# Protective versus deleterious immune responses that impact vaccine efficacy against Staphylococcus aureus bloodstream infection

> **NIH NIH R01** · INTEGRATED BIOTHERAPEUTICS, INC. · 2021 · $745,628

## Abstract

Staphylococcus aureus (SA) is a major human pathogen that can cause life threatening systemic infections. In
fact, S. aureus is the most common cause of nosocomial bacteremia with a prevalence of 26%. Despite
improvements in clinical care, SA bloodstream infection (BSI) continues to pose a major challenge due to high
rate of treatment failure and mortality. Infections that are caused by methicillin-resistant SA (MRSA) strains are
becoming increasingly resistant to antibiotics, leading to treatment failures and poor patient outcomes. If host-
directed therapies such an effective SA vaccine can provide an alternative to antibiotics, a greater understanding
of immune mechanisms that promote protection is essential. This is especially important since all SA vaccination
attempts over the past two decades have failed in human trials. Notably, in a recent trial, a vaccine targeting SA
iron surface determinant B (IsdB) against SA infections following cardiothoracic surgery had the opposite effect
and patients who were vaccinated and suffered a SA infection had a 2-fold higher rate of multiorgan failure and
a 5-fold higher mortality than placebo controls. While reasons for this catastrophic outcome are still unknown, a
post-hoc study suggested that absent or low serum T cell cytokine levels (IL-2 and IL-17) at the time of
vaccination predisposed them for treatment failure. There is therefore an urgent need to understand the
underlying immunological mechanisms that lead to these deleterious outcomes. Our preliminary findings in mice
recapitulate deleterious immune responses triggered by immunizing mice with a lethally irradiated whole cell
vaccine or by intradermal exposure to SA that led to exacerbated disease and mortality upon SA BSI challenge.
This phenotype was associated with a CD4 T cell mediated, IFNγ-dependent immunopathology and likely an
imbalance of Th1/Th17 responses. The goal of this proposal is to test the overarching hypothesis that prior
exposure to SA antigens and virulence factors or cutaneous SA infection impact natural- and vaccine-elicited
CD4 T cell responses during a subsequent SA BSI. To this end, using mice we will fully characterize the T cell
responses to two vaccine platforms and will evaluate how the initial response to SA surface antigens or to a
toxoid vaccine differentially regulate the CD4 T cell response, and consequently the vaccine-elicited immunity
against subsequent SA BSI and if these responses can be influenced by different vaccine adjuvants (Aim 1).
Using WT mice and human HLA-DR4 transgenic mice as well as several WT and isogenic mutant SA strains we
will investigate how pore forming toxins and superantigens modulate CD4 T cell responses that affect natural
and vaccine induced immunity against SA BSI (Aim 2). We will also establish and use a novel nonhuman primate
model of SA BSI and evaluate the impact of pre-exposure on vaccine immunogenicity, with a focus on CD4 T
cell responses, and efficacy of our multivalent...

## Key facts

- **NIH application ID:** 10126802
- **Project number:** 5R01AI146177-02
- **Recipient organization:** INTEGRATED BIOTHERAPEUTICS, INC.
- **Principal Investigator:** M Javad Aman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $745,628
- **Award type:** 5
- **Project period:** 2020-03-12 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126802

## Citation

> US National Institutes of Health, RePORTER application 10126802, Protective versus deleterious immune responses that impact vaccine efficacy against Staphylococcus aureus bloodstream infection (5R01AI146177-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10126802. Licensed CC0.

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