# Iterative Microbial Production and Systems Immunology to Design QS-21 Adjuvants

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2024 · $868,830

## Abstract

Project Summary/Abstract
 Vaccines composed solely of antigens are often poorly immunogenic; increasing intensity and length of
the induced immune response is required to achieve desirable vaccine efficacy. Adjuvants (adjuvare, to help)
are biomolecules used for >100 years to enhance human immune responses to vaccine antigens. Vaccines
containing adjuvants are spectacularly successful, with billions of doses administered to save millions of lives
each year. Despite this success, there is only a limited set of FDA-approved adjuvants (e.g., aluminum salts, oil-
in-water emulsions, CpG oligonucleotides, and an extract [aka QS-21] from the Chilean soapbark tree [Quillaja
saponaria]) owing to the intrinsic toxicity of new adjuvant candidates, difficulty to source and produce them, and
their poor ability to induce long-term immunogenicity. Ongoing efforts to tailor adjuvant bioactivity are limited
because their structure-activity relationships and mechanisms of action are not fully understood. Herein, we
propose to address this challenge by engineering adjuvants through iterative diversification of their molecular
structures (synthetic biology) and deduction of their molecular-level immunogenic mechanisms (systems-level
immunology), an approach that will enable the rapid discovery of improved adjuvants. Recently, we engineered
yeast (Saccharomyces cerevisiae) to produce QS-21 from simple sugars by upregulating native yeast pathways
and heterologously expressing 38 proteins from six other organisms. We also have extensive experience in
profiling (in vitro and in vivo) immunogenicity (innate and adaptive) of small molecules (e.g., adjuvants)
associated with both bacterial and viral antigens. Together, we are uniquely positioned to redesign the microbial
biosynthetic pathway for QS-21 to access its scalable production as well as that of its natural (i.e., QS-7) and
new-to-nature (i.e., a “core pharmacophore”) analogs (Specific Aim 1). QS-21, QS-7, and a “core
pharmacophore” will be starting points for a rapid pipeline that iteratively studies their mechanisms of action
through systems- and molecular-level immunology studies (Specific Aim 2) and diversifies their molecular
structures using combinatorial synthetic biology approaches (Specific Aim 3). Ultimately, this interdisciplinary
and innovative approach will establish a framework to discover the structure-activity relationships that govern
adjuvant immunogenicity and apply this knowledge to design and deploy best-in-class adjuvants that transform
the prevention and treatment of disease.

## Key facts

- **NIH application ID:** 10943067
- **Project number:** 1R01AI186111-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** JAY D KEASLING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $868,830
- **Award type:** 1
- **Project period:** 2024-07-18 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10943067

## Citation

> US National Institutes of Health, RePORTER application 10943067, Iterative Microbial Production and Systems Immunology to Design QS-21 Adjuvants (1R01AI186111-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10943067. Licensed CC0.

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