R01AI158836

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, and 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.

The General Hospital Corporation

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Boston, Massachusetts 021142621 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the End Date has been extended from 08/31/26 to 08/31/27 and the total obligations have increased 298% from $839,632 to $3,339,208.