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

Award Number: R01AI146177
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/12/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Protective versus deleterious immune responses that impact vaccine efficacy against Staphylococcus aureus bloodstream infection - 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 toxoid vaccine (Aim 3). The ultimate goal of this proposal is to understand protective vaccine-induced immunity against SA BSI in complementary pre-clinical models to deepen our understanding of immunity to SA BSI to help guide more effective vaccines to prevent disastrous outcomes in future clinical trials.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $556,328 )
2024	2024	ABVACC, INC.	4 RESEARCH CT	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	003	5	3/28/2024	NON-COMPETING CONTINUATION	$619,311
2024	2023	ABVACC, INC.	4 RESEARCH CT	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	4	1/19/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$13,387
2024	2023	ABVACC, INC.	4 RESEARCH CT	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	002	4	3/26/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$62,983
2024	2022	INTEGRATED BIOTHERAPEUTICS, LLC	4 RESEARCH CT STE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	3	1/19/2024	NON-COMPETING CONTINUATION	-$13,387
														Subtotal = $556,328

Issue Date FY: 2023 ( Subtotal = $726,553 )
2023	2023	ABVACC, INC.	4 RESEARCH CT	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	4	4/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$726,553
2023	2022	INTEGRATED BIOTHERAPEUTICS INC	4 RESEARCH CT	POTOMAC	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	3	4/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $726,553

Issue Date FY: 2022 ( Subtotal = $727,487 )
2022	2022	INTEGRATED BIOTHERAPEUTICS, INC.	4 RESEARCH COURT, SUITE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	3	2/24/2022	NON-COMPETING CONTINUATION	$727,487
														Subtotal = $727,487

Issue Date FY: 2021 ( Subtotal = $745,628 )
2021	2021	INTEGRATED BIOTHERAPEUTICS, INC.	4 RESEARCH COURT, SUITE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	2/23/2021	NON-COMPETING CONTINUATION	$745,628
2021	2021	INTEGRATED BIOTHERAPEUTICS, INC.	4 RESEARCH COURT, SUITE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	2	9/27/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $745,628

Issue Date FY: 2020 ( Subtotal = $743,809 )
2020	2020	INTEGRATED BIOTHERAPEUTICS, INC.	4 RESEARCH COURT, SUITE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	1	6/12/2020	NEW	$0
2020	2020	INTEGRATED BIOTHERAPEUTICS, INC.	4 RESEARCH COURT, SUITE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	1	3/12/2020	NEW	$743,809
														Subtotal = $743,809

Grand Total All Awards = $3,499,805

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

Award Number: R01AI146177

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/12/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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