To the content
4 . 2022

Sustained effect of LACTIN-V (Lactobacillus crispatus CTV-05) on genital immunology following standard bacterial vaginosis treatment: results from a randomised, placebo controlled trial

Abstract

Background. Bacterial vaginosis might increase HIV risk by eliciting genital inflammation and epithelial barrier disruption, whereas vaginal Lactobacillus crispatus is associated with immune quiescence and HIV protection. We investigated the effect of a live biotherapeutic containing L crispatus CTV-05 (LACTIN-V) on genital immunology and key vaginal bacteria.

Methods. This substudy included women aged 18–45 years who participated in the randomised, placebo-controlled, phase 2b trial of LACTIN-V to reduce bacterial vaginosis recurrence, conducted at four universities and hospitals in the USA. Women with negative results for sexually transmitted infection, pregnancy, and urinary tract infection were provided a 5-day course of vaginal metronidazole 0.75% gel. Those who met at least three of four clinical Amsel criteria for bacterial vaginosis and had a Nugent score of 4–10 from Gram staining were eligible. Participants in the LACTIN-V trial were randomly assigned (2:1) to receive either LACTIN-V or placebo, applied vaginally once per day for 5 days during the first week and then twice per week for 10 more weeks. Follow-up visits occurred 4, 8, 12, and 24 weeks after enrolment. Soluble immune factors and the absolute abundance of bacterial taxa were assayed by mutliplex ELISA and quantitative PCR. The primary outcomes were vaginal levels of IL-1α and soluble E-cadherin at 24 weeks (ie, 13 weeks after treatment cessation).

Findings. Between Feb 21, 2020 and March 18, 2021, we characterised genital immune parameters and the vaginal microbiota in a subset of 66 highly adherent participants who were randomly selected, with no exclusion criteria, from those who had attended all study follow-up visits (n=166) in the larger LACTIN-V clinical trial (n=228). 32 (48%) participants received LACTIN-V and 34 (52%) received placebo. LACTIN-V treatment was significantly associated with lower concentrations of the proinflammatory cytokine IL-1α (β coefficient 0.310, SE 0.149; p=0.042) and soluble E-cadherin (0.429, 0.199; p=0.035), a biomarker of epithelial barrier disruption.

Interpretation. Vaginal administration of LACTIN-V following standard bacterial vaginosis therapy resulted in a sustained reduction in genital inflammation and a biomarker of epithelial integrity. The potential of LACTIN-V to reduce HIV susceptibility merits further investigation.

Funding. Canadian Institute of Health Research and National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Copyright. © 2022 Authors. Published by Elsevier Ltd. (Elsevier Ltd.). This article is in the public domain under the CC BY 4.0 license. Corrections have been made to this online publication. The corrected version first appeared on thelancet website. com/microbe June 2, 2022

Armstrong E., Hemmerling A., Miller S., Burke K.E., Newmann S.J., Morris S.R., Reno H., Huibner S., Kulikova M., Nagelkerke N., Coburn B., Cohen C.R., Kaul R. Sustained effect of

LACTIN-V (Lactobacillus crispatus CTV-05) on genital immunology following standard bacterial vaginosis treatment: results from a randomised, placebo-controlled trial. Lancet Microbe. 2022 Jun; 3 (6): e435–e442. DOI: https://doi.org/10.1016/S2666-5247(22)00043-X

Epub 2022 Apr 21. Erratum in: Lancet Microbe. 2022 Jul; 3 (7). PMID: 35659905. PMCID: PMC9188188

References

1.Low N., Chersich M.F., Schmidlin K., et al. Intravaginal practices, bacterial vaginosis, and HIV infection in women: individual participant data meta-analysis. PLoS Med. 2011; 8: e1000416.

2.Atashili J., Poole C., Ndumbe P.M., Adimora A.A., Smith J.S. Bacterial vaginosis and HIV acquisition: a meta-analysis of published studies. AIDS. 2008; 22: 1493–501.

3.Ravel J., Gajer P., Abdo Z., et al. Vaginal microbiome of reproductive- age women. Proc Natl Acad Sci USA. 2011; 108 (suppl 1): 4680–87.

4.McKinnon L.R., Achilles S.L., Bradshaw C.S., et al. The evolving facets of bacterial vaginosis: implications for HIV transmission. AIDS Res Hum Retroviruses. 2019; 35: 219–28.

5.Nold C., Anton L., Brown A., Elovitz M. Inflammation promotes a cytokine response and disrupts the cervical epithelial barrier: a possible mechanism of premature cervical remodeling and preterm birth. Am J Obstet Gynecol. 2012; 206: 208.e1–7.

6.Anton L., Sierra L.J., DeVine A., et al. Common cervicovaginal microbial supernatants alter cervical epithelial function: mechanisms by which Lactobacillus crispatus contributes to cervical health. Front Microbiol. 2018; 9: 2181.

7.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: 29–37.

8.Arnold K.B., Burgener A., Birse K., et al. Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of proteases, mucosal barrier proteins, and an influx of HIV-susceptible target cells. Mucosal Immunol. 2016; 9: 194–205.

9.Masson L., Passmore J.A.S., Liebenberg L.J., et al. Genital inflammation and the risk of HIV acquisition in women. Clin Infect Dis. 2015; 61: 260–69.

10.Masson L., Mlisana K., Little F., et al. Defining genital tract cytokine signatures of sexually transmitted infections and bacterial vaginosis in women at high risk of HIV infection: a cross-sectional study. Sex Transm Infect. 2014; 90: 580–7.

11.Joag V., Obila O., Gajer P., et al. Impact of standard bacterial vaginosis treatment on the genital microbiota, immune milieu, and ex vivo human immunodeficiency virus susceptibility. Clin Infect Dis. 2019; 68: 1675–83.

12.McClelland R.S., Lingappa J.R., Srinivasan S., et al. Evaluation of the association between the concentrations of key vaginal bacteria and the increased risk of HIV acquisition in African women from five cohorts: a nested case-control study. Lancet Infect Dis. 2018; 18: 554–64.

13.Srinivasan S., Richardson B.A., Wallis J., et al. Vaginal microbiota and HIV acquisition risk among African women. In: Conference on Retroviruses and Opportunistic Infections. Boston, MA, March 4–7, 2018: Abstr 268.

14.Anahtar M.N., Byrne E.H., Doherty K.E., et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity. 2015; 42: 965–76.

15.Ojala T., Kankainen M., Castro J., et al. Comparative genomics of Lactobacillus crispatus suggests novel mechanisms for the competitive exclusion of Gardnerella vaginalis. BMC Genomics. 2014; 15: 1070.

16.Bradshaw C.S., Morton A.N., Hocking J., et al. High recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence. J Infect Dis. 2006; 193: 1478–86.

17.Yang S., Reid G., Challis J.R.G., et al. Effect of oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 on the vaginal microbiota, cytokines and chemokines in pregnant women. Nutrients. 2020; 12: 368.

18.Happel A.U., Singh R., Mitchev N., et al. Testing the regulatory framework in South Africa – a single-blind randomized pilot trial of commercial probiotic supplementation to standard therapy in women with bacterial vaginosis. BMC Infect. Dis. 2020; 20: 491.

19.Bisanz J.E., Seney S., McMillan A., et al. A systems biology approach investigating the effect of probiotics on the vaginal microbiome and host responses in a double blind, placebo-controlled clinical trial of post-menopausal women. PLoS One. 2014; 9: e104511.

20.Cohen C.R., Wierzbicki M.R., French A.L., et al. Randomized trial of LACTIN-V to prevent recurrence of bacterial vaginosis. N Engl J Med. 2020; 382: 1906– 15.

21.Mohammadi A., Bagherichimeh S., Perry M.C., et al. The impact of cervical cytobrush sampling on cervico-vaginal immune parameters and microbiota relevant to HIV susceptibility. Sci Rep. 2020; 10: 8514.

22.Baron R.M., Kenny D.A. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol. 1986; 51: 1173–82.

23.Sabo M.C., Lehman D.A., Pintye J.C., et al. Elevation of cervical C-X-C motif chemokine ligand 10 levels is associated with HIV-1 acquisition in pregnant and postpartum women. AIDS. 2020; 34: 1725–33.

24.Wang Z., He Y., Zheng Y. Probiotics for the treatment of bacterial vaginosis: a meta-analysis. Int J Environ Res Public Health. 2019; 16: e3859.

25.Shannon B., Gajer P., Yi T.J., et al. Distinct effects of the cervicovaginal microbiota and herpes simplex type 2 infection on female genital tract immunology. J Infect Dis. 2017; 215: 1366–75.

26.Gajer P., Brotman R.M., Bai G., et al. Temporal dynamics of the human vaginal microbiota. Sci Transl Med. 2012; 4: 132ra52.

27.Happel A.U., Kullin B., Gamieldien H., et al. Exploring potential of vaginal Lactobacillus isolates from South African women for enhancing treatment for bacterial vaginosis. PLoS Pathog. 2020; 16: e1008559.

28.Hearps A.C., Tyssen D., Srbinovski D., et al. Vaginal lactic acid elicits an anti-inflammatory response from human cervicovaginal epithelial cells and inhibits production of pro-inflammatory mediators associated with HIV acquisition. Mucosal Immunol. 2017; 10: 1480–90.

29.Delgado-Diaz D.J., Tyssen D., Hayward J.A., Gugasyan R., Hearps A.C., Tachedjian G. Distinct immune responses elicited from cervicovaginal epithelial cells by lactic acid and short chain fatty acids associated with optimal and non-optimal vaginal microbiota. Front Cell Infect Microbiol. 2020; 9: 446.

30.Kreisel K.M., Spicknall I.H., Gargano J.W., et al. Sexually transmitted infections among US women and men: prevalence and incidence estimates, 2018. Sex Transm Dis. 2021; 48: 208–14.

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)

CHIEF EDITORS
CHIEF EDITOR
Sukhikh Gennadii Tikhonovich
Academician of the Russian Academy of Medical Sciences, V.I. Kulakov Obstetrics, Gynecology and Perinatology National Medical Research Center of Ministry of Healthсаre of the Russian Federation, Moscow
CHIEF EDITOR
Kurtser Mark Arkadievich
Academician of the Russian Academy of Sciences, MD, Professor, Head of the Obstetrics and Gynecology Subdepartment of the Pediatric Department, N.I. Pirogov Russian National Scientific Research Medical University, Ministry of Health of the Russian Federation
CHIEF EDITOR
Radzinsky Viktor Evseevich
Corresponding Member of the Russian Academy of Sciences, MD, Professor, Head of the Subdepartment of Obstetrics and Gynecology with a Course of Perinatology of the Medical Department in the Russian People?s Friendship University

Journals of «GEOTAR-Media»