How bacteria-fighting viruses could go mainstream

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Lynn Cole had a blood infection she couldn't shake. For years, she was in and out of the hospital. Each time antibiotics would force the infection to retreat. Each time it came roaring back.

In the summer of 2020, the bacteria flooding Cole's bloodstream stopped responding to antibiotics. She was running out of time. Her doctors decided they had to try a different approach, and asked the US Food and Drug Administration to allow them to administer an experimental therapy, a virus known as a bacteriophage. Bacteriophages - or phages - are tiny viruses that infect and destroy bacteria.

What happened next? The details came out this week in a case study in mBio. The phages worked. Cole recovered with remarkable speed. But then the therapy failed. Cole's case highlights the enormous promise of phage therapy, but it also shows just how much we have to learn.

Welcome back to the Checkup. Let's talk phages. (Or rather, let's talk about phages again.) What will it finally take to bring phage therapy into mainstream medicine?

Phage therapy has been around for more than a century, but it fell out of fashion throughout most of the world with the advent of antibiotics. The deepening antimicrobial crisis, however, has rekindled people's interest and generated an enormous amount of excitement. Headlines have claimed that phages can save the world" and that one day, doctors might prescribe viruses instead of antibiotics."

The excitement reached a fever pitch in recent years because of one particularly compelling story. In 2016, HIV researcher Tom Patterson picked up a deadly antibiotic-resistant infection in Egypt. His wife, infectious disease epidemiologist Steffanie Strathdee, helped hunt for the phage therapy that ultimately cured him. Strathdee gave a TED talk. She and Patterson wrote a book. She told her story in People magazine.

Stories like this have cast phages as a miracle cure. And these tiny viruses do have a lot of things going for them. They target bacteria with stunning specificity. We think of phage as a targeted missile," says Daria Van Tyne, an infectious disease researcher at the University of Pittsburgh and co-author of the new case study. This missile can take out a specific species or strain that is causing the infection, but to leave other commensal bacteria unharmed." What's more, phages aren't as likely to drive bacterial resistance as antibiotics. And they're wildly abundant. You can go to a drop of seawater and find trillions of phages," Van Tyne adds.

But for many people, phages aren't some miraculous elixir. In 2022, researchers published the largest series of case studies of phage therapy for antibiotic-resistant bacterial infections yet. Of the 20 people treated with phages, most with infections related to cystic fibrosis, 11 had a positive response to the therapy. However, only five managed to totally clear their infections. Another six had some partial response. The rest failed to respond or their results were inconclusive.

Let's go back to Lynn Cole.

When Cole first received phage therapy, she had been dealing with a blood infection for nearly a month. Her doctors tried a variety of antibiotics with no effect. But 24 hours after they administered phage therapy, Cole's infection was gone. She seemed cured.

About a month later, however, the infection returned. So the researchers found another phage that would work against the Enterococcus bacteria causing Cole's infection, and began administering both phages. That seemed to do the trick.

For four months, Cole was infection-free. She left the hospital and went on vacation with her family. But then the infection returned. Cole was out of options. She entered hospice, and seven months later she died of pneumonia.

Van Tyne and her colleagues have spent the past couple of years trying to explain why their phages failed. They don't yet have an answer, but they do have a hypothesis. A couple of weeks after Cole began receiving the second phage, she developed antibodies against both phages. Possibly that played a role in limiting how well they were able to find their bacterial targets and kill them," says Madison Stellfox, a physician and postdoc in Van Tyne's lab. She posits that perhaps the antibodies coated the phages so they couldn't enter the bacteria. Or maybe they helped the body clear the phages faster, so they didn't have time to work.

Cole isn't the only patient Van Tyne and her colleagues at the University of Pittsburgh have treated. Since Van Tyne started her own lab in 2018, she has developed a library that contains about 200 phages, most isolated from Pittsburgh's wastewater. Those phages target six or seven species of bacteria. They use that library to develop personalized therapies for patients with life-threatening infections. We're trying to match clinical isolates from infected patients with phages that are active on them," Van Tyne says.

The team has treated nearly 20 patients. Some have cleared their infections. Some, like Cole, have experienced temporary improvements. Some have had no response at all. But reassuringly, no one has been harmed by the therapy itself.

All these patients were treated under the FDA's compassionate use" program, which provides access to investigational therapies for people with life-threatening illnesses. Case studies can provide valuable insights, but they're not a pathway to regulatory approval. To move phages into mainstream medicine, we need clinical trials.

Alexander Sulakvelidze, president and chief executive officer at the phage company Intralytix, has been working to develop phage products since the 1990s. In the Republic of Georgia, where he was born, phage therapy is routinely used to treat infections.

But in the US phage therapy was a hard sell. Intralytix, which launched in 1998, started with baby steps, first seeking approval for phage products to fight bacterial contamination in food products. Now, however, the company is generating revenues, and it has three clinical trials underway to test phage cocktails against three antibiotic-resistant bacteria. But these are trials to assess safety, not the large pivotal trials needed for FDA approval. That's why I'm saying it will be several years until [these therapies] see the light of day," Sulakvelidze says.

The Los Angeles-based company Armata Pharmaceuticals, led by Deborah Birx (yes, that Deborah Birx), is also testing its phage therapies in trials. The company plans to launch an efficacy study, which could be used to seek regulatory approval, in the coming year, although it has yet to find a partner to help fund that endeavor. This kind of pivotal trial will help get pharma interested in phage therapy, and that's the only way it's going to get completely commercialized," Birx says. A pivotal trial will also provide some solid data on whether phages are effective. It is worth moving forward to get a definitive answer," she adds. Because otherwise we're just going to wait, and we'll be sitting here 20 years from now saying are phages important or not?'"

Read more from MIT Technology Review's archive

Dig way back in our archives, and you'll find a piece from 2001 about how phages could be turned into a new class of antibiotics. Paroma Basu has the story.

Last year, in a previous issue of the Checkup, Jessica Hamzelou wrote about the comeback of phage therapy.

A phage cocktail saved a teen with cystic fibrosis from an antibiotic-resistant infection. Charlotte Jee gave us the details in 2019.

DNA sequencing and AI could make it easier for doctors to match infections with the right phage cocktail, Emily Mullin wrote in 2018.

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