Suche
Mein Konto
This article is part of our October 2022 Immune Health special issue. Download the full issue here.
Study objective
Investigating the Effects of a Live Biotherapeutic Vaginal AgentL CrispatusCTV-05 (LACTIN-V) on genital immunology and important vaginal bacteria
Key to take away
This study suggests that vaginal use of LACTIN-V is associated with a sustained reduction in mucosal inflammation and possibly improved mucosal barrier function.
design
A substudy of a phase 2b, randomized, placebo-controlled trial of LACTIN-V to reduce recurrence of bacterial vaginosis
Participant
The original study recruited 228 women (aged 18-45 years) to participate in a Phase 2b trial of LACTIN-V to reduce recurrence of bacterial vaginosis. The subset of the study examined here included 66 women with high adherence to treatment who were randomly selected from the original study (32 in the LACTIN-V group; 34 in the placebo group). The average age was 33 years.
None of the women tested positive for human immunodeficiency virus (HIV), syphilis,Neisseria gonorrhoeae,Chlamydia trachomatisorTrichomonas vaginalisat the baseline. Pregnancy and urinary tract infection were negative in women. Participants' baseline characteristics and sexual behavior, including recent sexual intercourse and hormonal contraceptive use as well as ethnicity, did not differ significantly between groups. Women who met at least three of four clinical Amsel criteria for bacterial vaginosis and had a Nugent score of 4 to 10 based on Gram stain were eligible to participate.
intervention
All participants received a 5-day course of vaginal metronidazole 0.75% gel. After this treatment, they were randomly assigned to receive either LACTIN-V or a placebo, which was administered vaginally once a day for five days for the first week and then twice a week for another ten weeks. Follow-up assessments occurred 4, 8, 12, and 24 weeks after enrollment.
Lactobacillus crispatusCTV-05 (LACTIN-V) is a live biotherapeutic product containing a naturally occurring strain ofL Crispatus. LACTIN-V consists of a powder with 2 x 109colony forming units ofL CrispatusCTV-05 is preserved with inactive ingredients and is administered via a prefilled applicator.
Evaluated study parameters
The researchers examined soluble immune factors and the absolute abundance of bacterial taxa using multiplex ELISA and quantitative polymerase chain reaction (PCR).
Primary outcome
The primary outcomes were vaginal concentrations of interleukin 1 alpha (IL-1a) and soluble E-cadherin at 24 weeks (i.e., 13 weeks after completion of treatment, whether LACTIN-V or placebo).
Additional outcomes included vaginal concentrations of soluble immune factors and absolute abundances of major vaginal bacteriaL Crispatus,L CrispatusStrain CTV-05,Liners,L jensenii,L gasseri,Gardnerella vaginalis,Atopobium vaginae,Megasphaeraspecies andPrevotellaSpecies.
Key findings
Treatment with LACTIN-V was associated with significantly lower levels of the proinflammatory cytokine IL-1a (P=0.042), an inflammatory marker, and soluble E-cadherin (P=0.035), a biomarker for disruption of the epithelial barrier.
Furthermore, among the 6 exploratory endpoints, LACTIN-V was associated with increased levels of induced protein 10 (IP-10) at 23 weeks. Interferon (IFN) alpha 2a and IL-17A were undetectable in more than 50% of samples. Detectability of IFN-alpha 2a or IL-17A was not significantly associated with treatment.
transparency
This study was funded by the Canadian Institutes of Health and Research and the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID). One of the authors of this study, CR Cohen, MD, is chairman of the scientific advisory board of Osel, the biotherapeutics company whose product pipeline includes LACTIN-V. He reports grants from the NIAID and the NIH National Institute of Child Health and Human Development. He holds stock options in Osel and Evvy. Another author, B Coburn, PhD, reports grants from the Western Foundation, the Canadian Institutes of Health Research, the Canadian Cancer Society, the McLaughlin Foundation, the National Cancer Institute, and the Cystic Fibrosis Foundation, as well as research income from Nubiyota, a microbiome therapeutics company focused on developing novel microbiota-based drugs to restore gut balance. Co-author R Kaul reports on a grant from the Canadian Institutes of Health Research.
Implications and limitations for practice
Bacterial vaginosis (BV) affects 15 to 50% of women of childbearing age worldwide1The recurrence rate is quite problematic and even after treatment with an indicated antibiotic, 20 to 75% of women experience a recurrence within 3 months.2BV is associated with an increased risk of sexually transmitted infections (STIs), including HIV, as well as premature birth.3BV also leads to negative emotional, sexual and social effects and places an economic burden on patients. If we could reduce the risk of recurrence or even promote primary prevention, we would help find a much-needed solution to women's health.
I will address the study implications and limitations of the current study in a moment, but first let's look at the original study from which the current substudy emerged. I believe this study has larger implications for practice. The original study (Cohen et al.,NEJM, 2020) included a phase 2b trial to assess whether treatment with LACTIN-V following vaginal administration of metronidazole for BV reduced the incidence of BV recurrence. Women aged 18 to 45 years with BV completed a 5-day course of vaginal metronidazole gel (0.75%). Within 48 hours of completing this treatment, they were randomly assigned to receive vaginal LACTIN-V versus placebo for 11 weeks. The procedure required participants to insert an applicator every evening for five days and then twice a week for ten weeks. The primary outcome was the percentage of women who experienced recurrence of BV at week 12. The researchers randomized 228 women, including 152 in the treatment group and 76 in the placebo group. At week 12, BV recurrence was significantly lower in the LACTIN-V group, with a recurrence rate of 30% in the LACTIN-V group (compared to a recurrence rate of 45% in the placebo group) and with a sustained effect in the LACTIN-V treatment group at week 24.
The recurrence rate is quite problematic and even after treatment with an indicated antibiotic, 20 to 75% of women experience a recurrence within 3 months.
Now to our current substudy, which resulted in a sustained reduction in genital inflammation and a biomarker for epithelial integrity. LACTIN-V has been associated with the concentration of soluble immune factors and an abundance of multiple bacterial taxa, which bodes well for genital immunity. These persistent genital immune effects were primarily mediated by a reduced abundance of bacterial vaginosis-associated taxaPrevotellaspp andMegasphaeraspp and, to a lesser extent, increased amounts of itL Crispatus. There are strong associations between the vaginal microbiota and HIV risk, suggesting that vaginal microbiota predominance is promotedL Crispatusin the vagina could reduce the risk of HIV.
women withL CrispatusWomen with predominance in their vaginal ecosystem also have fewer transitions to bacterial vaginosis-type microbiota than women with othersLactobacillusdominant species such asLinersSupremacy. That suggests soL Crispatuscan competitively inhibit or exclude inflammatory bacterial vaginosis-associated bacteria. This is mediated in part by the production of lactic acid and antimicrobial metabolites. We have other evidence to support thisL Crispatusis an important producer of lactic acid in the vagina.4
There are some limitations to the study. The researchers assessed sexually transmitted diseases only at the initial screening and only tested them again if the women had symptoms. The stage of the menstrual cycle was not recorded unless the women were currently menstruating. Fluctuation in normal sex hormones is a potential factor in genital immunology and pH. The assays used were targeted qPCR rather than 16SrRNA gene sequencing, which limited the ability to assess the vaginal microbiota and identify contributions from other microbes. Only US women participated in the study, although it was an ethnically diverse cohort.
Disclosure of Conflicts of Interest
Dr. Tori Hudson is co-owner of a women's supplement company, Vitanica, which offers a wide range of women's health, nutritional and herbal products, including probiotic species and strains for oral and vaginal use to prevent and treat urogynecological diseases. She is also a medical advisor for Nutritional Fundamentals for Health, Symphony, Integrative Therapeutics and Gaia Herbs Pro.