Bacterial vaginosis can be devastating. The condition, caused by excessive bacterial growth in the vagina, often results in burning feelings, discharge and a bad odor. It is the most common vaginal infection in women between the ages of 15 and 44 in the U.S., where it affects 21.2 million of them. Although not life-threatening, it can cause infertility, premature births and increased susceptibility to sexually transmitted illnesses. As a result, it can lead to long-term disruptions in sexual relationships and quality of life. The current conventional treatment—a course of antibiotics—is not effective in all women. Aside from some over-the-counter probiotics that many experts say are ineffective, there have been no new treatments in decades.
Caroline Mitchell, an associate professor of obstetrics and gynecology at Massachusetts General Hospital, considers the lack of new therapies a glaring example of inequities in health care. “It is far bigger problem than people realize," she says. “We should be doing better for women.”
Recently researchers have been exploring a new approach to treating bacterial vaginosis that involves transplanting vaginal fluids from healthy women into the vaginas of those suffering from the condition. A new paper on the use of vaginal microbiota transplantation (VMT) was published last week in Nature Medicine. Four of the five women in the small study saw long-term improvement in their recurrent bacterial vaginosis after having the procedure, eliciting hope for a new treatment. But experts warn many risks and unknowns remain.
“I think that it’s still a very experimental procedure right now,” says Jacques Ravel, a microbial genomicist at the Institute for Genome Sciences at the University of Maryland School of Medicine and co-founder of LUCA Biologics, a biotechnology company dedicated to developing live biotherapeutics for women’s health. He was not involved in the new study.
A Delicate Balance
The vagina houses a complex microbial ecosystem that, in most women, is dominated by bacteria of the genus Lactobacillus. These microbes convert sugars shed from the vaginal wall into lactic acid, which provides an important first line of defense against pathogens. Bacterial vaginosis occurs when something disrupts this ecosystem, and anaerobic bacteria take over. These nasty invaders emit foul-smelling by-products, increase pH and leave the vagina susceptible to viruses, including HIV. Rates of relapse after antibiotic treatment can be as high as 70 percent, so for many, the condition becomes chronic.
VMT is one of two new approaches that rely on microbes to rebalance the vaginal microbial ecosystem. The other is targeted live biotherapeutics, in which lab-grown bacteria are introduced to the vagina. Of these therapeutics, LACTIN-V, a lab-grown species of Lactobacillus crispatus developed by California biotech company Osel, is the farthest along in the clinical pipeline. LACTIN-V recently completed a phase IIb trial, with results expected to be released in January 2020. And two clinical trials for VMT were recently approved by the Food and Drug Administration. Experts disagree over which approach is best, and both of them are controversial.
Critics of VMT describe the transplants as a crude tool and cite safety as the primary concern. “To be honest, I do not see them as a therapeutic procedure but, really, as a research-and-discovery tool. It might work, but safety has to be the upmost important outcome,” Ravel says. He warns that a host of unwanted organisms—potentially including viruses, such as human papillomavirus (HPV)—can be transplanted along with the beneficial bacteria. The only way to rule out this risk would be to test each transplant sample, but doing so would be impractical because of the cost and required sample size. A vaginal microbial donation usually produces about 300 microliters of fluid, according to Ravel, which amounts to a few droplets. Using some for testing would leave very little for the recipient.
Instead vaginal microbiota transplants would likely have to come from verified donors, who are only tested periodically, in between donations. But good donors are hard to find. In a recent study that outlined a method for screening a potential donor, researchers identified just one person out of 20 who tested negative for HPV. Ravel says it is easy to miss a viral infection such as HPV because it sheds its genetic material intermittently, as he showed in a 2014 paper. Thus, he says, a donor can test negative on one day but test positive on another. If the virus is shedding when the transplant donation is collected, it could be unsafe.
Even a pathogen-free donor’s microbiota can vary from one day to another, depending on factors such as her diet, stress level and menstrual cycle. Such variations in the bacteria present in the transplant could also affect its efficacy, Ravel says.
“The truth is that we are in a brave new world when it comes to understanding the human microbiome,” says Craig Cohen, a professor in the department of obstetrics, gynecology and reproductive sciences at the University of California, San Francisco, who was also not involved in the Nature Medicine study. Cohen led the phase IIb clinical trial of LACTIN-V. He thinks it would be difficult to ensure the safety of vaginal microbiota transplants in a wider population because of the amount of safety testing required and that it would be easier to ensure the safety of a lab-manufactured therapy. “We can potentially get a product to market that can really benefit women's health, depending on the results [of the clinical trial],” he says.
Laura Ensign, an associate professor at the Johns Hopkins University School of Medicine, agrees. "The goal should be that we have some sort of manufacturable product, like a [biotherapeutic],” because that has the advantage of being produced at a large scale, she says. Ensign, who was not part of the Nature Medicine study but co-authored the one on finding a donor for VMT, does think there may also be value to the procedure, especially in the interim period when biotherapeutics are undergoing clinical trials. She recently received FDA approval to begin a VMT trial.
It Is Still Early Days
Ensign believes much more research is needed to know exactly what approach will work and that VMT could help the science get there, because it demonstrates what happens when an entire community of microbes is transplanted together. She is concerned that a single strain of microbes will not be effective as a community and points to previous experiments that showed a single strain of bacteria could not successfully colonize a woman’s vagina. Ensign postulates there may be “helper” microbes that enable the dominant strains to establish themselves, but she acknowledges that researchers still have a lot to learn. “We need to really know what could be effective before we start narrowing down what a [manufactured] product would look like,” she says. Until the science catches up with her goal, Ensign hopes VMT will be a clinical tool to help women for whom antibiotics are not effective.
Mitchell, who also received approval for a clinical trial using VMT to treat bacterial vaginosis and was not part of the new study, echoes these sentiments. Ensign’s and Mitchell’s trials together plan to enroll about 170 patients—far more than the five people treated in the Nature Medicine paper.
“The value of VMT over inoculation of a single bacterium or small microbial consortium is that you have the potential to inoculate complex communities of microbes that naturally exist together in a particular human host,” says David Fredricks, a leading expert on vaginal microbial communities and a researcher at the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center, who did not work on the new study. He points out that reestablishing a healthy vaginal ecosystem can be a challenge because of the complex interactions between microbes.
“Reengineering the human microbiota is likely more challenging than simply applying a cocktail of bacterial strains to a mucosal surface,” Fredericks says, “regardless of whether these strains arise from a laboratory culture or human tissue or body fluid.”