VIBRANT: Vaginal lIve Biotherapeutic RANdomized Trial: A Phase 1 randomized trial of multi-strain vaginal L. crispatus live biotherapeutic products in people with bacterial vaginosis

IntroductionAn optimal vaginal microbiome is typically dominated by beneficial Lactobacillus species, whereas bacterial vaginosis (BV) is characterized by high microbial diversity and a paucity of vaginal lactobacilli. High recurrence rates of BV following antibiotic treatment may stem from poor recolonization by protective Lactobacillus species post-treatment. This has led to the hypothesis that live biotherapeutic interventions designed to promote Lactobacillus dominance could improve BV treatment outcomes. MethodsWe conducted a Phase I, double-blind, placebo-controlled randomized trial to evaluate two novel, vaginally delivered live biotherapeutic products (LBP), each containing multiple strains of Lactobacillus crispatus. The study was conducted at two sites: one in South Africa, and one in the United States. Eligible participants diagnosed with BV by Nugent score ([≥] 7) and Amsel criteria ([≥]3 out of 4 criteria), first received a course of oral metronidazole and were then randomized equally into one of five arms for 7 days of daily vaginal tablet use: a placebo, a 6-strain LBP (LC106), a 15-strain LBP (LC115), LC106 for 3 days followed by 4 days of placebo, or an unblinded overlap arm in which LC106 was initiated on day 3 of metronidazole treatment. The primary outcomes were safety and detection of any L. crispatus strains contained in the products, as determined by metagenomic sequencing within the first weeks of study participation. ResultsAcross all active arms combined, at least one LBP strain was detected in 66.1% (47/71) of participants at least once in the first five weeks of study participation. Among those with colonization in this period, nearly half (49%, 23/47) remained colonized with LBP strains at 12 weeks, demonstrating durable colonization despite a short initial treatment course. Colonization success was comparable across study arms and sites, although the study was not powered to detect small differences between arms. At both sites, participants were most often colonized by one of three component strains, with no geographic differences in strain colonization observed. Both LBP products were safe, acceptable and well tolerated, with no serious adverse events (AEs) reported. Local/genitourinary AEs occurred most often in the placebo arm. ConclusionIn this Phase 1 study of novel multi-strain L. crispatus LBPs, we demonstrated that the products were safe and acceptable, and established durable colonization after a short dosing course in geographically diverse populations. These results provide a foundation for the development of transformational interventions aimed at optimizing the vaginal microbiome.