Background Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention. Methods This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N = 17 535) to receive 3 PF-06425090 or placebo doses (0, 1, and 6 months). Primary end points were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary end points), and antibiotic use (post hoc analysis) PD3 were evaluated. Tolerability and safety were assessed. Results The primary end point was not met (17 PF-06425090 and 25 placebo recipients had first CDI episode ≥14 days PD3 [vaccine efficacy (VE) = 31.0% (96.4% confidence interval [CI], −38.7% to 66.6%)]; 24 PF-06425090 and 34 placebo recipients had first CDI episode ≥14 days PD2 [VE = 28.6% (96.4% CI, −28.4% to 61.0%)]. Median CDI duration was lower with PF-06425090 (1 day) versus placebo (4 days; 2-sided nominal P = .02). Of participants with first CDI episode, 0 PF-06425090 and 11 placebo recipients sought CDI-related medical attention (post hoc analysis estimated VE = 100%; 95% CI, 59.6% to 100.0%) and 0 PF-06425090 and 10 placebo recipients required antibiotic treatment (VE = 100%; 95% CI, 54.8% to 100.0%). Local reactions were more frequent in PF-06425090 recipients, and systemic events were generally similar between groups; most were mild to moderate. Adverse event rates were similar between groups. Conclusions Three PF-06425090 doses were safe and well tolerated. Although the primary end point was not met, PF-06425090 reduced symptom duration, CDI that required medical attention, and CDI-directed antibiotic treatment, highlighting its potential to reduce CDI-associated healthcare burden. Clinical Trials Registration NCT03090191.

中文翻译：

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CLOVER（艰难梭菌疫苗功效 tRial）研究：一项 3 期随机试验，调查解毒毒素 A/B 疫苗对 50 岁及以上艰难梭菌感染风险增加的成年人的疗效和安全性


背景 艰难梭菌感染 （CDI） 会导致大量死亡率和医疗保健负担。我们评估了解毒毒素 A/B PF-06425090 疫苗对 CDI 的一级预防。方法 这项 3 期观察者盲法研究将 CDI 风险增加 （N = 17 535） 的 ≥ 50 岁人群随机分配接受 3 剂 PF-06425090 或安慰剂剂量 （0、1 和 6 个月）。主要终点是第一次 CDI 发作 （24 小时内 ≥3 次不成形的粪便;中心实验室确认的毒素 A/B 阳性）≥第 3 次给药后 14 天 （PD3;第一原发性） 和第 2 剂后 （PD2;第二原发性）。评估 CDI 持续时间、需要 CDI 相关医疗护理 （次要终点） 和抗生素使用（事后分析） PD3。评估耐受性和安全性。结果未达到主要终点（17 名 PF-06425090 和 25 名安慰剂接受者首次发生 CDI 发作≥14 天 PD3 [疫苗效力 （VE） = 31.0%（96.4% 置信区间 [CI]，-38.7% 至 66.6%）];24 名 PF-06425090 和 34 名安慰剂接受者首次发生 CDI 发作≥14 天 PD2 [VE = 28.6%（96.4% CI，-28.4% 至 61.0%）]。PF-06425090 （1 天） 的中位 CDI 持续时间低于安慰剂 （4 天;2 侧标称 P = .02）。在首次 CDI 发作的参与者中，0 名 PF-06425090 和 11 名安慰剂接受者寻求与 CDI 相关的医疗护理（事后分析估计 VE = 100%;95% CI，59.6% 至 100.0%）和 0 名 PF-06425090 和 10 名安慰剂接受者需要抗生素治疗（VE = 100%;95% CI，54.8% 至 100.0%）。PF-06425090 受者局部反应更频繁，组间全身事件通常相似;大多数为轻度至中度。两组之间的不良事件发生率相似。结论 3 剂 PF-06425090 安全且耐受性良好。 虽然没有达到主要终点，但 PF-06425090 减少了症状持续时间、需要医疗护理的 CDI 和 CDI 指导的抗生素治疗，突出了其减轻 CDI 相关医疗保健负担的潜力。临床试验注册 NCT03090191.