# Building the foundations of commensal vaccines

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $770,910

## Abstract

PROJECT SUMMARY/ABSTRACT
Eliciting or suppressing an adaptive immune response has become central to oncology, autoimmunity, and
infectious disease. Checkpoint inhibitors have revolutionized the treatment of cancer, while TNF inhibitors and
other immune-suppressive biologics have become the standard of care in autoimmune diseases. Vaccines are
a stunning accomplishment of biomedical research; the mRNA vaccines for SARS-2 are only the latest example.
CAR-T cells induce long-term remission in acute lymphoblastic leukemia, a previously incurable disease.
However, current methods for modulating adaptive immunity have serious limitations. Checkpoint inhibitors and
biologics only work in a subset of patients, and global stimulation or suppression of immune function frequently
leads to autoimmunity or opportunistic infection. Despite their extraordinary properties, many vaccines require a
needle and a cold chain, making them difficult to deploy in low- and middle-income countries, and they fail to
induce mucosal immunity, so vaccinated people can infect others. Engineered T cells have not been successful
against solid tumors to date, and ex vivo T cell engineering is costly and difficult to scale.
Here, we propose to address these challenges by tapping into the host’s ‘colonist interaction program’. Certain
bacterial strains from the microbiome elicit a strikingly potent, specific, and durable immune response. In a new
unpublished project in the lab that inspired the work we propose here, we showed that the anti-commensal
immune response can be redirected against the host by engineering commensal bacteria to express host
antigens on their surface. Commensal bacteria have all the key attributes of an ideal vaccine vector: they induce
highly potent, antigen-specific T and B cell responses; colonization is durable on the timescale of years to
decades (experimental evidence suggests the same is true for the immune response they elicit); and colonists
modulate immune function safely, in a way that spares host tissue from autoimmune attack.
Our vision is to create a general platform for eliciting a potent and durable adaptive immune response in a way
that is safe and inexpensive. The kernel of our idea is to develop a set of vaccine scaffolds in which a
commensal is the adjuvant and colonization is the mode of administration. We propose a four-part process
to build the foundations of commensal vaccines: Goal 1: identify a core set of commensals with immune
modulatory properties; Goal 2: optimize CD8+ T cell induction for antitumor therapy; Goal 3: enhance B cell
induction for preventing viral infection; and Goal 4: redirect colonist-specific Tregs against autoimmune disease.
These goals can proceed in parallel, and success in any one of them would have a great deal of impact. We
note that although this work is applied, it will create useful tools for basic research into immune modulation by
the microbiome, just as biologics and methods for T cell engineering h...

## Key facts

- **NIH application ID:** 10709507
- **Project number:** 5R01AI175642-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** MICHAEL ANDREW FISCHBACH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $770,910
- **Award type:** 5
- **Project period:** 2022-09-23 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10709507

## Citation

> US National Institutes of Health, RePORTER application 10709507, Building the foundations of commensal vaccines (5R01AI175642-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10709507. Licensed CC0.

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