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Vaginal microbiota transplant to promote Lactobacillus-dominant cervicovaginal communities


PROJECT SUMMARY Vaginal colonization with a Lactobacillus-dominant microbial community is associated with lower risk for preterm birth, HIV acquisition, HPV persistence and cervical dysplasia. A diverse, Lactobacillus-deficient vaginal microbiota such as that seen in bacterial vaginosis (BV) is associated with mucosal inflammation, which is likely the mechanistic link to the adverse health outcomes seen with dysbiosis. Antibiotic treatment for BV achieves short term cure, but recurrence is common. Probiotic treatment to restore healthy lactobacilli is only moderately successful, even with daily treatment. These results emphasize the need for novel strategies to manipulate the genital microbiome and produce sustainable shifts away from dysbiosis. We propose a randomized clinical trial of vaginal microbiota transplant (VMT) with extensive characterization of donors, transplant material, recipients and engraftment, to identify determinants of vaginal microbial colonization and stability. Our team has already obtained an IND, successfully recruited donors, and generated preliminary data demonstrating stability of Lactobacillus in donated material. In Aim 1 we will enroll up to 25 healthy donors and 126 recipients with a history of recurrent BV and an abnormal Nugent score. Recipients receive 1 week of oral metronidazole and are randomized to VMT or saline placebo, two doses given on non-consecutive days in a single week. The primary outcome is prevalence of a Lactobacillus-dominant vaginal microbiota by 16S rRNA sequencing 1 month after intervention. Secondary outcomes include adverse events, Lactobacillus dominance over the entire 6 month follow up, and prevalence of BV by Nugent score at 1, 3 & 6 months. In Aim 2 we will characterize the impact of vaginal fluid transplantation on recipient microbiome (Aim 2.1) and mucosal inflammation (Aim 2.2). For Aim 2.1 we will use 16S rRNA sequencing, qPCR and shotgun metagenomic sequencing (SMS) to define the kinetics of Lactobacillus colonization and community diversity over the 6 months following study intervention. In Aim 2.2 we will assess the impact of VMT vs. placebo on soluble markers of inflammation in vaginal fluid and endocervical immune cell activation. In Aim 3 we will identify genetic characteristics of both successful donations and Lactobacillus isolates cultivated from successful VMT donors and recipients (Aim 3.1). We will compare isolates in vitro to test functional metrics for future selection of strains for novel products (Aim 3.2). We will also compare metabolic profiles of successful vs. unsuccessful donations (Aim 3.3). The resulting isolate collection and database of genes and metabolites associated with achieving Lactobacillus dominance will provide a basis for design of a novel live biotherapeutic for prevention of BV and its associated sequelae. Execution of these three aims will also provide novel insights into determinants of vaginal Lactobacillus colonization and the causal relationship between Lactobacillus and protection from BV, moving the field forward whether or not our trial demonstrates a clinical benefit for VMT. Data obtained will provide guidance on what features are important for designing a synthetic intervention, which would be easier to scale up for widespread use than VMT.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.