Randomized trial of multi-strain Lactobacillus crispatus vaginal live biotherapeutic products after antibiotic therapy for bacterial vaginosis: study protocol for VIBRANT (vaginal lIve biotherapeutic RANdomized trial)

Callin Chetty¹, Nomfuneko Mafunda², Anna-Ursula Happel^{3

4}, Anam Khan², Briah Cooley Demidkina², Nonhlanhla Yende-Zuma¹, Yusra Saidi², Asthu Mahabeer Polliah¹, Lara Lewis¹, Farzana Osman¹, Precious Radebe¹, Jo-Ann S Passmore^{4

5

6}, Doug Kwon^{7

8

9}, Jacques Ravel^{10

11}, Sinaye Ngcapu¹, Lenine Liebenberg^{12

13}, Laura Symul¹⁴, Susan Holmes¹⁵, Caroline M Mitchell^{2

8

16}, Disebo Potloane¹

Affiliations

¹ Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.
² Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA, United States of America.
³ Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa.
⁴ Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
⁵ DSI-NRF Centre of Excellence in HIV Prevention, Centre for the AIDS Program of Research in South Africa (CAPRISA), UCT, Cape Town, South Africa.
⁶ National Health Laboratory Service, Cape Town, South Africa.
⁷ Ragon Institute of MGH, Harvard and MIT, Cambridge, United States of America.
⁸ Harvard Medical School, Boston, MA, United States of America.
⁹ Division of Infectious Disease, Massachusetts General Hospital, Boston, MA, United States of America.
¹⁰ Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States of America.
¹¹ Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, United States of America.
¹² Centre for Epidemic Response and Innovation (CERI), Stellenbosch University, Cape Town, South Africa.
¹³ Department of Medical Microbiology, University of KwaZulu-Natal, Durban, South Africa.
¹⁴ Department of Statistics, Universite Catholique de Louvain, Louvain, Belgium.
¹⁵ Department of Statistics, Stanford University, Palo Alto, United States of America.
¹⁶ Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA, United States of America.

PMID: 41050878
PMCID: PMC12495413
DOI: 10.1016/j.conctc.2025.101554

Randomized trial of multi-strain Lactobacillus crispatus vaginal live biotherapeutic products after antibiotic therapy for bacterial vaginosis: study protocol for VIBRANT (vaginal lIve biotherapeutic RANdomized trial)

Callin Chetty et al. Contemp Clin Trials Commun. 2025.

. 2025 Sep 16:48:101554.

doi: 10.1016/j.conctc.2025.101554. eCollection 2025 Dec.

Authors

Affiliations

¹ Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.
² Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA, United States of America.
³ Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa.
⁴ Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
⁵ DSI-NRF Centre of Excellence in HIV Prevention, Centre for the AIDS Program of Research in South Africa (CAPRISA), UCT, Cape Town, South Africa.
⁶ National Health Laboratory Service, Cape Town, South Africa.
⁷ Ragon Institute of MGH, Harvard and MIT, Cambridge, United States of America.
⁸ Harvard Medical School, Boston, MA, United States of America.
⁹ Division of Infectious Disease, Massachusetts General Hospital, Boston, MA, United States of America.
¹⁰ Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States of America.
¹¹ Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, United States of America.
¹² Centre for Epidemic Response and Innovation (CERI), Stellenbosch University, Cape Town, South Africa.
¹³ Department of Medical Microbiology, University of KwaZulu-Natal, Durban, South Africa.
¹⁴ Department of Statistics, Universite Catholique de Louvain, Louvain, Belgium.
¹⁵ Department of Statistics, Stanford University, Palo Alto, United States of America.
¹⁶ Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA, United States of America.

PMID: 41050878
PMCID: PMC12495413
DOI: 10.1016/j.conctc.2025.101554

Abstract

Background: Globally, approximately 30 % of women have bacterial vaginosis (BV). Antibiotic treatment is frequently followed by recurrence, likely due to lack of colonization with beneficial lactobacilli.

Methods: This is a Phase 1, randomized, placebo-controlled trial of vaginal live biotherapeutic products (LBP) after antibiotic treatment for BV to establish Lactobacillus colonization. The LBP are vaginal tablets containing 6 L. crispatus strains (LC106) or 15 L. crispatus strains (LC115), at 2 x 10⁹ colony forming units (CFU) per dose. Participants with BV in the United States and South Africa will receive seven days of oral metronidazole twice daily and will be randomized 1:1:1:1:1 to: seven days placebo; seven days LC106; three days LC106/four days placebo; seven days LC106 starting day 3 of the metronidazole course; or seven days LC115. Safety will be assessed by the number and percentage of ≥ Grade 2 related adverse events during or after product use. The primary outcome is LBP colonization defined as relative abundance ≥5 % of any LBP strain or ≥10 % of a combination of LBP strains by metagenomic sequencing any time in the 5 weeks after randomization. A generalized linear model will measure the association between treatment group and colonization, adjusting for site.

Conclusions: This study seeks to establish proof of concept for a multi-strain LBP to promote vaginal L. crispatus colonization in two geographically distinct populations.

Trial registration: South African National Clinical Trials Registry (SANCTR DOH-27-102023-8342; October 27, 2023) and ClinicalTrials.gov (NCT06135974; November 11, 2023).

Protocol version: 2.0 dated October 03, 2023.

Keywords: Bacterial vaginosis; Lactobacillus crispatus; Live biotherapeutic product; Vaginal health; Vaginal microbiome; Women's health.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for this journal and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests.

Figures

**Fig. 1**
Study schema showing dosing regimen and distribution of participants across the five treatment arms. All participants receive oral metronidazole (MTZ) between visit 1 and visit 2. Between visit 1 and visit 6 participants collect daily vaginal swabs at home. **Arm 1: Placebo.** Vaginal placebo tablet daily for 7 days after the completion of metronidazole. **Arm 2: LC106.** Vaginal 6-strain LBP tablet daily for 7 days after the completion of metronidazole. **Arm 3: Short course LC106**. Vaginal 6-strain LBP tablet daily for 3 days, then 4 days of placebo, following completion of metronidazole. **Arm 4: Crossover LC106**. Vaginal 6-strain LBP tablet daily for 7 days starting on day 3 of metronidazole treatment. **Arm 5**: **LC115**. Vaginal 15-strain LBP tablet daily for 7 days after the completion of metronidazole. (d = days, wk = week).

See this image and copyright information in PMC

References

1. Brotman R.M., Shardell M.D., Gajer P., et al. Interplay between the temporal dynamics of the vaginal microbiota and human papillomavirus detection. J. Infect. Dis. 2014;210(11):1723–1733. doi: 10.1093/infdis/jiu330. - DOI - PMC - PubMed
1. DiGiulio D.B., Callahan B.J., McMurdie P.J., et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc. Natl. Acad. Sci. U. S. A. 2015;112(35):11060–11065. doi: 10.1073/pnas.1502875112. - DOI - PMC - PubMed
1. Gosmann C., Anahtar M.N., Handley S.A., et al. Lactobacillus-Deficient cervicovaginal bacterial communities are associated with increased HIV acquisition in young South African women. Immunity. 2017;46(1):29–37. doi: 10.1016/j.immuni.2016.12.013. - DOI - PMC - PubMed
1. Hillier S.L., Nugent R.P., Eschenbach D.A., et al. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. The Vaginal Infections and Prematurity Study Group. N. Engl. J. Med. 1995;333(26):1737–1742. - PubMed
1. Usyk M., Zolnik C.P., Castle P.E., et al. Cervicovaginal microbiome and natural history of HPV in a longitudinal study. PLoS Pathog. 2020;16(3) doi: 10.1371/journal.ppat.1008376. [published Online First: 2020/03/28] - DOI - PMC - PubMed

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov

LinkOut - more resources

Full Text Sources
- Elsevier Science
- PubMed Central
Medical
- ClinicalTrials.gov
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Randomized trial of multi-strain Lactobacillus crispatus vaginal live biotherapeutic products after antibiotic therapy for bacterial vaginosis: study protocol for VIBRANT (vaginal lIve biotherapeutic RANdomized trial)

Affiliations

Randomized trial of multi-strain Lactobacillus crispatus vaginal live biotherapeutic products after antibiotic therapy for bacterial vaginosis: study protocol for VIBRANT (vaginal lIve biotherapeutic RANdomized trial)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Associated data

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous