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Vaginal microbiome transplantation in women with intractable bacterial vaginosis

Abstract

We report the results of a first exploratory study testing the use of vaginal microbiome transplantation (VMT) from healthy donors as a therapeutic alternative for patients suffering from symptomatic, intractable and recurrent bacterial vaginosis (ClinicalTrials.gov NCT02236429). In our case series, five patients were treated, and in four of them VMT was associated with full long-term remission until the end of follow-up at 5–21 months after VMT, defined as marked improvement of symptoms, Amsel criteria, microscopic vaginal fluid appearance and reconstitution of a Lactobacillus-dominated vaginal microbiome. One patient presented with incomplete remission in clinical and laboratory features. No adverse effects were observed in any of the five women. Notably, remission in three patients necessitated repeated VMT, including a donor change in one patient, to elicit a long-standing clinical response. The therapeutic efficacy of VMT in women with intractable and recurrent bacterial vaginosis should be further determined in randomized, placebo-controlled clinical trials.

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Fig. 1: Clinical features of VMT.
Fig. 2: Metagenomic microbiome assessment of the vaginal microbiome following VMT.

Data availability

The sequencing data has been deposited at the European Nucleotide Archive with accession number PRJEB34085. All other requests for raw and analyzed data, generated as part of a clinical trial, will be promptly reviewed by the Hadassah-Hebrew University Medical Center and the Weizmann Institute of Science to verify whether the request is subject to intellectual property confidential obligations or affects patient confidentiality.

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Acknowledgements

We thank the members of the Hadassah-Hebrew University Medical Center Department of Obstetrics and Gynecology, the Elinav lab at the Weizmann Institute of Science and members of the DKFZ Cancer–Microbiome division for insightful discussions. We thank S.M. Cohen for expert editing. All cartoons were created, under a license, using BioRender software. The study was supported by a grant from the Joint Research Fund of the Hebrew University of Jerusalem and Hadassah Medical Center. H.S. is the incumbent of the V.R. Schwartz Research Fellow Chair. E.E. is supported by Yael and Rami Ungar, the Leona M. and Harry B. Helmsley Charitable Trust, the Adelis Foundation, the Pearl Welinsky Merlo Scientific Progress Research Fund, the Lawrence and Sandra Post Family Foundation, the Daniel Morris Trust, the Park Avenue Charitable Fund, the Hanna and Dr. Ludwik Wallach Cancer Research Fund, the Howard and Nancy Marks Charitable Fund, Aliza Moussaieff, the estate of Malka Moskowitz, the estate of Myron H. Ackerman, the estate of Bernard Bishin for the WIS-Clalit Program, Donald and Susan Schwarz, and grants funded by the European Research Council, the Israel Science Foundation, the Israel Ministry of Science and Technology, the Israel Ministry of Health, the Helmholtz Foundation, the Else Kroener Fresenius Foundation, the Garvan Institute, the European Crohn’s and Colitis Organization, the Deutsch-Israelische Projektkooperation and the Wellcome Trust. E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair, a senior fellow at the Canadian Institute of Advanced Research and an international scholar at the Bill & Melinda Gates Foundation and the Howard Hughes Medical Institute.

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Authors

Contributions

A.L.-S., D.G.-W. and E.E. conceived the study. A.L.-S. recruited and supervised the participants and performed all clinical procedures. Y.C. performed all computational analyses. M.D.-B. performed sample preparation, processing and sequencing. A.L. and U.M. assisted with the computational analysis. J.S. and A.E.M. provided microbiology insights and support. S.Y. contributed to study conception and design. H.S. supervised all lab work. A.L.-S, D.G.-W., Y.C. and E.E. interpreted the experiments and wrote the manuscript.

Corresponding authors

Correspondence to Ahinoam Lev-Sagie or Eran Elinav.

Ethics declarations

Competing interests

E.E. is a paid consultant at DayTwo and BiomX. None of this work is related to, funded or endorsed by, shared or discussed with or licensed to any commercial entity. None of the other authors has any competing interest.

Additional information

Peer review information Joao Monteiro was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1

Clinical background of donors and recipients.

Extended Data Fig. 2

Recipient clinical parameters over time.

Extended Data Fig. 3

Recipient pre-VMT and post-VMT range of clinical values throughout the follow-up period.

Extended Data Fig. 4 Genus-level 16S recombinant DNA assessment of the vaginal microbiome following VMT.

(a) 16S principal coordinates analysis using UniFrac distances colored by Amsel criteria scores, n = 50 total recipient samples; (b) Bray-Curtis distances from baseline, correlated with the Amsel criteria scores measured on the same day. A–E are the individual VMT recipients.

Extended Data Fig. 5 Metagenomic compositional assessment of the vaginal microbiome following VMT.

(a) Bray-Curtis distances from baseline, correlated with the Amsel criteria scores measured on the same day; (b) Bray-Curtis distances from respective donor, correlated with the Amsel criteria scores measured on the same day; (c) Metagenomic assessment of the change in the microbiome composition at the Genus level following VMT in absolute values; (d) Change in microbiome in the genus level following VMT; (e) PCA performed on the metagenomic taxonomic data colored by Amsel criteria scores and divided into cluster using 2-means algorithm (n = 47 total recipient samples); (f) PCA colored by relative abundance of Bifidobacterium and of Lactobacillus genus (n = 47 total recipient samples). A–E are the individual VMT recipients.

Extended Data Fig. 6 Metagonomic functional (KEGG) assessment of the vaginal microbiome following VMT.

(a) Bray-Curtis distances from baseline, correlated to Amsel criteria scores and their components, measured on the same day; (b) Change in microbiome functional KEGG gene annotated following VMT; (c) Metagenomic bar plot denoting the KEGG genes that most contributed to the first principal component. A–E are the individual VMT recipients.

Extended Data Fig. 7 Metagonomic functional (GO) assessment of the vaginal microbiome following VMT.

(a) Bray-Curtis distances from baseline, correlated to Amsel criteria scores measured on the same day; (b), (c), principal component analysis, n = 50 total recipient samples, colored by (b), Amsel criteria score, (c) relative abundance of Bifidobacterium and of Lactobacillus genus; (d) Change in microbiome functional GO terms annotated following VMT; (e) Metagenomic bar plot denoting the GO terms that most contributed to the second principal component. A–E are the individual VMT recipients.

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Lev-Sagie, A., Goldman-Wohl, D., Cohen, Y. et al. Vaginal microbiome transplantation in women with intractable bacterial vaginosis. Nat Med 25, 1500–1504 (2019). https://doi.org/10.1038/s41591-019-0600-6

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