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Immunodominance of Epitopes and Protective Efficacy of HI Antigen Are Differentially Altered Using Different Adjuvants in a Mouse Model of Staphylococcus aureus Bacteremia.

ABSTRACT: HI, a fusion protein that consists of the alpha-toxin (Hla) and the N2 domain of iron surface determinant B (IsdB), is one of the antigens in the previously reported S. aureus vaccine rFSAV and has already entered phase II clinical trials. Previous studies revealed that HI is highly immunogenic in both mice and healthy volunteers, and the humoral immune response plays key roles in HI-mediated protection. In this study, we further investigated the protective efficacy of immunization with HI plus four different adjuvants in a mouse bacteremia model. Results showed that HI-mediated protection was altered in response to different adjuvants. Using antisera from immunized mice, we identified seven B-cell immunodominant epitopes on Hla and IsdB, including 6 novel epitopes (Hla_1-18, Hla_84-101, Hla_186-203, IsdB_342-359, IsdB_366-383, and IsdB_384-401). The immunodominance of B-cell epitopes, total IgG titers and the levels of IFN-γ and IL-17A from mice immunized with HI plus different adjuvants were different from each other, which may explain the difference in protective immunity observed in each immunized group. Thus, our results indicate that adjuvants largely affected the immunodominance of epitopes and the protective efficacy of HI, which may guide further adjuvant screening for vaccine development and optimization.

SUBMITTER: Chen Z

PROVIDER: S-EPMC8190387 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Several management strategies may improve outcomes in patients with Staphylococcus aureus bacteremia.To review evidence of management strategies for S. aureus bacteremia to determine whether transesophageal echocardiography is necessary in all adult cases and what is the optimal antibiotic therapy for methicillin-resistant S. aureus (MRSA) bacteremia.A PubMed search from inception through May 2014 was performed to identify studies addressing the role of transesophageal echocardiography in S. aureus bacteremia. A second search of PubMed, EMBASE, and the Cochrane Library from January 1990 through May 2014 was performed to find studies addressing antibiotic treatment for MRSA bacteremia. Studies reporting outcomes from antibiotic therapy for MRSA bacteremia were included. All searches, which were limited to English and focused on adults, were augmented by review of bibliographic references from included studies. The quality of evidence was assessed using the Grades of Recommendation, Assessment, Development and Evaluation system with consensus of independent evaluations by at least 2 of the authors.In 9 studies with a total of 4050 patients, use of transesophageal echocardiography was associated with higher rates of a diagnosis of endocarditis (14%-28%) compared with transthoracic echocardiography (2%-15%). In 4 studies, clinical or transthoracic echocardiography findings did not predict subsequent transesophageal echocardiography findings of endocarditis. Five studies identified clinical or transthoracic echocardiography characteristics associated with low risk of endocarditis (negative predictive values from 93% to 100%). Characteristics associated with a low risk of endocarditis include absence of a permanent intracardiac device, sterile follow-up blood cultures within 4 days after the initial set, no hemodialysis dependence, nosocomial acquisition of S. aureus bacteremia, absence of secondary foci of infection, and no clinical signs of infective endocarditis. Of 81 studies of antibiotic therapy for MRSA bacteremia, only 1 high-quality trial was identified. In that study of 246 patients with S. aureus bacteremia, daptomycin was not inferior to vancomycin or an antistaphylococcal penicillin, each in combination with low-dose, short-course gentamicin (clinical success rate, 44.2% [53/120] vs 41.7% [48/115]; absolute difference, 2.4% [95% CI, -10.2% to 15.1%]).All adult patients with S. aureus bacteremia should undergo echocardiography. Characteristics of low-risk patients with S. aureus bacteremia for whom transesophageal echocardiography can be safely avoided have been identified. Vancomycin and daptomycin are the first-line antibiotic choices for MRSA bacteremia. Well-designed studies to address the management of S. aureus bacteremia are needed.

Project description:ObjectiveTo identify risk factors and outcomes associated with thrombocytopenia at sepsis onset in Staphylococcus aureus bacteremia.Patients and methodsThis single-center, retrospective, cohort study consists of all adult patients with a first episode of clinical S aureus bacteremia between April 1, 1988, and September 30, 1994, and between January 1, 1999, and December 31, 2007. Thrombocytopenia was defined as a platelet count less than 150 × 10(9)/L. The primary outcome was 30-day all-cause mortality. Risk factors for 30-day all-cause mortality were identified using univariate and multivariable analyses. Multivariable analysis was conducted using forward step logistic regression analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for risk of death.ResultsA total of 1052 patients had clinical S aureus bacteremia. Thrombocytopenia at sepsis onset was present in 235 patients (22.3%). Thrombocytopenia was associated with community-acquired bacteremia, infections caused by methicillin-sensitive S aureus, high-magnitude bacteremia (defined as >4 positive blood cultures [? 3 separate positive blood culture sets]), and endocarditis. Patients with thrombocytopenia presented more commonly with severe sepsis reflected by septic shock and acute renal failure. Thirty-day mortality was significantly higher among patients with thrombocytopenia (132/235 [56.2%]) vs those without thrombocytopenia (281/817 [34.4%]; P<.001). Higher mortality was associated with the degree of thrombocytopenia. In multivariable analysis, thrombocytopenia at baseline remained an independent risk factor for 30-day mortality (OR, 2.82; 95% CI, 1.87-4.24). The adjusted association between thrombocytopenia and death remained similar among the 917 patients with monomicrobial bacteremia (OR, 2.88; 95% CI, 1.83-4.53) and the 945 patients who did not die within the first 48 hours (OR, 2.88; 95% CI, 1.87-4.45.).ConclusionWe observed a strong association between thrombocytopenia at sepsis onset and all-cause mortality in S aureus bacteremia, possibly related to mechanisms other than sepsis alone.

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Immunodominance of Epitopes and Protective Efficacy of HI Antigen Are Differentially Altered Using Different Adjuvants in a Mouse Model of Staphylococcus aureus Bacteremia.

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