New model for vaginal microbiome transplantation

Lactobacillus bacteria colonies

Bacterial vaginosis is a condition affecting thousands of women worldwide, and is associated not only with vaginal symptoms but with pregnancy-related complications including preterm labor and stillbirth. Now researchers have come up with an effective way to replace the unhealthy vaginal microflora with a ready-to-use microbiome - called a vaginal microbiome transplantation (VMT).

Long back in the 19th century, childbirth was an extremely dangerous affair, dominated by hemorrhage and sepsis. However, it was known that if the vaginal bacteria were predominantly from genus Lactobacillus, the risk of sepsis was low. In this, it spells the exact opposite of the gut microbiome, where greater numbers of different bacterial species typically means health and diversity.

In the vagina, the replacement of Lactobacilli by other bacterial species is called bacterial vaginosis (BV) and is linked to a higher risk of sexually transmitted infections (STIs), urinary tract infections (UTIs), preterm labor, and some cancers of the female reproductive tract. The solution is simple: bring back the original Lactobacillus monoculture. However, this is difficult to achieve. Researcher Ethel Weld says, “We have very few treatment options available for BV, none of them fully curative or restorative.” Up to 70% of BV relapses after antibiotic treatment.

This new research built upon the success of fecal transplants to correct gut dysbiosis, where fecal samples from healthy people are carefully treated to remove undesirable matter and then inserted into the gut of patients with unhealthy gut microbiomes. This has shown great promise in restoring the normal bacterial diversity and has resulted in alleviation of symptoms due to poor gut health. The research is published in the journal Frontiers in Cellular and Infection Microbiology.

Epidemiological studies also show that vaginal microflora can be transferred, from woman to woman, as seen in lesbians who have sex with each other. However, says Weld, the challenge is to “first determine how to screen donors to find those with minimal risk of transmissible pathogens, and optimal vaginal microbiota for transplant.” The risk of inadvertently introducing harmful organisms into the gut must be minimized, while the sample introduced must contain the right organisms in the right proportion.

Donor selection

To achieve this risk, Weld and her team devised a screening method and did a pilot study on 20 healthy young women between 25 and 35 years. The components of the screening program included a questionnaire on medical history, followed by tests on blood, urine and vaginal fluid as well as vaginal swab culture.

The vaginal samples supplemented the blood tests to confirm the absence or presence of infection, and also to build up a picture of how the vaginal microbiome structure relates to its functioning in health and disease. One thing they discovered from the pilot study was that a Lactobacillus crispatus-dominated vaginal microbiome was associated with greater lactic acid production, a more acidic milieu and better resistance to HIV, in concordance with earlier studies.

The researchers found that they could evolve a logical sequence of testing, using inexpensive but dependable tests to identify unsuitable samples during the screening process. Later on, the best donors could be tested to identify their fitness, using the more expensive and time-consuming tests which include more sensitive tests for potential infections and the number of Lactobacilli in the “graft.” This would also require avoiding vaginal penetration, sexual intercourse included.

However, they are still working on defining the right mix of bacteria, and also on finding out whether different people require different types of microflora communities. They discovered that a vaginal swab is just as good as taking vaginal fluid samples when it comes to understanding the composition of the vaginal microbiome. The concentrations of L- and D-lactic acid mirrors the Lactobacillus species in the vagina.

They also came up with suggested inclusion criteria for VMT donation, namely, a pH of 4.2 or less, and a Nugent score of 2 or less. The recipients must be screened intensively for STIs, like the donors, to help determine the safety of the procedure, which would be difficult if they already have one or more infections. Some of these are notorious for occasional viral shedding, such as HSV-1, HSV-2 and HPV, so repeated screening will be necessary to maximize the rates of detection.

Wanted: donors for VMT

The ideal microbiome is rarely to be found, however. In the current study, many of the women had already taken part in previous studies performed by the same team and were often either White or East Asian. The rates of BV in both these US communities are low. Thus, they had enhanced chances of being good donors. In fact, 35% of the women passed the initial screening, but this figure is likely to fall significantly in real-life clinical trials drawing on an unselected population.

The study identifies the need to choose donors from a broader pool, with more women from other backgrounds, as this will help to discover whether racial origin or ethnicity affects the outcome of the VMT.

A potential deterrent to many would-be donors is the need to avoid vaginal sex for a month or longer, throughout the collection period, to allow complete testing of vaginal samples before a woman is determined to be suitable. In such a situation, a potential solution is to identify a small pool of willing and eligible donors who have met all the protocol criteria and who can donate vaginal samples (after repeat screening) on separate occasions. Such a woman is dubbed a “super-donor.” Samples collected this way could be banked until they are used.

Another potential avenue to obtain VMT samples is via laboratory culture of desired strains of Lactobacillus for VMT. This depends on research-established understanding of the different species that co-exist and their role in the vagina,their interactions and the importance of their products. At this point, VMT may become independent of actual living donors. Instead, laboratories will be able to culture the required strains and mix them together in the right proportions, to obtain standardized VMTs. Ensign concludes, “We anticipate that the trajectory of VMT will likely follow that of fecal transplantation, with efforts to cultivate uniform, standardized transplants that have similar therapeutic efficacy to donor material.”

Journal reference:

DeLong Kevin, Bensouda Sabrine, Zulfiqar Fareeha, Zierden Hannah C., Hoang Thuy M., Abraham Alison G., Coleman Jenell S., Cone Richard A., Gravitt Patti E., Hendrix Craig W., Fuchs Edward J., Gaydos Charlotte A., Weld Ethel D., Ensign Laura M., Conceptual Design of a Universal Donor Screening Approach for Vaginal Microbiota Transplant, Frontiers in Cellular and Infection Microbiology, DOI=10.3389/fcimb.2019.00306, https://www.frontiersin.org/article/10.3389/fcimb.2019.00306