Pfizer Vaccine Clinical Research & Development, 500 Arcola Rd, Collegeville, PA, USA.
Pfizer Vaccine Research & Development, Horizon Building, Honey Lane, Hurley, Berkshire SL6 6RJ, UK.
Vaccine. 2021 Sep 24;39(40):5991-6003. doi: 10.1016/j.vaccine.2021.05.028. Epub 2021 Sep 3.
Two phase 1/phase 2 studies assessed 2 formulations of investigational bivalent Clostridioides (Clostridium) difficile vaccine (QS-21 adjuvanted toxoid and toxoid-alone) in healthy adults 50-85 years of age.
The QS-21 adjuvanted toxoid vaccine study randomized subjects 3:1 to 100 μg QS-21-containing C difficile vaccine or placebo administered in a shortened-month (Months 0, 1, 3) or day (Days 1, 8, 30) regimen. The toxoid-alone vaccine study randomized subjects 3:3:1 to receive 100 or 200 μg unadjuvanted C difficile vaccine formulation or placebo in Stages 1 and 2 (sentinel cohorts of different age groups), and 3:1 to receive the selected dose of unadjuvanted C difficile vaccine formulation or placebo in Stage 3 (Days 1, 8, 30). Safety was the primary outcome for both studies. Immunogenicity was determined by measuring serum toxin A- and B-specific neutralizing antibodies.
In the day regimen, 10 reports across both studies of grade 3 injection site redness postdose 2 triggered predefined stopping rules. Local reactions in both studies were more common among vaccine versus placebo recipients. Injection site pain predominated and was generally mild in severity. Systemic events were infrequent and generally mild-to-moderate in severity. Adverse events were reported by 50.0%-75.0% and 16.7%-50.0% of subjects in the QS-21 and toxoid-alone studies, respectively. Immune responses peaked around Day 37 (shortened-month regimen) or between Day 15 and Month 2 (day regimen) and remained above baseline throughout follow-up.
Both formulations demonstrated robust immunogenicity. Both studies stopped early due to grade 3 injection site redness postdose 2 of the day regimen; neither formulation progressed to later stage development. Instead, an aluminum hydroxide-containing formulation of the vaccine candidate administered at 0, 1, and 6 months, which was safe and immunogenic in phase 1 and 2 studies, advanced to phase 3 studies.
两项 1 期/2 期研究评估了两种研究用双价艰难梭菌（梭状芽胞杆菌）疫苗（含 QS-21 佐剂的类毒素和类毒素单一组分）在 50-85 岁健康成年人中的效果。
QS-21 佐剂类毒素疫苗研究将受试者随机分为 3:1 组，分别接受 100μg 含 QS-21 的艰难梭菌疫苗或安慰剂，在缩短的一个月（第 0、1、3 个月）或一天（第 1、8、30 天）方案中给药。类毒素单一组分疫苗研究将受试者随机分为 3:3:1 组，在第 1 阶段和第 2 阶段（不同年龄组的哨点队列）中分别接受 100 或 200μg 未佐剂的艰难梭菌疫苗或安慰剂，在第 3 阶段（第 1、8、30 天）中接受选定剂量的未佐剂的艰难梭菌疫苗或安慰剂。两项研究的主要终点均为安全性。通过测量血清毒素 A 和 B 特异性中和抗体来确定免疫原性。
在一天方案中，两项研究中共有 10 例 2 剂后出现 3 级注射部位发红的报告，触发了预先设定的停止规则。与安慰剂组相比，两研究中的局部反应更为常见。注射部位疼痛为主，通常为轻度。全身不良事件很少见，一般为轻中度。在 QS-21 组和类毒素单一组分组中，分别有 50.0%-75.0%和 16.7%-50.0%的受试者报告了不良事件。免疫应答在缩短的一个月方案中于第 37 天（Day 37）或在第 15 天至第 2 个月（Day 15）之间达到峰值，并且在整个随访期间均保持在基线以上。
两种制剂均显示出较强的免疫原性。由于一天方案中第 2 剂后出现 3 级注射部位发红，两项研究均提前终止；两种制剂均未进入后期开发阶段。相反，一种在第 1 期和第 2 期研究中安全且具有免疫原性的含铝佐剂候选疫苗制剂，在 0、1 和 6 个月时给药，推进至第 3 期研究。
