Mucosal administration of anti-bacterial antibody provides long-term cross-protection against Pseudomonas aeruginosa respiratory infection

Abstract

Bacterial respiratory infections, associated with acute, sometimes recurrent infections and with chronic respiratory diseases, are a major threat for human health. Mucosal administration of therapeutic antibodies (Ab), using the airways as a delivery route, has a tremendous opportunity to benefit to patients with respiratory infections, with remarkable preclinical achievements in both viral and bacterial respiratory infection models and ongoing clinical developments. The primary mode of action of anti-infective Ab delivered through the airways is pathogen neutralization and to a lesser extent, Fc-mediated direct recruitment of immune effectors to facilitate their elimination. Using a mouse model of acute pneumonia induced by P. aeruginosa, a bacterium frequently associated with multidrug resistance and a high rate of recurrence, we characterized an immunomodulatory mode of action of anti-bacterial Ab. Beyond the rapid and efficient containment of the primary infection, the anti-infective Ab delivered through the airways harnessed adaptive immunity to provide a long-term response, preventing from a secondary pathogen infection. This effect is specific and dependent on the Ab dose, intensity of infection and antigen expression by the pathogen upon primary infection. As shown by adoptive transfer experiments, it is mediated by a sustained and protective humoral immune response. Interestingly, the long-lasting response protected partially against secondary infections due to heterologous P. aeruginosa strains. Overall, our findings suggest that mucosal delivery of Ab through the airways offers a dual advantage: a rapid onset of action to neutralize respiratory bacteria and a long-term protection against secondary infections, thereby opening novel perspectives for the development of anti-infective antibody delivered to the lung mucosa, to treat respiratory infections.