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Vaginal Microbiota Transplant Without Pretreatment Fails to Resolve Dysbiosis in RCT
In a double-blind randomised controlled trial, vaginal microbiota transplantation (VMT) administered without antibiotic pretreatment showed no statistically significant advantage over placebo in resolving vaginal dysbiosis, with the hazard ratio slightly favouring placebo and a wide confidence interval indicating substantial imprecision (HR 0.65, 95% CI 0.20–2.16, p=0.49). A small uncontrolled extension study suggested that antiseptic pretreatment before VMT may improve engraftment in refractory cases, but this signal remains preliminary.
What Was Studied
The trial investigated whether vaginal microbiota transplantation — the direct transfer of donor vaginal secretions rich in Lactobacillus species — could restore a healthy, Lactobacillus-dominated microbiome in women with confirmed vaginal dysbiosis, without the use of antibiotic pretreatment. This question matters because a Lactobacillus-dominated vaginal environment is associated with reduced susceptibility to infection and better reproductive outcomes, yet effective interventions to correct dysbiosis remain limited.
How It Was Studied
This was a single-centre, double-blind, randomised controlled trial conducted at Copenhagen University Hospital in Denmark between June 2021 and March 2023. Eligible recipients were otherwise healthy, premenopausal, non-pregnant women aged 18–40 with molecular vaginal dysbiosis, defined as less than 10% total relative abundance of Lactobacillus spp and greater than 20% combined abundance of Gardnerella spp, Fannyhessea vaginae, and Prevotella spp. Forty-nine women were enrolled and randomised 3:1 to receive up to three administrations of VMT (n=37) or placebo (n=12) across three consecutive menstrual cycles, with follow-up extending to six cycles. Vaginal microbiome composition was assessed by shotgun metagenomic sequencing, and randomisation was stratified by hormonal contraceptive use. An uncontrolled extension study also evaluated antiseptic pretreatment in refractory participants.
What Was Observed
- No significant benefit over placebo: The primary outcome — resolution of dysbiosis at any point during follow-up, defined as ≥70% relative abundance of Lactobacillus spp and <10% combined abundance of the three dysbiotic taxa — showed no meaningful difference between the VMT and placebo arms. The hazard ratio of 0.65 (95% CI 0.20–2.16, p=0.49) is consistent with no effect, and the very wide confidence interval means the true direction of any effect cannot be reliably determined from this dataset.
- Promising signal from antiseptic pretreatment: In the extension study, five of ten refractory women (50%) who received antiseptic pretreatment followed by VMT achieved microbiome conversion. While this suggests pretreatment may help clear resident dysbiotic organisms and promote donor engraftment, this arm was small and uncontrolled, limiting the strength of any inference.
- Comparable and manageable safety profile: Adverse events occurred in 15 of 37 VMT participants (42%) and 5 of 12 placebo participants (42%), with identical rates across groups. No serious adverse events were recorded, no participant withdrew due to adverse effects, and a single pregnancy and one new HPV infection were both deemed unrelated to the intervention.
Why This Matters
This trial represents one of the first rigorous attempts to apply microbiota transplantation to the vaginal niche, extending the broader concept of donor microbiome transfer beyond the gut. The null result in the antibiotic-free protocol challenges the assumption that VMT alone can overcome the resilience of an established dysbiotic community. The extension data further suggest that the resident microbiome may need to be disrupted before donor strains can successfully colonise, pointing toward pretreatment as a necessary component of future VMT protocols.
How to Read This Result
Given the small sample size (N=49), single-centre design, and wide confidence intervals, this trial was underpowered to detect a modest benefit, and neither a meaningful effect nor the absence of one can be firmly concluded; the extension findings are hypothesis-generating only and require confirmation in larger, controlled trials with donor engraftment as a prespecified outcome.
Limitations
The most important constraint is the small overall sample size of 49 participants, which substantially limits statistical power and increases the risk that a true effect, if present, went undetected. The trial was conducted at a single centre in Denmark, which may restrict generalisability. The absence of antibiotic pretreatment in the main trial may itself have been a structural barrier to engraftment rather than a neutral design choice. The extension study of antiseptic pretreatment involved only ten women without a control arm, making its 50% conversion rate difficult to interpret. Finally, donor engraftment — arguably a more direct measure of transplant success — was not used as the primary endpoint, meaning the trial may not have captured the mechanistic signal most relevant to this intervention.