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Enhanced Staphylococcus aureus vaccine protection by uncoupling of the alpha-toxin-ADAM10 interaction

ABSTRACT: Staphylococcus aureus is the leading global cause of bacterial infection-associated mortality, as vaccine development has been elusive. S. aureus alpha-toxin (Hla) is an essential virulence factor in disease. In children, the anti-Hla neutralizing antibody response is the only known correlate of human protective immunity. We demonstrate that the anti-Hla response is limited in the first 2 years of life, illuminating a vaccine-targetable population. We assessed whether Hla antigenic variants would enhance vaccine-mediated immunity in neonatal mice. We identified a variant (HlaH35L/R66C/E70C, HlaHRE) that elicits a nearly 100-fold increase in the neutralizing anti-Hla antibody response compared to other candidate Hla antigens. HlaHRE immunization durably protects against skin and soft tissue infection, enhancing the T follicular helper response and germinal center B cell response. Protective immunity was also conferred to offspring following maternal immunization with HlaHRE. These findings thereby define a novel path for universal S. aureus vaccine development at the maternal-infant interface.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Escherichia Coli

SUBMITTER: Byoung-Kyu Cho

LAB HEAD: Young Ah

PROVIDER: PXD047859 | Pride | 2024-08-13

REPOSITORIES: Pride

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			Action	DRS
	20230405_bkc_23-0244_Wardenburg_Tomaszewski_Sample.mgf	Mgf
	20230405_bkc_23-0244_Wardenburg_Tomaszewski_Sample.raw	Raw
	20230405_bkc_23-0244_Wardenburg_Tomaszewski_Sample.zhrm	Other
	23-0244_1custom.fasta	Fasta

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Project description:Human papilloma (HPV) virus-like particle (VLP) vaccines were recently licensed. Though neutralizing antibody titers are thought to be the main effectors of protection against infection, early predictors of long-term efficacy are not yet defined and a comprehensive understanding of innate and adaptive immune responses to vaccination is still lacking. Here, microarrays were used to compare the gene expression signature in HPV-16 L1 VLP-stimulated PBMC from 17 vaccine and 4 placebo recipients before vaccination, and 1 month after receiving the second immunization. Vaccination with HPV-16 L1 VLP was associated with modulation of genes involved in the inflammatory/defense response, cytokine, interferon and cell cycle pathways in VLP-stimulated PBMC. In addition, there was up-regulation of probesets associated with cytotoxic (GZMB, TNFSF10) and regulatory (INDO, CTLA4) activities. The strongest correlations with neutralizing antibody titers were found for cyclin d2 (CCND2) and galectin (LGALS2). Twenty-two differentially expressed probesets were selected for confirmation by RT-PCR in an independent sample set. Agreement with the microarray data was seen for over two-thirds of these probesets. Up-regulation of immune/defense response genes by VLP, in particular interferon-induced genes was observed in PBMC collected prior to vaccination, with many of these genes being further induced following vaccination. In conclusion, we used gene expression profiling to identify important innate and adaptive response related- genes induced by vaccination with HPV VLP. Further studies are needed to identify gene expression signatures of immunogenicity and long-term protection with potential utility in prediction of long-term HPV vaccination outcomes in clinical trials. Experiment Overall Design: Microarrays (Affymetrix Human Focus) were used to compare the gene expression signature in PBMCs stimulated for 3 days with media alone, Sf9/baculovirus insect cell lysate, and HPV-16 L1 VLP expressed from baculovirus-infected Sf9 insect cells from 17 vaccine and 4 placebo recipients before vaccination, and 1 month after receiving the second immunization (2 months after the initial immunization. Post-vaccination baculovirus sample for Pt078 and pre-vaccination baculovirus sample for Pt082 failed QC.

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Enhanced Staphylococcus aureus vaccine protection by uncoupling of the alpha-toxin-ADAM10 interaction

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