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The Quest to Make a Vaccine for Urinary Tract Infections

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If you are alive and in possession of a vagina, chances are you will have a urinary tract infection at some point in your life. UTIs are one of the most common bacterial infections, which might lead you to assume that modern medicine has nearly perfected its treatment options for this uncomfortable and potentially dangerous condition.

Unfortunately, you’d be wrong.

“If you have a run-of-the-mill urinary tract infection, you tend to get a lower-grade antibiotic,” Paul Garofolo, the co-founder and CEO of pharmaceutical company Locus Biosciences, told The Daily Beast. “And nowadays, 50 percent of the time you’re back in the doctor’s office within 30 to 90 days saying, ‘Hey, I got another one.’ And you’re pissed.”

The data show that as many as one in four of people who contract a UTI will have a recurrent infection, defined as more than one UTI in a six-month period, or more than three annually. Not only are these acutely painful, they can be frustrating and anxiety-inducing to deal with again and again. One study of 29 women with recurrent UTIs found that patients were worried about “creating a monster of a UTI infection that will be resistant to anything” and having other drug-resistant infections in the future. Others complained that using antibiotics for a UTI is “like killing a mosquito with a grenade,” but that doctors were unwilling to look to other treatments.

A number of factors we’re still investigating play a role in how susceptible someone is to recurrent UTIs, including the composition of the microorganisms in the urogenital tract, hormone levels, antibiotic resistance, and the body’s own immune system.

What is known, however, is that a course of antibiotics routinely prescribed for a UTI today is a ticking time bomb. “The fact that UTIs are very common, along with the fact that we don’t always do testing in a laboratory to determine which antibiotics are best suited, means it’s a good recipe for creating resistance,” Lisa Bebell, an infectious disease physician at Massachusetts General Hospital, told The Daily Beast. Broad-spectrum antibiotics that are used as second- and third-line defenses can have ripple effects on the body’s microbiome, and even lead to increased susceptibility for UTIs in the future by setting the stage for a vaginal yeast infection.

Unsurprisingly, scientists and patients want a better alternative. More modern UTI research today, of the kind Locus Biosciences is pursuing, take unusual and experimental approaches to see what treatments might clear the infection without wreaking more havoc on the body (and we’re talking about therapies that definitively cure or prevent infection—not cranberry juice).

James Cook / Massachusetts General Hospiral

Crucially, this new research builds off of a counterintuitive and audacious proposal: What if we treated a bacterial infection with something other than antibiotics?

“The goal is most definitely to eventually knock antibiotics out of the treatment paradigm for these infections,” Garofolo said.

A Post-Antibiotic World

A fundamental question that could lead to better treatments is why certain people are more likely to contract a UTI that just won’t go away. Age matters a fair amount, as UTI rates are higher in young, sexually active women and postmenopausal women than in other groups. A confluence of research is starting to demonstrate that hormones and microbial communities may play a larger role than previously thought. One paper, published by researchers from Texas on Friday in the journal Cell Reports Medicine, clears up some of the murkiness surrounding these relationships, starting with the misconception that the breeding grounds for UTI-causing bacteria—the urinary tract and bladder—are sterile.

“Decades of medical dogma have assumed sterility of urine and the urinary tract; however, a robust body of work has established the existence of a human urogenital microbiome,” the authors wrote in the study. The microbiome consists of all the living microorganisms that reside in the human body, and disruptions in their balance may predispose people to certain diseases.

The Texas researchers studied the microbiomes and urine of 75 postmenopausal women with varying histories of UTIs, to figure out whether recurrent UTIs correlated with irregular microbiomes, and to identify causes for the imbalance. They found that the urogenital microbiomes of women with a history of recurrent UTIs had higher levels of bacterial groups that are commonly found during an active infection, versus women without a history of UTIs. On the other hand, women without a recurrent UTI history had higher levels of estrogen that were associated with more Lactobacillus species—probiotic strains of bacteria that may protect against infection.

“The fact that UTIs are very common, along with the fact that we don’t always do testing in a laboratory to determine which antibiotics are best suited, means it’s a good recipe for creating resistance.”

— Lisa Bebell, Massachusetts General Hospital

Topical or vaginal estrogen cream for people who have gone through menopause may be helpful to break the cycle of recurrent UTIs, said Bebell, who was not involved with the research. She added that “the jury’s still out” and definitive evidence of estrogen’s benefit is needed.

At least one other trial is looking at whether another hormone—testosterone—can help prevent UTIs. In a small pilot trial published in May, researchers in New York found that a vaginal testosterone cream increased the abundance of Lactobacillus species and improved overall vaginal health. Larger sample sizes and longer follow-up will be needed to tell if the hormone can prevent UTIs, the authors wrote.

Others are pursuing a more permanent solution to UTIs: a vaccine that can be offered on a yearly or semiannual basis. Although some vaccines are already available to prevent UTIs in countries outside the U.S., Soman Abraham, a pathology researcher at Duke University School of Medicine, told The Daily Beast that these existing methods have not shown high levels of efficacy. “We believe that one reason why those current immune vaccines are not that protective is the antibody levels [they produce] aren’t high enough,” he said.

Abraham and his team think they may have found a better version, however—one that has been shown to reduce harmful bacteria in the bladders of mice threefold. The body responds to bacteria in the urinary tract by shedding cells in the walls of the bladder and calling off other immune cells until this process is complete; the vaccine, in contrast, overrides those signals and gives the fighters the go-ahead to take care of the bacteria before they can multiply. Abraham and his team are working to demonstrate their vaccine’s safety in other animals so that they can eventually test it in humans.

Race for the Cure

While estrogen, probiotics, and vaccines could be effective measures at preventing UTIs, there remains the issue of treating a UTI once contracted. For that, researchers have at least one surprising solution in the pipeline: phage therapy.

There’s another reason why using antibiotics to treat UTIs is like putting a square peg in a round hole, said Greg German, a medical microbiologist at the University of Toronto. Bacteria in the urogenital tract form biofilms, which are like a “wall of defense” that antibiotics can only partially permeate. Bacteria behind the biofilm remain unharmed, and can then reinfect an individual once they’ve finished a course of drugs.

“After medical school, I had a chance to treat patients with drug resistant infections and was very frustrated for all the patients having to use IV therapy extensively,” German told The Daily Beast. “I wanted to see if there was anything else that could be done; phage therapy was a natural opportunity.”

“I always tell people, Hugh Hefner died from this. A urinary tract infection can be fairly scary.”

— Paul Garofolo, Locus Biosciences

Bacteriophages are naturally occurring viruses that have evolved to be highly infectious to very specific strains or species of bacteria. As opposed to a broad-spectrum antibiotic that kills good and bad microorganisms with little discrimination, a cocktail of phages can instead wipe out the most common cause of UTIs, Escherichia coli, and have no other impact on the rest of the microbiome. German is recruiting for a single-person clinical trial that will test out a phage cocktail’s effectiveness at treating a drug-resistant UTI when the viruses are applied topically with a sponge.

One clinical trial that Garofolo’s company is recruiting for combines phage therapy with a first-line antibiotic; once they can demonstrate effectiveness with this combination, studies down the line can test the phages on their own for patients as a potentially life-saving treatment. “I always tell people, Hugh Hefner died from this,” he added. “A urinary tract infection can be fairly scary” for the millions of older adults who seek care for them each year.

These trials are critically important, and so is integrating alternative therapies into clinical practice as they are shown to be safe and effective, German said. One could envision a future where patients use these interventions in tandem—preventing infections with vaccines, creams, and probiotics, and treating ones that slip through the cracks with phages and first-line antibiotics.

“We need to come up with new techniques and strategies to target the germs in the bladder and in the kidney,” said German. “We’re running out of antibiotics, and the bacteria are evolving or outsmarting those antibiotics faster than we can provide them.”

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Science

Scientists discover world’s largest bacterium, the size of an eyelash | Microbiology

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Scientists have discovered the world’s largest known bacterium, which comes in the form of white filaments the size of human eyelashes, in a swamp in Guadeloupe.

At about 1cm long, the strange organism, Thiomargarita magnifica, is roughly 50 times larger than all other known giant bacteria and the first to be visible with the naked eye. The thin white strands were discovered on the surfaces of decaying mangrove leaves in shallow tropical marine marshes.

The discovery was a surprise because, according to models of cell metabolism, bacteria should simply not grow this big. Previously scientists had suggested an upper possible size limit about 100 times smaller than the new species.

“To put it into context, it would be like a human encountering another human as tall as Mount Everest,” said Jean-Marie Volland, a scientist at Lawrence Berkeley National Laboratory who co-authored the study.

Thiomargarita magnifica has been found to contain three times as many genes as most other bacteria. Photograph: Vol­lard et al.

The organism was discovered by Olivier Gros, a marine biology professor at the Université des Antilles in Guadeloupe, while searching for symbiotic bacteria in the mangrove ecosystem.

“When I saw them, I thought: strange,” said Gros. The lab first conducted microscopic analyses to establish that the strands were single cells. Closer inspection also revealed a strange internal structure. In most bacteria, the DNA floats around freely inside the cell. Thiomargarita magnifica appears to keep its DNA more organised inside membrane-bound compartments throughout the cell. “And this is very unexpected for a bacterium,” said Volland.

The bacterium was also found to contain three times as many genes as most bacteria and hundreds of thousands of genome copies spread throughout each cell, making it unusually complex.

Scientists are not yet sure how the bacteria evolved to be so big. One possibility is that it adapted to evade predation. “If you grow hundreds or thousands of times bigger than your predator you cannot be consumed by your predator,” said Volland.

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However, becoming big would have meant losing some of bacteria’s traditional advantages, including being uniquely able to move around and colonise new niches. “By leaving the microscopic world these bacteria have definitely changed the way they interact with their environment,” said Volland.

The bacteria have not yet been found in other locations – and had disappeared from the original site when the researchers returned recently, perhaps because they are seasonal organisms. But in the paper, published in the journal Science, the authors conclude that the discovery “suggests that large and more complex bacteria may be hiding in plain sight”.

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Science

Geophysicists Mapped the ‘Plumbing’ Under Yellowstone

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Heart Spring in Yellowstone National Park.
Photo: Daniel SLIM / AFP (Getty Images)

A team of geophysicists recently strung a large wire loop from a helicopter and flew over Yellowstone National Park in order to see its hidden underground networks. They managed to collect a trove of data that highlighted electrical and magnetic properties of the water and earth under the park, as well as how the hot springs are more interconnected than previously thought.

Yellowstone is a 3,500-square-mile park that has numerous hot springs on its surface, most famously Old Faithful, one of the park’s 500-odd geysers. But these researchers wanted to know more about how the water underground was sourced and how interconnected the entire system was. Their findings were published this week in Nature.

“We produced images of Yellowstone’s subsurface hydrothermal ‘plumbing’ system—the pathways that hydrothermally heated waters take to reach the surface,” said Steve Holbrook, a geophysicist at Virginia Tech and a co-author of the paper, in an email to Gizmodo. “We see clear geological controls on the hydrothermal plumbing—in particular, the roles of deep faults, shallow fractures, and the boundaries at the base of the thick lava flows (tuff and rhyolite), all of which guide the movement of water.”

Yellowstone’s ‘Old Faithful’ geyser erupts around every 90 minutes. Photo from June 1, 2011.
Photo: MARK RALSTON/AFP (Getty Images)

The researchers generated over 2,500 miles of helicopter line data by flying a 80-foot-wide hexagonal instrument called SkyTEM over the park. SkyTEM sent electromagnetic pulses to the ground roughly every 90 feet. The pulses travel up to around 2,300 feet beneath the surface before bouncing back to a detector on the instrument.

“If we picture the helicopter flying over a football field, we could picture one sounding being taken at the back of the home end zone, the next one at the 20 yard line, the next one at midfield, then one at the other 20 yard line, and finally one at the back of the visitor’s end zone—five soundings total over the full length of the field,” Holbrook said. “Then we put those soundings next to each other over very long transects, and we get a picture of layers in the subsurface—how deep they are, which way they’re dipping, and so forth.”

The researchers also took magnetic field measurements, which gave them information on the magnetic properties of rocks as deep as 8,200 feet below Yellowstone. Taken together, the data allowed them to map out the electrically conductive and resistive elements beneath the surface: effectively, the plumbing of Yellowstone.

A significant finding from the work was how connected distant features are underground. Old Faithful and the park’s Upper Geyser basin share a hydrothermal source with the park’s Firehole Meadows at just 650 below the surface, though the sites are over 6 miles away from one another.

Holbrook added that the hydrothermal connection also implies connections in the various hot springs’ geochemistry and microbiology. Yellowstone’s hot springs are unique for their extremophile life; hardy critters like cyanobacteria that thrive in scalding temperatures make good subjects for scientists trying to figure out what alien life may be like. The newly discovered hydrothermal connections between different areas of the park may change biologists’ understanding of extremophile evolution.

“We plan to work with microbiologists looking to link areas of groundwater and gas mixing to regions of extreme microbial diversity, geologists using our models to map lava flows and estimate eruptive volumes, and hydrologists interested in incorporating flow paths and regions of hot and cold fluids to determine how the underground water flows,” said Carol Finn, a geophysicist with the U.S. Geological Survey and the paper’s lead author, in an email to Gizmodo.

“In the future, the integration of our models with new, deeper-sensing electromagnetic data offers the possibility of imaging the connections between Yellowstone’s shallow and deep hydrothermal systems and magma, providing a complete view of the system,” Finn added.

The immense amount of data the team collected is just waiting to be gleaned for more insights. The airborne research is just the first pass at a literally in-depth look at Yellowstone’s fundamental processes.

More: 5 National Parks to Visit Before You and/or They Die

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Science

How Life in the ‘Deep Biosphere’ Thrives Despite Temperatures That Would Fry Humans

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The Japanese scientific drilling ship used to detect microbes living deep below the seafloor.
Photo: JAMSTEC

A science expedition in 2016 revealed a subsurface habitat in which microbes were found living at temperatures approaching 250 degrees Fahrenheit. Now, a follow-up study reveals how this remarkable microbial community manages to beat the heat.

High metabolic rates make life possible for microorganisms living in sediments buried deep beneath the seafloor, according to new research published in Nature Communications. The study, led by marine geomicrobiologist Tina Treude from the University of California Los Angeles, casts subsurface microbes in a new light, showing some of them to be surprisingly active and capable of thriving in deep and hot conditions.

“We always found that microbes in the deep biosphere are an extremely sluggish community that slowly nibbles on the last remains of million-year-old, buried organic matter. But the deep biosphere is full of surprises,” Bo Barker Jørgensen, a microbiologist at Aarhus University in Denmark, said in a University of California press release. “To find life thriving with high metabolic rates at these high temperatures in the deep seabed nourishes our imagination of how life could evolve or survive in similar environments on planetary bodies beyond Earth.”

In an email, Virginia Edgcomb, a geologist at Woods Hole Oceanographic Institution who wasn’t involved in the new study, said she’s excited by the research because it shows “we cannot assume that microbial activities are insignificant simply because of the depth below seafloor or extreme temperatures,” particularly when “sufficient sources of carbon and energy are available.”

In this case, the required sources of carbon and energy were found in the Nankai Trough subduction zone off Japan. Seven years ago, a scientific expedition led by the same team drilled 3,930 feet (1,200 meters) below the seafloor, pulling up marine sediment samples and evidence of the extremophile microbes. They did so to investigate the temperature limit of the deep subseafloor biosphere and the extent to which life might be resident in this extreme habitat. Incredibly, they found a small community of microbes that appeared to be thriving despite temperatures reaching 250 degrees F (120 degrees C). It wasn’t totally obvious to the researchers how this was possible, prompting further study.

For the new investigation, Treude and her colleagues ran radiotracer experiments to measure the metabolic rates of the microbes, which they did under highly sterile conditions to prevent contamination. This wasn’t easy, given the low population density of the microbes; less than 500 cells were present in each cubic centimeter of sediment. The team also made special provisions to ensure that the observed metabolic rates were the same in the lab as they would be in the microbes’ natural environment.

This work resulted in the discovery of the microorganisms’ rapid metabolism, which the researchers say is what makes it possible for them to survive such extreme conditions. The scientists theorize that the high metabolic rates are a necessity, allowing the microbes to repair cells damaged by heat.

“The energy required to repair thermal damage to cellular components increases steeply with temperature, and most of this energy is likely necessary to counteract the continuous alteration of amino acids and loss of protein function,” said Treude.

At the same time, the microbes have ample access to nutrients supplied by the heating of organic materials, specifically hydrogen and acetate from water leaking through the marine sediment.

The new observations “might seem counterintuitive to many, which is that cells living close to the thermal limits of life at this location, and so deep below the seafloor, where we would expect them to be barely eking out an existence, are actually very active,” said Edgcomb. But their high rate of activity is for a very interesting reason: “To be able to provide enough energy to repair thermal cell damage so they can survive,” she added.

In an email, Jennifer Biddle, an associate professor at the University of Delaware who’s not affiliated with the research, said the new work “appears well done” and “nicely compliments” pre-existing work showing changes to microbial communities and increases in cell division as sediment temperatures get hotter. An argument presented in the new paper is that cells only get kick-started once they’re already buried—a finding that agrees with recent research co-authored by Biddle demonstrating that “once cells find their ‘happy place’ in the subsurface, they have plenty of power to grow,” she said.

One limitation, Biddle said, is that the researchers described microbial activity but didn’t provide any names or identify the microbes in question. She said “it would be great to know who is there, so we could even better estimate how fast they may be going,” adding that it would also be good to “culture some of these subsurface lineages to test their thermal ranges and how they may have adapted to this environment.”

Interestingly, these subseafloor microbes approach the thermal limits of life as we know it, but some scientists think microbes can survive in even hotter environments. Sounds like we need to dig a bit deeper next time, as even more extreme microbes could still be waiting to be found.

More: Ancient Microbes Spring to Life After 100 Million Years Under the Seafloor.

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World

China approves another COVID-19 vaccine for emergency use

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TAIPEI, Taiwan (AP) — China has approved a new COVID-19 vaccine for emergency use, one that was developed by the head of its Center for Disease Control, adding a fifth shot to its arsenal.

Gao Fu, the head of China’s CDC, led the development of a protein subunit vaccine that was approved by regulators last week for emergency use, the Chinese Academy of Sciences’ Institute of Microbiology said in a statement Monday.

It is the fifth coronavirus vaccine approved in China and the fourth to be given emergency use approval. Three of those given emergency approval have since been approved for general use. All were developed by Chinese companies.

The latest vaccine was developed jointly by Anhui Zhifei Longcom Biopharmaceutical Co. Ltd. and the Chinese Academy of Sciences. The team finished phase 1 and phase 2 clinical trials in October and is currently conducting the last phase of trials in Uzbekistan, Pakistan and Indonesia, according to the statement.

The vaccine was approved for use in Uzbekistan on March 1. It’s a three-dose shot that is spaced out with one month each between shots, a company spokesperson said. Like other vaccines China has developed so far, it can be stored at normal refrigeration temperatures.

There is no publicly available information in peer-reviewed scientific journals about the clinical trial data showing efficacy or safety. A spokesperson for the company said that the data could not be shared at this time but that the company was providing the information to health authorities.

The protein subunit vaccine is similar to many of the other vaccines that have been approved globally in that it trains the body to recognize the spike protein that covers the surface of the coronavirus, although the difference lies in how it tells the body to recognize the protein. Scientists grow a harmless version of the protein in cells and then purify it, before it is assembled into a vaccine and injected.

China has been slow in vaccinating its population of 1.4 billion people, despite having four vaccines approved for general use. The latest numbers, according to government officials at a press briefing Monday in Beijing, is that it has administered 64.98 million doses of vaccines.

China has targeted what it considers key populations for vaccination thus far, namely health care workers, those who work at the border or customs, and specific industries the government has selected. Other groups that have been notably absent thus far in comparison to many other countries are the elderly and those with pre-existing conditions.

The approved vaccines have previously been limited to adults 18-59 years old, as officials cited a lack of clinical trial data for those who are older, although the government appears to be signaling the limits are now being set aside.

“We will promptly carry out mass vaccination of relevant populations,” Li Bin, a vice chair on the National Health Commission, said Monday.

China’s official Xinhua News Agency reported over the weekend that in certain neighborhoods in Beijing, local health centers started to offer the vaccines to those aged 60 and older.

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This story has been corrected to show that the vaccine trains the body to recognize the spike protein that covers the surface of the coronavirus, not the surface of the coronavirus vaccine.

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