# Vaccine Assembly from Surface Proteins of Staphylococcus aureus

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $410,000

## Abstract

ABSTRACT
Staphylococcus aureus is a human-adapted pathogen that replicates by asymptomatically colonizing its host.
Nasal colonization is observed in the first weeks of life and persists despite the development of serum IgG
against staphylococcal antigens. S. aureus is also an invasive pathogen, causing soft tissue, wound, lung,
skeletal and bloodstream infections in community- and hospital-settings. Infection with antibiotic-resistant
strains, designated methicillin-resistant S. aureus (MRSA), is associated with treatment failure and poor
disease outcomes. MRSA and methicillin-sensitive (MSSA) strains are frequent causes of infectious disease
morbidity and mortality in the United States. It is not always clear why colonization progresses to infection but
such transition indicates that antibody responses elicited upon colonization are not protective. The surface of
S. aureus is coated with over 10,000 molecules of Staphylococcal protein A (SpA) linked to peptidoglycan by
the Sortase A enzyme. Using genetic and biochemical schemes, we found that peptidoglycan-modified SpA
diverts antibodies away from their intended targets by interacting with the Fcg domain of IgG and by blocking
complement activation. Thus, surface exposed SpA neutralizes the effector functions of pathogen-specific
antibodies, including antibodies elicited by candidate vaccines. SpA is also released from the bacterial
envelope and binds the variant heavy chains of VH3-IgM that serves as the B cell receptor (BCR) in
approximately half of human B cells. SpA-BCR interactions prevent the development of neutralizing anti-SpA
antibodies and instead trigger B cell proliferation and the secretion of VH3-rearranged antibodies with no
specificity toward S. aureus. Carefully applied molecular engineering yielded the non-toxigenic SpA* vaccine
that elicits SpA-neutralizing antibodies. When tested in our mouse model of colonization that takes advantage
of the mouse-adapted strain WU1, we found that SpA* immunization leads to broad spectrum anti-S. aureus
immune responses. We presume that some of these antibodies target the colonization factors of S. aureus that
we seek to identify in this proposal. We also presume that during colonization SpA diffuses into nasal-
associated lymphoid tissues to reprogram their B cell repertoire. Lastly, we will evaluate mechanisms of
protection against colonization by examining the contribution of serum opsonophagocytic antibodies and
luminal IgA for the nasopharyngeal clearance of S. aureus.

## Key facts

- **NIH application ID:** 10793588
- **Project number:** 5R01AI052474-20
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Dominique Missiakas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2002-06-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793588

## Citation

> US National Institutes of Health, RePORTER application 10793588, Vaccine Assembly from Surface Proteins of Staphylococcus aureus (5R01AI052474-20). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10793588. Licensed CC0.

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