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Updated: Oct 10, 2025
Murine Oropharyngeal Aspiration Model of Ventilator-associated and Hospital-acquired Bacterial Pneumonia
Published on: June 28, 2018
Antivirulence Bispecific Monoclonal Antibody-Mediated Protection against Pseudomonas aeruginosa Ventilator-Associated
Fábio Aguiar-Alves1,2, Hoan N Le1, Vuvi G Tran1
1Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Franciscogrid.266102.1, San Francisco, California, USA.
Abstract:
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.
Insights
MEDI3902, a novel antibody, protected rabbits from ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Prophylactic treatment with MEDI3902 significantly improved survival and reduced lung inflammation and systemic disease markers.
Area of Science:
- Infectious Diseases
- Immunology
- Pulmonary Medicine
Background:
- Ventilator-associated pneumonia (VAP) is a severe complication of mechanical ventilation, often caused by Pseudomonas aeruginosa.
- Pseudomonas aeruginosa utilizes virulence factors like the type 3 secretion system (PcrV) and Psl exopolysaccharide to establish infection.
- Effective therapeutic strategies against P. aeruginosa VAP are urgently needed.
Purpose of the Study:
- To evaluate the protective efficacy of MEDI3902, a bispecific antibody targeting PcrV and Psl, against Pseudomonas aeruginosa VAP in a rabbit model.
- To characterize the correlates of protection conferred by MEDI3902, including survival, lung pathology, bacteremia, and systemic biomarkers of acute respiratory distress syndrome (ARDS).
Main Methods:
- A rabbit model of VAP was established using lung-protective, low-tidal-volume mechanical ventilation.
- Rabbits received prophylactic infusions of MEDI3902 or an isotype-matched control IgG (c-IgG) prior to Pseudomonas aeruginosa challenge.
- Survival rates, lung histopathology, bacteremia levels, and longitudinal ARDS-associated biomarkers (including blood gas analysis, lactate, and white blood cell counts) were assessed.
Main Results:
- Prophylactic MEDI3902 treatment resulted in 100% survival, while all control rabbits succumbed to infection within 44 hours (P < 0.01).
- MEDI3902-treated rabbits exhibited significantly reduced lung necrosis, hemorrhage, inflammation, and edema compared to c-IgG treated rabbits.
- MEDI3902 prophylaxis markedly decreased high-grade bacteremia (38% vs 100%, P = 0.026) and prevented the development of ARDS-associated systemic pathophysiological changes.
Conclusions:
- MEDI3902 demonstrates potent prophylactic efficacy against Pseudomonas aeruginosa VAP in a clinically relevant rabbit model.
- The antibody's protective effects are associated with reduced bacterial burden, attenuated lung injury, and preservation of systemic physiological parameters.
- MEDI3902 holds promise as a potential therapeutic agent for preventing or mitigating the severity of P. aeruginosa VAP.
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