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Preventing lung pathology and mortality in rabbit Staphylococcus aureus pneumonia models with cytotoxin-neutralizing monoclonal IgGs penetrating the epithelial lining fluid.

ABSTRACT: Staphylococcus aureus pneumonia is associated with high mortality irrespective of antibiotic susceptibility. Both MRSA and MSSA strains produce powerful cytotoxins: alpha-hemolysin(Hla) and up to five leukocidins - LukSF-PV, HlgAB, HlgCB, LukED and LukGH (LukAB) - to evade host innate defense mechanisms. Neutralizing cytotoxins has been shown to provide survival benefit in rabbit S. aureus pneumonia models. We studied the mechanisms of protection of ASN100, a combination of two human monoclonal antibodies (mAbs), ASN-1 and ASN-2, that together neutralize Hla and the five leukocidins, in rabbit MRSA and MSSA pneumonia models. Upon prophylactic passive immunization, ASN100 displayed dose-dependent increase in survival and was fully protective against all S. aureus strains tested at 5 or 20?mg/kg doses. Macroscopic and microscopic lung pathology, edema rate, and bacterial burden were evaluated 12?hours post infection and reduced by ASN100. Pharmacokinetic analysis of ASN100 in bronchoalveolar-lavage fluid from uninfected animals detected efficient penetration to lung epithelial lining fluid reaching peak levels between 24 and 48?hours post dosing that were comparable to the mAb concentration measured in serum. These data confirm that the ASN100 mAbs neutralize the powerful cytotoxins of S. aureus in the lung and prevent damage to the mucosal barrier and innate immune cells.

SUBMITTER: Stulik L

PROVIDER: S-EPMC6441091 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Preventing lung pathology and mortality in rabbit Staphylococcus aureus pneumonia models with cytotoxin-neutralizing monoclonal IgGs penetrating the epithelial lining fluid.

Stulik Lukas L Rouha Harald H Labrousse Delphine D Visram Zehra Claire ZC Badarau Adriana A Maierhofer Barbara B Groß Karin K Weber Susanne S Kramarić Miroslava Dominis MD Glojnarić Ines I Nagy Gábor G Croisier Delphine D Nagy Eszter E

Scientific reports 20190329 1

Staphylococcus aureus pneumonia is associated with high mortality irrespective of antibiotic susceptibility. Both MRSA and MSSA strains produce powerful cytotoxins: alpha-hemolysin(Hla) and up to five leukocidins - LukSF-PV, HlgAB, HlgCB, LukED and LukGH (LukAB) - to evade host innate defense mechanisms. Neutralizing cytotoxins has been shown to provide survival benefit in rabbit S. aureus pneumonia models. We studied the mechanisms of protection of ASN100, a combination of two human monoclonal ...[more]

PMID: 30926865

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Project description:Ventilator-associated pneumonia is an important clinical manifestation of the nosocomial pathogen Pseudomonas aeruginosa. We characterized the correlates of protection with MEDI3902, a bispecific human IgG1 monoclonal antibody that targets the P. aeruginosa type 3 secretion system PcrV protein and the Psl exopolysaccharide, in a rabbit model of ventilator-associated pneumonia using lung-protective, low-tidal-volume mechanical ventilation. Rabbits infused with MEDI3902 prophylactically were protected, whereas those pretreated with irrelevant isotype-matched control IgG (c-IgG) succumbed between 12 and 44 h postinfection (100% survival [8/8 rabbits] versus 0% survival [8/8 rabbits]; P < 0.01 by log rank test). Lungs from rabbits pretreated with c-IgG, but not those pretreated with MEDI3902, had bilateral, multifocal areas of marked necrosis, hemorrhage, neutrophilic inflammatory infiltrate, and diffuse fibrinous edema in alveolar spaces. All rabbits pretreated with c-IgG developed worsening bacteremia that peaked at the time of death, whereas only 38% of rabbits pretreated with MEDI3902 (3/8 rabbits) developed such high-grade bacteremia (two-sided Fisher's exact test, P = 0.026). Biomarkers associated with acute respiratory distress syndrome were evaluated longitudinally in blood samples collected every 2 to 4 h to assess systemic pathophysiological changes in rabbits pretreated with MEDI3902 or c-IgG. Biomarkers were sharply increased or decreased in rabbits pretreated with c-IgG but not those pretreated with MEDI3902, including the ratio of arterial oxygen partial pressure to the fraction of inspired oxygen of <300, hypercapnia or hypocapnia, severe lactic acidosis, leukopenia, and neutropenia. Cytokines and chemokines associated with acute respiratory distress syndrome were significantly downregulated in lungs from rabbits pretreated with MEDI3902, compared with c-IgG. These results suggest that MEDI3902 prophylaxis could have potential clinical utility for decreasing the severity of P. aeruginosa ventilator-associated pneumonia.

Project description:BackgroundNeutralizing monoclonal antibodies (mAbs) were authorized for the treatment of COVID-19 outpatients based on clinical trials completed early in the pandemic, which were underpowered for mortality and subgroup analyses. Real-world data studies are promising for further assessing rapidly deployed therapeutics.Research questionDid mAb treatment prevent progression to severe disease and death across pandemic phases and based on risk factors, including prior vaccination status?Study design and methodsThis observational cohort study included nonhospitalized adult patients with SARS-CoV-2 infection from November 2020 to October 2021 using electronic health records from a statewide health system plus state-level vaccine and mortality data. Using propensity matching, we selected approximately 2.5 patients not receiving mAbs for each patient who received mAb treatment under emergency use authorization. The primary outcome was 28-day hospitalization; secondary outcomes included mortality and hospitalization severity.ResultsOf 36,077 patients with SARS-CoV-2 infection, 2,675 receiving mAbs were matched to 6,677 patients not receiving mAbs. Compared with mAb-untreated patients, mAb-treated patients had lower all-cause hospitalization (4.0% vs 7.7%; adjusted OR, 0.48; 95% CI, 0.38-0.60) and all-cause mortality (0.1% vs 0.9%; adjusted OR, 0.11; 95% CI, 0.03-0.29) to day 28; differences persisted to day 90. Among hospitalized patients, mAb-treated patients had shorter hospital length of stay (5.8 vs 8.5 days) and lower risk of mechanical ventilation (4.6% vs 16.6%). Results were similar for preventing hospitalizations during the Delta variant phase (adjusted OR, 0.35; 95% CI, 0.25-0.50) and across subgroups. Number-needed-to-treat (NNT) to prevent hospitalization was lower for subgroups with higher baseline risk of hospitalization; for example, multiple comorbidities (NNT = 17) and not fully vaccinated (NNT = 24) vs no comorbidities (NNT = 88) and fully vaccinated (NNT = 81).InterpretationReal-world data revealed a strong association between receipt of mAbs and reduced hospitalization and deaths among COVID-19 outpatients across pandemic phases. Real-world data studies should be used to guide practice and policy decisions, including allocation of scarce resources.

Dataset Information

Preventing lung pathology and mortality in rabbit Staphylococcus aureus pneumonia models with cytotoxin-neutralizing monoclonal IgGs penetrating the epithelial lining fluid.

Publications

Preventing lung pathology and mortality in rabbit Staphylococcus aureus pneumonia models with cytotoxin-neutralizing monoclonal IgGs penetrating the epithelial lining fluid.

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