Hemmerling Anke, Mitchell Caroline M, Demby Suuba, Gebremichael Musie, Elsherbini Joseph, Xu Jiawu, Xulu Nondumiso, Shih Johnathan, Dong Krista, Govender Vaneshree, Pillay Vanessa, Ismail Nasreen, Casillas Gardenia, Moodley Jayajothi, Bergerat Agnes, Brunner Tess, Liebenberg Lenine, Ngcapu Sinaye, Mbano Ian, Lagenaur Laurel, Parks Thomas P, Ndung'u Thumbi, Kwon Douglas S, Cohen Craig R
Department of Obstetrics, Gynecology & Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA.
Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Lancet Microbe. 2025 Apr 3:101037. doi: 10.1016/j.lanmic.2024.101037.
Absence of vaginal lactobacilli and accompanying genital inflammation is associated with HIV acquisition. We aimed to assess how a vaginal live biotherapeutic containing Lactobacillus crispatus affects cervicovaginal microbiota and markers of HIV susceptibility in South African women.
This randomised, placebo-controlled, phase 2 trial evaluated LACTIN-V (L crispatus CTV-05), a vaginal live biotherapeutic, compared with placebo in cisgender women in South Africa, aged 18-23 years, recruited at a community-based research clinic. Eligible participants with a Nugent score of 4-10 (indicating intermediate vaginal microbiota or bacterial vaginosis) completed 7 days of oral metronidazole and were randomly assigned (2:1) to LACTIN-V (2 × 10 colony forming units per dose) or placebo (the substrate alone) via an independently generated randomisation sequence. Pharmacists, participants, and investigators were masked to treatment assignment. The study product (or placebo) was dosed daily for 5 days in week 1, then twice per week for an additional 3 weeks. Adverse events were evaluated 4 weeks and 8 weeks after starting the study product. Vaginal swabs (for 16S rRNA sequencing of the vaginal microbiome) and cervicovaginal lavage (for Luminex analysis of immune markers) were collected before metronidazole treatment, before study product (or placebo) administration, and at the week 4 and week 8 follow-up visits. An endocervical cytobrush for flow cytometry analysis of immune cell populations (including CD3CD4 T cells, and presence of CCR5 and the activation markers CD38 or HLA-DR) was collected before study product use and at 4 weeks and 8 weeks after study product use. The coprimary outcomes for the trial were (1) safety and acceptability of LACTIN-V, as measured by number of adverse events and a validated questionnaire; (2) presence of a Lactobacillus-dominant vaginal microbial community by 16S rRNA gene sequencing at week 4 and week 8; and (3) comparison of change in genital tract inflammatory markers from before metronidazole treatment to week 4 and week 8 between groups. Safety analyses were done in the intention-to-treat population and efficacy analyses in a modified intent-to-treat population (ie, excluding one person assigned placebo who erroneously received LACTIN-V). This trial is completed and registered on ClinicalTrials.gov (NCT05022212).
45 Black South African women were randomly assigned to receive LACTIN-V (n=32) or placebo (n=13). One woman in each group discontinued the trial during the intervention and two women discontinued during the follow-up. No severe or serious adverse events were observed. Solicited adverse events occurred in 35 (78%) of 45 participants with no significant difference by group (risk ratio 1·17, 95% CI 0·79-1·75; p=0·44). All local solicited adverse events were mild. 32 (71%) of 45 participants strongly agreed or agreed they would use the product again. L crispatus dominant microbiomes were identified in 13 (41%) of 32 participants in the LACTIN-V group at week 4 and eight (26%) of 31 at week 8, compared with none at week 4 and one (9%) of 11 in week 8 in the placebo group (week 4 p=0·0088; week 8 p=0·40). The proportion of activated endocervical HIV target cells out of total T cells increased from after metronidazole treatment to week 4 in the placebo group (median log fold change 1·891, IQR 1·731-4·018) but not in the LACTIN-V group (1·062, 0·449-1·424; p=0·016). Changes in the concentrations of 13 immune markers from before metronidazole treatment to week 4 or week 8 were not significantly different by group.
The use of LACTIN-V after metronidazole significantly increased vaginal L crispatus colonisation during 4 weeks of use, although this increase was transient, and women in the placebo group had an increase in endocervical CD4 HIV target cells during recovery compared with the LACTIN-V group. These results show that vaginal colonisation with an L crispatus live biotherapeutic is possible in an African context, and that optimisation of this strategy might be a way to decrease risk for HIV.
US National Institute of Child Health and Human Development and US National Institute of Allergy and Infectious Diseases.
阴道内缺乏乳酸杆菌以及伴随的生殖器炎症与获得性HIV感染有关。我们旨在评估一种含卷曲乳杆菌的阴道活菌生物疗法对南非女性宫颈阴道微生物群和HIV易感性标志物的影响。
这项随机、安慰剂对照的2期试验在南非一家社区研究诊所招募的18 - 23岁顺性别女性中，评估了一种阴道活菌生物疗法LACTIN-V（卷曲乳杆菌CTV-05）与安慰剂的效果。纽金特评分4 - 10分（表明阴道微生物群处于中间状态或细菌性阴道病）的合格参与者完成7天的口服甲硝唑治疗，然后通过独立生成的随机序列随机分配（2:1）至LACTIN-V组（每剂2×10菌落形成单位）或安慰剂组（仅底物）。药剂师、参与者和研究人员对治疗分配情况不知情。研究产品（或安慰剂）在第1周每天给药1次，持续5天，然后每周给药2次，再持续3周。在开始研究产品后4周和8周评估不良事件。在甲硝唑治疗前、研究产品（或安慰剂）给药前以及第4周和第8周随访时收集阴道拭子（用于阴道微生物群的16S rRNA测序）和宫颈阴道灌洗液（用于免疫标志物的Luminex分析）。在使用研究产品前以及使用研究产品后4周和8周收集用于免疫细胞群体流式细胞术分析（包括CD3CD4 T细胞以及CCR5和激活标志物CD38或HLA-DR的存在情况）的宫颈细胞刷。该试验的共同主要结局为：（1）通过不良事件数量和一份经过验证的问卷衡量LACTIN-V的安全性和可接受性；（2）在第4周和第8周通过16S rRNA基因测序确定是否存在以乳酸杆菌为主导的阴道微生物群落；（3）比较两组从甲硝唑治疗前到第4周和第8周生殖道炎症标志物的变化。在意向性治疗人群中进行安全性分析，在改良意向性治疗人群（即排除一名被分配到安慰剂组但错误接受LACTIN-V的人）中进行疗效分析。该试验已完成并在ClinicalTrials.gov上注册（NCT05022212）。
45名南非黑人女性被随机分配接受LACTIN-V（n = 32）或安慰剂（n = 13）。每组各有1名女性在干预期间退出试验，2名女性在随访期间退出。未观察到严重或重大不良事件。45名参与者中有35名（78%）发生了预期不良事件，两组之间无显著差异（风险比1.17，95%置信区间0.79 - 1.75；p = 0.44）。所有局部预期不良事件均为轻度。45名参与者中有32名（71%）强烈同意或同意她们会再次使用该产品。在第4周时，LACTIN-V组32名参与者中有13名（41%）鉴定出以卷曲乳杆菌为主导的微生物群落，第8周时有8名（26%）；相比之下，安慰剂组在第4周时无此类情况，第8周时有1名（9%）（第4周p = 0.0088；第8周p = 0.40）。从甲硝唑治疗后到第4周，安慰剂组总T细胞中活化的宫颈HIV靶细胞比例增加（中位数对数倍变化1.891，四分位间距1.731 - 4.018），而LACTIN-V组未增加（1.062，0.449 - 1.424；p = 0.016）。从甲硝唑治疗前到第4周或第8周，13种免疫标志物浓度的变化在两组之间无显著差异。
甲硝唑治疗后使用LACTIN-V在使用的4周内显著增加了阴道卷曲乳杆菌的定植，尽管这种增加是短暂的，并且与LACTIN-V组相比，安慰剂组女性在恢复过程中宫颈CD4 HIV靶细胞有所增加。这些结果表明，在非洲背景下用卷曲乳杆菌活菌生物疗法进行阴道定植是可行的，并且优化这一策略可能是降低HIV风险的一种方法。
美国国家儿童健康与人类发展研究所和美国国家过敏与传染病研究所。
