# Leveraging immunostimulatory pathways that enhance BCG vaccination for the rational design of synthetic neonatal vaccine formulations

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2020 · $207,000

## Abstract

PROJECT SUMMARY
Inadequate stimulation of the neonatal immune system and the requirement for multiple booster administrations
have limited the efficacy of the majority of current vaccine formulations. These issues contribute to a window of
vulnerability during which neonates and infants are highly susceptible to infection, resulting in over 2 million
deaths worldwide each year. Despite numerous shortcomings, including waning protection following childhood
and ineffectiveness for adults, the Bacille Calmette-Guerin (BCG) attenuated vaccine against Mycobacterium
tuberculosis (Mtb) safely elicits Th1 neonatal immune responses and requires only a single administration at the
time of birth. Thus, although BCG is in dire need of improvement, it is not burdened by several critical deficiencies
effecting most currently administered immunizations. Furthermore, patients immunized with BCG and other
attenuated vaccines have demonstrated enhanced and more effective immune responses upon infection with
unrelated pathogens later in life resulting lowered overall mortality. These off-target nonspecific benefits are
often referred to as heterologous effects and suggest that immunostimulation by BCG and other attenuated
vaccines may “train” neonatal immune cells for lasting immunological advantages. Thus there is a critical need
to improve the majority of current vaccine formulations to achieve one-shot neonatal immunization while ensuring
programming of neonatal immunity for retention of heterologous effects of attenuated vaccines. Furthermore,
the current global shortage in BCG calls attention to the current lack of scalable synthetic formulations that can
achieve similar and potentially improved efficacy relative to immunization with live attenuated pathogens.
By identifying and mechanistically investigating the principle immunological responses elicited by the BCG
vaccine, synthetic formulations can be rationally designed to mimic the beneficial immunostimulatory pathways
of BCG while avoiding and improving upon its shortcomings. Both the immunological pathways and duration of
immunostimulation elicited by BCG vaccination have been linked to its efficacy as a neonatal vaccine. This
proposal aims to apply a synthetic vaccine depot loaded with strategically selected adjuvant combinations and
possessing highly tunable release kinetics to mimic key pathways and duration of immunostimulation of BCG.
The influences of these pathways on leukocytes, particularly with respect to memory T cell generation and
heterologous immunity, will be investigated in vivo with a humanized mouse model and in vitro using human
derived immune cell populations. The following aims will be achieved:
• Aim 1: Synthetically mimic the release kinetics of BCG for sustained immunostimulation in an in vivo neonatal
 vaccination model.
• Aim 2: Identify the principle immunostimulatory and “training” effects of the most and least effective
 formulations from Aim 1 on human neonatal leukocytes in...

## Key facts

- **NIH application ID:** 9820711
- **Project number:** 5R21AI137932-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** David James Dowling
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $207,000
- **Award type:** 5
- **Project period:** 2018-11-08 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9820711

## Citation

> US National Institutes of Health, RePORTER application 9820711, Leveraging immunostimulatory pathways that enhance BCG vaccination for the rational design of synthetic neonatal vaccine formulations (5R21AI137932-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9820711. Licensed CC0.

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