed that vaccine-induced T
cell-independent (TI) and early extrafollicular T cell-dependent (TD) B cell responses, including neutralizing
IgM, can limit dissemination of pathogenic RABV into the CNS, providing partial protection in mice. We also
showed that free rabies particles migrate to subcapsular sinus macrophages in the draining lymph node,
transferring RABV antigen directly to B cells. We aim to exploit these findings to develop a single-dose RABV
vaccine regimen. Specifically, we hypothesize that a replication-deficient, matrix gene-deleted RABV-based
vaccine (RABV-ΔM) with enhanced tropism to follicular B cells will result in antigen-specific B cells rapidly
differentiating into IgM and IgG plasma cells, thereby increasing the kinetics, magnitude and quality of early B
cell responses. In this proposal, our goals are to clone, recover and characterize RABV-ΔM-based vaccines
with enhanced tropism to follicular B cells. Next, the new vaccines will be tested in well-described mouse
models of rabies immunogenicity and post-exposure protection. Finally, we will confirm that the genetic
modifications introduced into RABV-ΔM do not adversely affect safety and stability. In addition to expanding
our knowledge of RABV immunity, key insights will be gained regarding how viral vaccines interact with and
activate follicular B cells to induce rapid and potent immunity against viral infections. The major milestone at
the completion of this project is the identification of a safe vaccination regimen that induces potent and rapid TI
and extrafollicular TD B cell responses more effectively than the multi-dose human rabies vaccine, without the
need for RIG. In summary, single-dose vaccine strategies capable of eliciting rapid and robust B cell responses
will improve the efficacy of human rabies vaccines, reduce the cost associated with rabies prevention and save
lives.

## Key facts

- **NIH application ID:** 9812215
- **Project number:** 5R01AI123272-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Matthias Johannes Schnell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2016-11-22 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9812215

## Citation

> US National Institutes of Health, RePORTER application 9812215, Development of a single-dose rabies virus vaccine (5R01AI123272-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9812215. Licensed CC0.

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