Dr. Graham Hatfull on Trialing Bacteriophages for Unprecedented Therapeutic Gains
By Brittany Wade
February 7, 2023 | In 2019, antimicrobial-resistant pathogens claimed the lives of 1.27 million people worldwide, prompting the Centers for Disease Control and Prevention to label them an “urgent global public health threat.”
While certain pathogens continue rendering antibiotics useless, doctors eagerly seek alternate antibacterial avenues. “These are physicians who have patients in the direst of circumstances. The antibiotics are often not well-tolerated. They’re toxic, and physicians are out of options,” Graham Hatfull, Ph.D., professor of biological sciences at the University of Pittsburgh, tells Deborah Borfitz, Clinical Research News senior writer and host of the Scope of Things podcast.
Hatfull’s lab aims to mitigate this global health threat by studying and expounding upon the clinical use of bacteriophages. These viruses—also known as phages—infect and kill bacteria and are quickly gaining popularity as a new and promising therapeutic tool.
Phages are not only viable antibacterial entities but—in many cases—may be superior to antibiotics. Phages already exist within the human body and cannot replicate in human cells, posing a minimal risk. Hatfull adds, “It is very rare to see any adverse reactions [with phages]. They seem to be very well-tolerated. This is a welcomed relief for many patients.”
Phages also help patients with chronic comorbidities. For example, those with cystic fibrosis (CF)—a genetic disorder associated with breathing and digestive complications—often experience exacerbated symptoms caused by Mycobacterium abscessus and Pseudomonas infections. When CF patients need a lung transplant, phages excel at fighting infections during the immunosuppressive state, stabilizing the body and decreasing the probability of tissue rejection.
Additionally, phages are relatively easy to isolate, have demonstrated documented success against stubborn and highly resistant pathogenic strains, and are naturally abundant. “There’s probably more bacteriophage particles in the world than all other forms of life taken together… If you take a spoonful of seawater or pond water and measure the number of virus particles sitting in the teaspoon, it would be about a million,” says Hatfull.
With so many positive attributes, scientists are working diligently to learn more about these viruses and conduct studies to justify broader use.
Trialing Phage Therapy
In 2021, Hatfull led a study in which 20 patients with a nontuberculous Mycobacterium infection received phage therapy. More than half exhibited “favorable clinical or microbiological responses” after treatment (Clinical Infectious Diseases, DOI: 10.1093/cid/ciac453). Each patient was administered a single phage—as opposed to a phage cocktail—and remarkably, there were no signs of phage resistance or adverse reactions from any patient.
The U.S. Food and Drug Administration (FDA) authorized Hatfull’s study for compassionate use in patients for whom phage therapy was a last resort. Before phages can enter randomized controlled trials successfully, scientists must expand the library of known phages and the potential diseases they cure. The phage community has cataloged over 22,000 phages thus far, but only approximately three dozen have been identified for therapeutic use.
Hatfull’s team is also working on a genomic analysis project to sequence the viruses and secure a better understanding of their genetic profiles. They hope to pinpoint functional similarities by grouping phages with similar genomes. Hatfull says, “Phage discovery and understanding what the phage population looks like is the primary driver of [our research]. It fuels the utility of phages. Using them to treat patients with similar types of infections is a productive outcome and a development that is very motivating and stimulating.”
Hatfull believes that the most pressing work of getting phages to randomized controlled trials exists on the microbiological level. Assisting in these efforts is a group of undergraduate “phage hunters” who spend two-semester stints discovering, isolating, naming, and researching new phages. Co-administrated by Hatfull’s team, SEA-PHAGES—Science Education Alliance-Phage Hunters Advancing Genomics and Evolutionary Science—is a student-oriented phage discovery program in multiple American universities with some contributions from India, Germany, and Taiwan. Approximately 40,000 students have participated since the program's inception in 2008.
Hatfull reports that several other compassionate use studies are underway in the United States and beyond. In Australia, a national network of phage scientists—called Phage Australia—established the necessary infrastructure to increase the use of phage therapy across the continent. The United Kingdom and Belgium are also developing similar action plans.
Still, the goal is to use standardized trials to showcase phages’ therapeutic power. “We would like to conduct randomized standard clinical trials to… have controlled studies that will give us definitive answers on how well they work and how we may be able to use them: dose, roots of administration, different types of outcomes, etc.,” says Hatfull. He reports that a handful of standardized trials are currently under review and waiting for approval by the FDA.