Cross-reactive anti-prophage antibodies and bacterial heteroresistance implicated in phage therapeutic failure

Phage therapy is an exciting strategy against antimicrobial-resistant bacterial infections, but critical knowledge gaps regarding its clinical application persist. Here we present a case study of a 22-year-old male patient with cystic fibrosis, presenting with a recurrent, invasive and ultimately lethal Bordetella bronchialis infection, who failed compassionate-use phage therapy. Using longitudinal clinical samples, we found that our patient harbored pre-existing antibodies against active prophages induced from the genome of the infecting pathogen. Notably, these antibodies may have contributed to clinical failure by cross-reacting with and effectively neutralizing therapeutic phage. We also uncovered bacterial heteroresistance, characterized by bacterial subpopulations from the initial infection with reduced phage susceptibility, as a possible further contributor to treatment failure. These findings highlight the intricate interplay between host immunology, bacterial genetic diversity and phage biology, bearing broad importance for clinical phage therapy. Future phage therapy patients, especially those with chronic infections, should be screened for antiphage immunity and bacterial heteroresistance before phage treatment.