Phage Therapy is on the Rise
The technique of targeting bacteria with viruses that destroy them is making a comeback, and it could help in the battle against antibiotic resistance.
In December of 2008, Minnesotan chef John Haverty was pumping gas into his car when he slipped and fell on a patch of ice. He twisted his right knee, ripping open the sutures still embedded in his skin from a knee replacement several weeks prior. Realizing what had happened, Haverty finished filling his gas tank and then took himself to the emergency room.
The doctors cleaned his knee, repaired the sutures, and sent Haverty on his way. But by that point, bacteria had already worked their way into the flesh of Haverty’s knee. “We weren’t aware of the [infection] at the time,” Haverty says. “But that bacterial [infection] was present for the next 13 years.”
Over the course of the next decade, Haverty would try almost every antibiotic in medicine’s arsenal. One infection would clear and then another would emerge soon after. After years of failed antibiotic use, numerous severe reactions to different antibiotics, and 18 separate surgical procedures, Haverty’s doctor at the Mayo Clinic in Rochester, Minnesota, told him their only option left was to amputate his entire right leg. The proposed amputation of his limb at the hip would leave Haverty unable to be fitted for a prosthesis, and he faced the prospect of being bound to a wheelchair for the rest of his life.
In the United States, stories like Haverty’s are not unusual. Antibiotic-resistant bacterial infections are growing more and more common, and doctors often run out of ways to treat them effectively. According to the Centers for Disease Control and Prevention (CDC), at least 2.8 million people in the United States suffer from antibiotic-resistant infections each year, and more than 35,000 people die. This alarming increase in cases of resistant infections is accompanied by a global struggle to discover new and effective antibiotics. The World Health Organization’s 2020 report on antibacterial agents in clinical and preclinical development found that 80 percent of the new antibacterial agents approved since 2017 have very little clinical benefit as they are derived from existing drug classes where resistance mechanisms are already well established.
The day after Haverty received the news that amputation was his only remaining option, he got a call from an infectious disease doctor at the Mayo Clinic. The doctor told Haverty about something called phage therapy, which involves treating the infection with viruses known as bacteriophages. It is a very old idea, hotly pursued in the 1920s and 1930s before the discovery of penicillin, and it has been re-emerging over the last two decades as a new, experimental treatment. The doctor thought it might be able to save Haverty’s leg. “Why not take a chance if the other result is amputation?” Haverty asked himself. “I was willing to do anything before I had to lose my leg.”
“Phage therapy gave me my life back.”
Phage therapy takes advantage of the fact that just as there are viruses that infect humans, insects, plants, and even other viruses there are also viruses that infect bacteria. Bacteriophages (“bacteria eaters” in Latin) are those viruses. They can selectively target and kill bacteria without harming human cells, and that presents an opportunity to use them to create potent and targeted therapies against antibiotic-resistant bacterial infections.
Even though research on bacteriophages for treating infections fell by the wayside after the advent of antibiotic discovery in the United States, phage therapy actually continued in earnest for years in the former Soviet Union. Places like Ukraine and Georgia were hotbeds for studying and implementing phage therapy for decades during the Cold War. The Eliava Phage Therapy Center in Tbilisi, Georgia has been researching the use of phages continuously since 1923. The United States is now following their lead as desperation for new treatments grows.
One last shot to save his leg
The Mayo Clinic helped put Haverty in touch with Adaptive Phage Therapeutics, a biotech company working to develop phage therapy against the most problematic drug-resistant bacterial infections. They are building an arsenal of phages that can be deployed to fight resistant infections. Haverty’s type of infection, a prosthetic joint infection, just so happened to be one that Adaptive Phage Therapeutics was building a clinical trial for.
“The [Mayo Clinic] called us and said that they would love to try phage therapy before they resort to amputation,” says Greg Merril, the company’s founder and CEO. “So they sent over a culture of his infection and we sent back phage.”
In early 2019, Haverty underwent intravenous phage therapy infusions five days a week for eight weeks. On the first day of treatment, his leg was red and swollen, and he was in a tremendous amount of pain. “He couldn’t bend his knee,” Merril says. But within 48 hours of receiving treatment, Haverty’s knee had almost no sign of infection.
“I went from having only a 10- to 15-degree flex in my knee to 90 degrees. I could go to restaurants without putting my leg on a chair. I could drive my car again. Phage therapy gave me my life back,” Haverty says. He is scheduled to start his next round of phage therapy soon with Adaptive Phage Therapeutics to address a lingering strain of bacteria. He is hopeful that this will be his last phage treatment and the end of over a decade of chronic infection.
For Merril, phage therapy is the next step in bacterial treatment—and one he hopes will permanently relegate stories like Haverty’s into the pages of history. His company is creating a growing collection of hundreds of bacteriophages, each of which is specific for a certain strain of bacteria. This ever-expanding library is called PhageBank. And they recently entered into a partnership with the Mayo Clinic to test the bacteria taken from people like Haverty against panels of phages from their library. They also have five clinical trials in progress to gauge the effectiveness of phage therapy against several types of infections, including diabetic foot osteomyelitis, prosthetic joint infection, chronic recurrent UTI, ophthalmic infection, and cystic fibrosis-related lung infection.
Experts say the viruses also have the potential to become a prophylactic or preventative treatment. PhagePro, an early-stage biotech company based in Boston, is working to use oral phage therapy as a way to prevent cholera infections.
According to Minmin Yen, PhagePro’s founder and CEO, family members, caregivers, and people living with someone infected with cholera are at much greater risk of contracting the gut infection themselves. So if household transmission can be halted, it stops the potential for a larger outbreak. There are already antibiotics on the market effective against cholera, but using them to prevent infections is fraught because that could lead to the emergence of much more dangerous and hard-to-treat antibiotic-resistant strains.
“The idea is that the phages would already be in the area where the infection would take place so they can kill the bacteria before they begin colonizing.”
“Antibiotic-resistant [cholera] is a huge problem, so antibiotics as prophylaxis are not going to work,” Yen says. “Phages, I think, are a great solution that combines the philosophy of prevention over treatment to stop a problem before it arises.”
PhagePro has been working closely with the International Center for Diarrheal Disease Research, Bangladesh to develop and test an oral phage therapy that will essentially inoculate a person against cholera. “It’s a different mechanism than a vaccine, which uses the body’s own immune system to mount defenses,” Yen says. “Phages are much more direct. The idea is that the phages would already be in the area where the infection would take place so they can kill the bacteria before they begin colonizing.”
Cholera is not a commonplace infection in the United States, but in countries like Bangladesh, India, and Haiti, cholera outbreaks can be a serious health risk. According to the World Health Organization, there are between one to four million cases of cholera worldwide each year. In 2019, nearly one million cholera cases were reported in 31 countries. Refugee camps also tend to be at a much higher risk for cholera due to poor hygiene and sanitation. There is a cholera vaccine that is used during outbreaks, but it takes two to three weeks before a person is protected.
“So, what do you do in that intervening time?” Yen asks. “We think phages could be a really helpful complement because they would immediately protect a person while they wait.” Yen hopes that PhagePro will begin clinical trials in Bangladesh soon to push their prophylactic phages forward, though there is still a long way to go. No form of phage therapy is currently FDA approved, so it can only be used in emergency, experimental, or compassionate use cases.
The rise of antibiotic resistance may have one silver lining. It is helping to create a thriving industry for phage therapy. The NIH is jumping on board and, in 2021, awarded 2.5 million dollars in grant money to help support phage therapy research. Several companies are also taking center stage in their efforts to bring phage into mainstream medicine. To name a few, Armata Pharmaceuticals, Intralytix, Locus Biosciences, and Adaptive Phage Therapeutics are building robust systems and research protocols to support phage therapy as it evolves. There is even a peer-reviewed journal that started in 2019 called PHAGE that is entirely dedicated to bacteriophages and new research surrounding these bacteria-eating viruses. As conferences pop up around the globe, phage therapy is gaining more and more traction as a potential way to curb the tide of antibiotic-resistant infections.
“Everyone wants this to work. And people are starting to notice. And the more attention [phage therapy] gets and the more people who are drawn to the field, the more innovation happens,” Yen says. “What’s really exciting is we’re starting to build an infrastructure, something that will last. And I think we are just on the cusp of that.”