Neutralizing antibodies after nebulized phage therapy in cystic fibrosis patients

Abstract

Background Cystic fibrosis (CF) patients are prone to recurrent multi-drug-resistant (MDR) bacterial lung infections. Under this scenario, phage therapy has been proposed as a promising tool. However, the limited number of reported cases hampers the understanding of clinical outcomes. Anti-phage immune responses have often been overlooked and only described following invasive routes of administration. Methods Three monophage treatments against Staphylococcus aureus and/or Pseudomonas aeruginosa lung infections were conducted in cystic fibrosis patients. In-house phage preparations were nebulized over 10 days with standard-of-care antibiotics. Clinical indicators, bacterial counts, phage and antibiotic susceptibility, phage detection, and immune responses were monitored. Findings Bacterial load was reduced by 3–6 log in two of the treatments. No adverse events were described. Phages remained in sputum up to 33 days after completion of the treatment. In all cases, phage-neutralizing antibodies were detected in serum from 10 to 42 days post treatment, with this being the first report of anti-phage antibodies after nebulized therapy. Conclusions Nebulized phage therapy reduced bacterial load, improving quality of life even without bacterial eradication. The emergence of antibodies emphasizes the importance of long-term monitoring to better understand clinical outcomes. These findings encourage the use of personalized monophage therapies in contrast to ready-to-use cocktails, which might induce undesirable antibody generation. Funding This study was supported by the Spanish Ministry of Science, Innovation and Universities; Generalitat Valenciana; and a crowdfunding in collaboration with the Spanish Cystic Fibrosis Foundation. • First report of anti-phage-neutralizing antibodies after nebulized therapies • Long-term follow-up is crucial; antibodies are detected up to 42 days after treatment • The generation of antibodies does not prevent a favorable clinical outcome • Phages can remain in the body after treatment is ceased Multi-drug-resistant (MDR) bacteria are a global health threat, especially for cystic fibrosis (CF) patients with recurrent lung infections. Phages are a promising alternative, but the limited number of clinical trials and the lack of standardized monitoring protocols are an obstacle to their routine use in clinics. The authors describe phage therapy treatments in patients with CF, reporting for the first time the emergence of anti-phage-neutralizing antibodies after nebulization. Their results highlight the importance of assessing the immunogenicity of phage therapeutics regardless of route of administration and the use of personalized phage therapy versus ready-to-use cocktails. This work contributes to the understanding of phage therapy and remarks on the need to regulate and implement phage therapy through clinical trials. Bernabéu-Gimeno et al. describe three nebulized phage therapy treatments in two patients with cystic fibrosis. The authors report for the first time the emergence of anti-phage antibodies after nebulized phage therapy, demonstrating the immunogenicity of phages regardless of the route of administration.

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