The success of fecal microbiota transplantation (FMT) as a treatment for Clostrioides difficile infection (CDI) has stirred excitement about the potential for microbiota transplantation as a therapy for a wide range of diseases and conditions. In this article, we discuss vaginal microbiota transplantation (VMT) as “the next frontier” in microbiota transplantation and identify the medical, regulatory, and ethical challenges related to this nascent field. We further discuss what we anticipate will be the first context for testing VMT in clinical trials, prevention of the recurrence of a condition referred to as bacterial vaginosis (BV). We also compare clinical aspects of VMT with FMT and comment on how VMT may be similar to or different from FMT in ways that may affect research design and regulatory decisions.
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References
1.
J.Ravel, P.Gajer, and Z.Abdo, et al., “Vaginal Microbiome of Reproductive-Age Women,”Proceedings of the National Academies of Science U.S.A.108, supp. 1 (2011): 4680–4687.
2.
J.Bilardi, S.Walker, and R.McNair, et al., “Women's Management of Recurrent Bacterial Vaginosis and Experiences of Clinical Care: A Qualitative Study,”PLoS One11, no. 3 (2016): e0151794.
3.
R.Amsel, P.A.Totten, and C.A.Spiegel, et al., “Nonspecific Vaginitis. Diagnostic Criteria and Microbial and Epidemio-logic Associations,”American Journal of Medicine74, no. 1 (1983): 14–22.
4.
L.R.McKinnon, S.L.Achilles, and C.S.Bradshaw, et al., “The Evolving Facets of Bacterial Vaginosis: Implications for HIV Transmission,”AIDS Research and Human Retroviruses35, no. 3 (2019): 219–228.
5.
D.H.Martin and J.M.Marrazzo, “The Vaginal Microbiome: Current Understanding and Future Directions,”Journal of Infectious Diseases214, Supp. 1 (2016): S36–41.
6.
C.A.Muzny and J.R.Schwebke, “Pathogenesis of Bacterial Vaginosis: Discussion of Current Hypotheses,”Journal of Infectious Diseases214, Supp. 1 (2016): S1–5.
7.
K.Murphy and C.M.Mitchell, “The Interplay of Host Immunity, Environment and the Risk of Bacterial Vaginosis and Associated Reproductive Health Outcomes,”Journal of Infectious Diseases214, Supp. 1 (2016): S29–35.
8.
C.S.Bradshaw and J.D.Sobel, “Current Treatment of Bacterial Vaginosis-Limitations and Need for Innovation,”Journal of Infectious Diseases214, Supp. 1 (2016): S14–20.
9.
Martin and Marrazzo, supra note 5; Muzny and Schwebke, supra note 6.
10.
Murphy and Mitchell, supra note 7.
11.
C.Kenyon, R.Colebunders, and T.Crucitti, “The Global Epidemiology of Bacterial Vaginosis: A Systematic Review,”American Journal of Obstetrics and Gynecology209, no. 6 (2013): 505–523.
12.
E.H.Koumans, M.Sternber, and G.McQuillan, et al., “The Prevalence of Bacterial Vaginosis in the United States, 2001-2004; Associations with Symptoms, Sexual Behaviors, and Reproductive Health,”Sexually Transmitted Diseases34, no. 11 (2007): 864–69.
13.
V.L.Bonham, E.D.Green, and E.J.Perez-Stable, “Examining How Race, Ethnicity, and Ancestry Data Are Used in Biomedical Research,”Journal of the American Medical Association320, no. 15 (2018): 1533–1534.
14.
Murphy and Mitchell, supra note 7.
15.
Id.
16.
Ravel, Gajer, and Abdo, supra note 1.
17.
McKinnon, Achilles, and Bradshaw, et al., supra note 4.
18.
Gajer, Brotman, and Bai, et al., supra note 1; J.Ravel, R.M.Brotman, and P.Gajer, et al., “Daily Temporal Dynamics of Vaginal Microbiota before, during and after Episodes of Bacterial Vaginosis,”Microbiome1, no. 1 (2013): 29, doi: 10.1186/2049-2618-1-29.
19.
S.B.Smith and J.Ravel, “The Vaginal Microbiota, Host Defence and Reproductive Physiology,”Journal of Physiology595, no. 2 (2017): 451–463.
20.
Amsel, supra note 3; Nugent supra note 11.
21.
J.E.Bilardi, S.Walker, and M.Temple-Smith, et al., “The Burden of Bacterial Vaginosis: Women's Experience of the Physical, Emotional, Sexual and Social Impact of Living with Recurrent Bacterial Vaginosis,”PLoS One8, no. 9 (2013): e74378.
22.
Id.
23.
R.M.Brotman, M.A.Klebanoff, and T.R.Nansel, et al., “Bacterial Vaginosis Assessed by Gram Stain and Diminished Colonization Resistance to Incident Gonococcal, Chlamydial, and Trichomonal Genital Infection,”Journal of Infectious Diseases202, no. 12 (2010): 1907–1915.
24.
P.Mastromarino, B.Vitali, and L.Mosca, “Bacterial Vaginosis: a Review on Clinical Trials with Probiotics,”New Microbiologica36, no. 3 (2013): 229–238.
25.
Chen, Song, and Wei, et al., supra note 19.
26.
B.D.Taylor, T.Darville, and C.L.Haggerty, “Does Bacterial Vaginosis Cause Pelvic Inflammatory Disease?”Sexually Transmitted Diseases40, no. 2 (2013): 117–122.
27.
K.Thomas-White, S.C.Forster, and N.Kumar, et al., “Culturing of Female Bladder Bacteria Reveals an Interconnected Urogenital Microbiota,”Nature Communications9, no. 1 (2018): art. no. 1557.
28.
A.H.Sumati and N.K.Saritha, “Association of Urinary Tract Infection in Women with Bacterial Vaginosis,”Journal of Global Infectious Diseases1, no. 2 (2009): 151–152.
29.
W.Xuet al., “Mini-Review: Perspective of the Microbiome in the Pathogenesis of Urothelial Carcinoma,”American Journal of Clinical and Experimental Urology2, no. 1 (2014): 57–61.
30.
Bradshaw and Sobel, supra note 8.
31.
J.D.Sobel, C.Schmitt, and C.Meriwether, Long-Term Follow-up of Patients with Bacterial Vaginosis Treated with Oral Metronidazole and Topical Clindamycin,”Journal of Infectious Diseases167, no. 3 (1993): 783–784.
32.
E.R.Boskey, T.R.Moench, P.S.Hees, and R.A.Cone, “A Self-Sampling Method to Obtain Large Volumes of Undiluted Cervicovaginal Secretions,”Sexually Transmitted Diseases30, no. 2 (2003): 107–109.
33.
H.L.Gardner and C.D.Dukes, “Haemophilus Vaginalis Vaginitis: A Newly Defined Specific Infection Previously Classified Non-Specific Vaginitis,”American Journal of Obstetrics and Gynecology69, no. 5 (1955): 962–976.
34.
Id.
35.
J.M.Marrazzo, L.A.Koutsky, and D.A.Eschenbach, et al., “Characterization of Vaginal Flora and Bacterial Vaginosis in Women Who Have Sex with Women,”Journal of Infectious Diseases185, no. 9 (2002): 1307–1313.
36.
J.M.Marrazzo, K.K.Thomas, K.Agnew, and K.Ringwood, “Prevalence and Risks for Bacterial Vaginosis in Women Who Have Sex with Women,”Sexually Transmitted Diseases37, no. 5 (2010): 335–339.
37.
J.M.Marrazzo, M.Antonio, K.Agnew, and S.L.Hillier, “Distribution of Genital Lactobacillus Strains Shared by Female Sex Partners,”Journal of Infectious Diseases199, no. 5 (2009): 680–683.
38.
Id.
39.
L.A.Vodstrcil, S.M.Walker, and J.S.Hocking, et al., “Incident Bacterial Vaginosis (BV) in Women Who Have Sex with Women Is Associated with Behaviors that Suggest Sexual Transmission of BV,”Clinical Infectious Diseases60, no. 7 (2015): 1042–1053.
40.
N.T.Muelleret al., “Bacterial Baptism: Scientific, Regulatory Issues Raised by Vaginal Seeding of C-Section-Born Babies,”Journal of Law, Medicine & Ethics47, no. 4 (2019): 568-578.
41.
See alsoN.Muelleret al., “Bacterial Baptism: Scientific, Medical and Regulatory Issues Raised by Vaginal Seeding of C-section-born babies,”Journal of Law, Medicine & Ethics47, no. 4 (2019): 568-578.
42.
T.Olszak, D.An, and S.Zeissig, et al., “Microbial Exposure during Early Life Has Persistent Effects on Natural Killer T Cell Function,”Science336, no. 6080 (2012): 489–493.
43.
M.G.Dominguez-Bello, K.M.De Jesus-Laboy, and N.Shen, et al., “Partial Restoration of the Microbiota of Cesarean-Born Infants Via Vaginal Microbial Transfer,”Nature Medicine22, no. 3 (2016): 250–253. See also Mueller, supra note 40.
44.
Id.
45.
N. Mueller et al., supra note 40.
46.
J.Qin, R.Li, and J.Raes, et al., “A Human Gut Microbial Gene Catalogue Established by Metagenomic Sequencing,”Nature464, no. 7285 (2010): 59–65.
47.
C.M.Theriot and V.B.Young, “Interactions between the Gastrointestinal Microbiome and Clostridium difficile,”Annual Review of Microbiology69 (2015): 445–461.
48.
B.B.Oakley, T.L.Fiedler, J.M.Marrazzo, and D.N.Fredricks, “Diversity of Human Vaginal Bacterial Communities and Associations With Clinically Defined Bacterial Vaginosis,”Applied and Environmental Microbiology74, no. 15 (2008): 4898–4909.
49.
C.Staley, C.R.Kelly, and L.J.Brandt, et al., “Complete Micro-biota Engraftment Is Not Essential for Recovery from Recurrent Clostridium difficile Infection Following Fecal Microbiota Transplantation,”mBio7, no. 6 (2016): e01965-16, DOI: 10.1128/mBio.01965-16.
50.
C.S.Smillie, J.Sauk, and D.Gevers, et al., “Strain Tracking Reveals the Determinants of Bacterial Engraftment in the Human Gut Following Fecal Microbiota Transplantation,”Cell Host Microbe23, no. 2 (2018): 229–40 e5.
51.
M.I.Petrova, G.Reid, M.Vaneechoutte, and S.Lebeer, “Lactobacillus iners: Friend or Foe?”Trends in Microbiology25, no. 3 (2017): 182–191.
52.
Gajer, Brotman, and Bai et al., supra note 1.
53.
B.Eiseman, W.Silen, G.S.Bascom, and A.J.Kouvar, “Fecal Enema as an Adjunct in the Treatment of Pseudomembranous Enterocolitis,”Surgery44, no. 5 (1958): 854–859.
54.
E.van Nood, A.Vreize, amd M.Niewdown, et al., “Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile,”New England Journal of Medicine368, no. 5 (2013): 407–415.
55.
21 U.S. Code §§ 331(k) and 334.
56.
21 U.S. Code § 379a.
57.
United States v. Regenerative Sciences LLC, 741 F.3d 1314 (D.C. Cir. 2014). See also N. Mueller et al., supra note 40.
58.
United States v. Kaplan, 836 F.3d 1199 (9th Cir. 2016). See also N. Mueller et al., supra note 40.
59.
See N. Mueller et al., supra note 40, citing United States v. Geborde, 278 F.3d 926 (9th Cir. 2002) and United States v. Kaplan, 836 F.3d 1199 (9th Cir. 2016).
60.
G.Reid, “Is Bacterial Vaginosis a Disease?”Applied Microbiology and Biotechnology102, no. 2 (2018): 553–558.
61.
R.J.Hickey, X.Zhou, and M.L.Settles, et al., “Vaginal Micro-biota of Adolescent Girls prior to the Onset of Menarche Resemble Those of Reproductive-Age Women,”MBio6, no. 2 (2015): e00097-15, doi: 10.1128/mBio.00097-15.
A.Khoruts, D.Hoffman, and F.Palumbo, “The Impact of Regulatory Policies on the Future of Fecal Microbiota Transplantation,”Journal of Law, Medicine & Ethics47, no. 4 (2019): 482-504.
64.
R.E.Sachs and C.A.Edelstein, “Ensuring the Safe and Effective FDA Regulation of Fecal Microbiota Transplantation,”Journal of Law and the Biosciences2, no. 2 (2015): 396–415.
65.
21 C.F.R. 1271.3. 2018.
66.
21 C.F.R. 1271.3 (f)(2). 2018.
67.
21 C.F.R. 1271.10. 2018.
68.
Id.
69.
21 C.F.R. 1271.85. 2018.
70.
21 C.F.R. 1271.150. 2018.
71.
21 C.F.R. 1271.290. 2018.
72.
21 U.S. Code § 355c. 2018.
73.
K.DeLong, et al., “Conceptual Design of a Universal Donor Screening Approach for Vaginal Microbiota Transplant,”Frontiers in Cellular and Infection Microbiology (2019), available at <https://www.frontiersin.org/articles/10.3389/fcimb.2019.00306/full> (last visited December 6, 2019).
74.
J.Haya, A.Garcia, and C. López-Manzanara, et al., “Importance of Lactic Acid in Maintaining Vaginal Health: A Review of Vaginitis and Vaginosis Etiopathogenic Bases and a Proposal for a New Treatment,”Open Journal of Obstetrics and Gynecology4 (2014): 787–799.
75.
G.Zarate, V.Santos, and M.E.Nader-Macias, “Protective Effect of Vaginal Lactobacillus paracasei CRL 1289 against Urogenital Infection Produced by Staphylococcus aureus in a mouse Animal Model,”Infectious Diseases in Obstetrics and Gynecology (2009): art. no. 48358.
76.
S.Yildirim, C.J.Yeoman, and S.C.Jange, et al., “Primate Vaginal Microbiomes Exhibit Species Specificity without Universal Lactobacillus Dominance,”The ISME Journal8 (2014): 2431–2444.
77.
G.T.Spear, D.Gilbert, and M.Sikaroodi, et al., “Identification of Rhesus Macaque Genital Microbiota by 16S Pyrosequencing Shows Similarities to Human Bacterial Vaginosis: Implications for Use as an Animal Model for HIV Vaginal Infection,”AIDS Research and Human Retroviruses26, no. 2 (2010): 193–200.
78.
L.M.Ensign and E.D.Weld, “Safety and Efficacy of Vaginal Microbiota Transplant (VMT) in Women with Bacterial Vaginosis (BV),”available at <https://clinicaltrials.gov/ct2/show/NCT03769688> (last visited October 3, 2019).
B.J.Stegmann and J.C.Carey, “TORCH Infections. Toxoplasmosis, Other (syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus (CMV), and Herpes infections,”Current Women's Health Reports2, no. 4 (2002): 253–258.
83.
S.P.Costello, M.A.Conlon, and M.S.Vuaran, S.P., et al., “Faecal Microbiota Transplant for Recurrent Clostridium difficile Infection Using Long-Term Frozen Stool is Effective: Clinical Efficacy and Bacterial Viability Data,”Alimentary Pharmacology and Therapeutics42, no. 8 (2015): 1011–1018.
C.M.Surawicz, L.J.Brandt, and D.G.Binion, et al., “Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections,”American Journal of Gastroenterology108, no. 4 (2013): 478–498, at 499.
87.
R.M.Brotman, M.D.Shardell, and P.Gajer, et al., “Association between the Vaginal Microbiota, Menopause Status, and Signs of Vulvovaginal Atrophy,”Menopause-the Journal of the North American Menopause Society21, no. 5 (2014): 450–458.
88.
L.Corey, A.Wald, and R.Patel, et al., “Once-daily Valacyclovir to Reduce the Risk of Transmission of Genital Herpes,”New England Journal of Medicine350, no. 1 (2004): 11–20.
89.
Khoruts, Hoffmann, and Palumbo, supra note 63.
90.
B.M.Ngugi, A.Hemmerling, and E.A.Bukusi, et al., “Effects of Bacterial Vaginosis-Associated Bacteria and Sexual Intercourse on Vaginal Colonization with the Probiotic Lactobacillus crispatus CTV-05,”Sexually Transmitted Diseases38, no. 11 (2011): 1020–1027.
91.
Gajer, Brotman, and Bai, et al., supra note 1.
92.
M.H.Woodworth, E.M.Neish, and N.S.Miller, et al., “Laboratory Testing of Donors and Stool Samples for Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection,”Journal of Clinical Microbiology55, no. 4 (2017): 1002–1010.
93.
U.S. Food and Drug Administration, Bacterial Vaginosis: Developing Drugs for Treatment, Guidance for Industry, August2019, available at <https://www.fda.gov/media/129530/download> (last visited October 3, 2019).
94.
U.S. Food and Drug Administration, Guidance for Industry and Food and Drug Administration Staff, Collection of Race and Ethnicity Data in Clinical Trials, October26, 2016, available at <https://www.fda.gov/media/75453/download> (last visited October 3, 2019).
95.
J.Heintzman and M.Marino, “Race and Ethnicity Data in Research,”JAMA321, no. 12 (2019): 1217–1218.
C.M.Pacheco, S.M.Daley, and T.Brown, et al., “Moving Forward: Breaking the Cycle of Mistrust Between American Indians and Researchers,”American Journal of Public Health103, no. 12 (2013): 2152–2159.
99.
D.J.Alcendor, “Evaluation of Health Disparity in Bacterial Vaginosis and the Implications for HIV-1 Acquisition in African American Women,”American Journal of Reproductive Immunology76, no. 2 (2016): 99–107.
100.
D.E.Hoffmann, J.D.Fortenberry, and J.Ravel, “Are Changes to the Common Rule Necessary to Address Evolving Areas of Research? A Case Study Focusing on the Human Microbiome Project,”Journal of Law, Medicine & Ethics41, no. 2 (2013): 454–469.
