Capsid & Tail

Capsid and Tail
a weekly phage periodical
Capsid & Tail

Capsid & Tail is a new micro-periodical that follows the ins and outs of phage therapy, research, and other applications.

Subscribe to get our future capsids!

Issue Four: Crowdsourcing
November 8th, 2018

Phage crowdsourcing

This is the second post in a series on how patients are being treated with phages outside of traditional clinical trials.

But First...

33,000: the number of deaths in Europe caused by antibiotic-resistant infections in 2015. Surprisingly, this new study found that 1/3 of these deaths were in Italy.

Antibiotic Resistance

How much should we worry about phage-induced spreading of antibiotic resistance? This review by Clara Torres-Barceló lays out some contrasting viewpoints and data on the matter.

Antibiotic ResistanceResearch

How big is the market for bacteriophage products? One group estimates that number to be $567.9 million USD.

Phage Industry

A high school sci-comm intern at the Innovative Genomics Institute developed Phage Invaders, a game where you control Cas9 to defend the city of Bacterium against viral infection. Try it here! Also, Jennifer Doudna is challenging others to beat her score…

Teaching ToolGame

Phage crowdsourcing

Last week, we covered how experimental phage treatments are done in the US.

The main issues with experimentally treating patients with phages are:
a) it’s time-consuming and expensive to prepare phages,
b) the right phages are not always at hand, and
c) it’s currently no one’s job.

To help surmount some of these obstacles, sometimes a phage crowdsourcing effort will begin.

If you’ve been involved in phage crowdsourcing and have any insights to share, we’d love to talk to you. Please reach out to us at [email protected]!

Phages can be crowdsourced?

Phage crowdsourcing was done for Tom Patterson and Mallory Smith.

Phage crowdsourcing tends to start with a physician asking for phages on behalf of a patient in need. As we covered last week, some therapeutic phage-producing companies (like Ampliphi or APT) take on emergency cases like these. Sometimes, however, they need extra help, and this is when phage crowdsourcing comes in.

At this point, emails get sent around to research labs around the world. These labs are asked to volunteer their phages, graduate students, postdocs, technicians, lab materials and time in pursuit of phage testing, isolation, propagation and purification.

Volunteers make the difference

In phage crowdsourcing cases, we at Phage Directory step in and send out a Phage Alert to anyone who’s signed up on our site. The emails then either flood or trickle in, generally depending on the organism.

On one side of the spectrum, we had an E. coli phage alert garner nearly a dozen responses from labs willing to help. On the other hand, about a week later, we had a Burkholderia phage alert go completely unanswered. (As many more people study and understand E. coli phages than Burkholderia phages, this was not necessarily surprising.)

Once we identify labs willing to help, we help get them the info they need. Instead of sending people blocks of text, we like to make personal introductions. Usually, this means introducing them to others who’ve been involved in past crowdsourcing efforts. We also help the patient’s medical team understand how and where to ship the patient’s clinical isolates for phage testing.

Pop-up phage-testing hubs

Some labs are willing to offer up their phages, but are not necessarily in a position to accept clinical isolates or produce phages for a patient. As well, the fewer labs the patient’s bacterial isolate needs to be sent to, the better. For these reasons, we help identify 1-2 labs willing to serve as “hubs”. Other volunteer labs are then asked to send their phages to these selected “hubs”.

The idea is that phage-testing hubs will:
a) receive the patient’s bacterial isolate(s),
b) receive the phages volunteered by other labs, and
c) test their own phages and all received phages to find those that can lyse the patient’s strain(s).

If any phages are identified that can potentially help the patient, the phage-testing hub (or another lab, depending on the capacities of the former) would propagate, purify and send the candidate phages to the medical team, which would administer the phages to the patient.

Who pays for this?

Right now, the costs of preparing emergency therapeutic phage preparations in the US are incurred by the volunteers doing the work: phage-producing companies or research labs. Patients are not charged.

Once phages are shown to be effective in controlled clinical trials (many of which are beginning in 2019, as we wrote about last week, more companies will likely start developing phage products as drugs. Eventually, full FDA approval should follow. With full FDA approval, phage treatments would presumably be covered by insurance companies. However, we are years away from that reality, so volunteers are stepping up now to help patients in need.

How can you help?

If your lab or company is interested in volunteering time, space, phages and/or expertise to this cause, please get in touch with us. If you want to talk to someone who’s been involved previously, ask us and we’ll connect you.

If you’re a medical professional with a patient who might qualify for experimental phage therapy, the Center for Innovative Phage Applications and Therapeutics (IPATH) has eligibility criteria and instructions here on how to proceed.

Next week, we’ll cover a unique way Belgium is making phage therapy more accessible.

Thanks for reading!
~ Jessica <>={

Issue Three: eIND
November 2nd, 2018

"The eIND route”: How do people currently get phage therapy in the US?

This is the first of a series of posts about how patients are being treated with phages outside of traditional clinical trials.

But First...

Save the date! The 23rd biennial Evergreen International Phage Meeting will be held in Olympia, WA Aug. 4-9, 2019. The organizers are in the process of selecting ~20 invited keynote speakers. Nominate speakers until Sept. 30! Please include the potential speaker’s full name, institution, and a detailed topic or title.

Conference

Phage Futures 2019 “super early bird pricing” ends today, Nov. 2 (Note: the student rate will still available until Nov. 30). Get 10% off with this code: PHDI10. Also, the organizers just announced that they’re accepting poster submissions until Dec. 17!

SponsorConferencePhage Therapy

Dr. Eleanor Jameson has an opening for a PhD student to study the role of phages in the gut microbiome at the University of Warwick. Apply here!

Jobs

Benler and colleagues at San Diego State University published a new paper that shows that diversity-generating retroelements (which lead to hypervariable proteins) are present in many prophages found in bacteria that live in the human gut. These elements were found in 92 phages, but their role is unknown.

ResearchProphages

"The eIND route” — How do people currently get phage therapy in the US?

Open up nearly any phage-related article, and the first paragraph will probably tell you that phage treatments have been going on for decades in Eastern Europe. But maybe your ears perked up when you heard that patients are now getting phage treatments in the USA, too.

How long has this been going on?

It’s pretty new. In 2016, Steffanie Strathdee and her team at UCSD were the first to get approval from the FDA to use phages on an experimental, emergency, last-resort basis in the US (we wrote about this in our first issue). This was to treat Tom Patterson.

How is this legal?

If a physician has a patient with a serious, multi-drug resistant infection that does not respond to antibiotics, they can get approval to use phages by filing an emergency investigational new drug (eIND) application (also known as Single Patient Expanded Access) with the FDA. Approval can be granted very quickly, and 99% of requests are approved. The eIND only applies to that specific patient, so a doctor has to apply separately for each new patient. Since Tom’s phage treatment in 2016, several other patients have been treated in this way.

Where do the phages come from?

The process of finding and preparing phages for patients in immediate need is actually a much bigger hurdle than securing FDA approval. As well, approval cannot even be granted until phages are found and someone has agreed to produce them for the patient in question.

In the US, two companies are participating in this process on an ongoing basis: Ampliphi and Adaptive Phage Therapeutics (APT). After receiving the patient’s isolate, they test the isolate for phage susceptibility, then propagate and purify the phages that work to kill the patient’s specific strain. Then, the phages are administered to the patient by the patient’s medical team.

The Center for Innovative Phage Applications and Therapeutics (IPATH) at UCSD in San Diego, which involves a team of physicians well-versed in phage therapy, has been involved in the treatment of at least 6 patients in this manner. APT has been involved in the treatment of at least 7 patients in this manner, and Ampliphi has treated patients this way as well.

Sometimes, physicians partner with academic groups to find and prepare phages to treat patients. For instance, the lab of Dr. Ry Young at Texas A&M was heavily involved in preparing phages for Tom Patterson’s case, as was the lab of Dr. Forest Rohwer at SDSU. At Yale, Dr. Benjamin Chan led a successful effort to treat a patient with an infected heart valve with a Pseudomonas aeruginosa phage in his collection.

An uphill battle

It’s very resource-intensive to round up and purify enough of the right phages for a patient. These days, the companies and labs that provide phages for emergency treatments are at or near capacity, and can’t take on all patients who qualify for phage treatments. If that weren’t enough, sometimes a patient is infected with a strain that no one’s phages will kill.

To help surmount some of these obstacles, sometimes a phage crowdsourcing effort will begin. Tune in next week for details on how this process works!

Thanks for reading!
-Jessica <>={

Issue Two: Clinical Trials
October 26th, 2018

Clinical trials: Are phages “there yet”?

You may have heard that phages "still haven’t made it through clinical trials.” What does this mean, and is anyone making any progress on this?

But First...

Dr. Urmi Bajpai invited phage researchers to join a newly unveiled global research consortium for promoting phage and lysin therapy: the International Bacteriophage Research Consortium. This is a collaboration between Acharya Narendra Dev College (University of Delhi, India) and Open Health Systems Laboratory (USA). Join the consortium here!

News

Chen et al. published a groundbreaking new study on the discovery of a new kind of phage transduction that leads to genome hypermobility. You’ve heard of generalized and specialized transduction—now there’s “lateral transduction.”

NewsResearch

Dr. Darren Smith posted a new 24-month postdoc position at Northumbria University in Newcastle upon Tyne, UK. The postdoc will study the ecology and biology of phages in the guts of pre-term infants. Apply by Nov 30, 2018.

Jobs

Eric Boodman wrote a great article on the background of Adaptive Phage Therapeutics (paywall)

News

Clinical trials: Are phages “there yet”?

You may have heard that phages "still haven’t made it through clinical trials.” What does this mean, and is anyone making any progress on this?

Do you have experience with or knowledge of clinical trials? If you have anything to add, please let us know on our feedback page.

We’d love to hear from you!

Are they toxic? Do they work?

To sell a phage as a drug in the US, you need to show the FDA that it’s safe in humans and that it works better than whatever’s already on the market to treat the condition you’re trying to treat. The European Medicines Agency (EMA) regulates drugs similarly in Europe.

Phase I, II, III… what?

You may have heard about phase I, II and III clinical trials. What do these mean? Put simply, phase I trials involve testing the drug on people to see if the drug is safe. Phase II trials involve testing for efficacy and looking for side-effects (usually 100-300 patients). Phase III trials are similar, but involve a lot more patients (usually 300-3000).

Are phages there yet?

Several research groups and companies around the world have completed phase I trials to show that phages are safe in humans. As well, many phage therapy case studies and case series have been done to evaluate phage efficacy. However, although case studies and case series can inform the design of randomized, controlled clinical trials, they do not replace them. Only a few randomized, controlled phase II clinical trials have been completed with phages, and those that have been completed have shown mixed outcomes.

In 2009, a small (24 patients) randomized, controlled phase II clinical trial in the UK showed that phages improved P. aeruginosa-induced ear infections. On the other hand, other randomized, controlled phase II phage trials have had things go wrong.

Are we learning anything?

We can learn a lot about how to do phage trials by scrutinizing the trials that didn’t show phage efficacy. For example, in 2013, a phase II trial was done to test the efficacy of E. coli phages on diarrhea in children, but the phages didn’t get rid of the diarrhea. However, it was later found that the diarrhea probably wasn’t caused by E. coli, so the fact that the E. coli phages didn’t help isn’t surprising. This trial emphasized the importance of pre-identifying the disease-causing organism before treating with phages.

As recently as this year, a phase II trial to test phage treatment of P. aeruginosa-infected burn wounds, known as PhagoBurn, was completed in France, Belgium and Switzerland by the French company Pherecydes Pharma. Unfortunately, this trial showed that phages were less effective than the standard of care for burn patients. However, the company admitted that mixing their phages in a cocktail actually inactivated most of their phages, so patients ended up getting far fewer phages than they were meant to. The surprising part is that this low-level phage treatment actually did help the patients. This trial underscored the importance of understanding the conditions that inactivate or destabilize a given phage before using it for therapy.

What will 2019 bring?

Looking forward, 2019 could be one of the biggest years yet for randomized, controlled clinical trials that look for phage efficacy. For instance, Ampliphi will be doing phase II phage trials to treat Staphylococcus aureus-induced bacteremia and prosthetic joint infections and P. aeruginosa-induced pneumonia and bacteremia. Intralytix will be doing phase II phage trials to treat adhesive invasive E. coli (AIEC) infections in inflammatory bowel disease patients. Adaptive Phage Therapeutics will be testing its phages on UTIs in children (paywall).

Large, controlled, randomized efficacy trials cost a lot more than small safety trials, so it’s a big deal that companies are making these investments. The bottom line is that it’s becoming clear that phages are safe and that they’re probably effective at treating infections—now it’s likely just a matter of getting the conditions right.

Thanks for reading! Next week, we’ll cover phage treatments that are done outside of traditional clinical trials—who’s getting treated and how does this work?

~ Jessica
<>={

Issue One
October 18th, 2018

Phage therapy returns
to the US

Hi everyone!

Welcome to the first issue of Capsid & Tail, a mini-periodical of links, topics, and commentary that covers the ins and outs of the phage world.

This first issue covers Dr. Steffanie Strathdee’s path to treating her husband, Dr. Tom Patterson, with phages—one of the first major phage therapy successes in the US in decades. This led to the creation of the Center for Innovative Phage Applications and Therapeutics, or IPATH, the first phage therapy center in North America.

We’re still working hard to make Capsid & Tail a great resource for all things phage. We’re eager to hear about what you like to read about! Just answer this short, one-question form.

What's New

Pherecydes published the long-awaited results of PhagoBurn, the first blinded, controlled, randomized phage trial on burn patients.

News

AmpliPhi just received positive FDA feedback for phase 2 clinical trials using their phage cocktails against Pseudomonas aeruginosa (AB-PA01) and Staphylococcus aureus (AB-SA01).

News

Steffanie Strathdee and Urmi S. Bajpai announced a new 12-month postdoc position starting July 2019. The postdoc will work on phages in Dr. Bajpai’s lab at ANDC in Delhi. Contact [email protected] to apply (fellowship application deadline is November 15, 2018).

Jobs

Phage Futures (January 29-30, 2019) is a translational phage therapy conference where Steffanie Strathdee, Tom Patterson, the FDA, and others will discuss how we move phage therapy forward in the US. Registration is open to all - use code “PHDI10” for 10% off. We’ll also be there!

Phage Futures 2019

SponsorConferencePhage Therapy

Phage therapy has been around for almost a century, but has had its various starts and stops. The attempts to use phages to battle against bacterial infections were more or less halted when antibiotics became a thing in the 40’s.

In the last decade, antibiotics have started to lose their edge against bacteria, and more people are now suffering from antibiotic resistant infections.

One of these people was Tom Patterson, who suffered a case from antibiotic-resistant Acinetobacter baumanii, which he caught from a vacation trip to Egypt. Luckily for him, his wife is the associate dean of global health sciences, and an unstoppable force of nature, and was able to save his life by gathering a crack team of doctors and researchers in the nick of time.

Watch her describe her efforts in her TedX talk:

or listen to an interview on iTunes or Stitcher with Steffanie and Tom:

You can also read the case study the medical team published or hear what their head doctor, Robert “Chip” Schooley has to say about the case on the JAMA podcast (iTunes or Stitcher).

More recently, Steffanie and Tom announced that they’re publishing a memoir to detail their experiences. It’s available for preorder on Amazon, so please check it out.

The Perfect Predator book cover

Next issue, we’ll cover phage clinical trials—what’s been done, what was learned, and what’s in the works.

Thanks for reading!
~ Jan and Jessica

<>={