Importance Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-β (Aβ). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aβ pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined. Objective To assess the safety and tolerability of the ACI-24 vaccine among adults with DS as well as its ability to induce immunogenicity measured by anti-Aβ immunoglobulin G titers. Design, Setting, and Participants This multicenter double-blind placebo-controlled dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020. A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate. Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27, 2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts (8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an additional 48 weeks of safety follow-up. Interventions Participants were randomized to receive 7 subcutaneous injections of ACI-24, 300 μg or 1000 μg, or placebo. Main Outcomes and Measures Primary outcomes were measures of safety and tolerability as well as antibody titers. Results Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years; 9 participants were women, and 7 were men. All participants were White, and 1 participant had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events [83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events [85.6%]). No amyloid-related imaging abnormalities with edema or cerebral microhemorrhage and no evidence of central nervous system inflammation were observed on magnetic resonance imaging scans. Increases in anti-Aβ immunoglobulin G titers were observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 μg and 2 receiving 1000 μg) compared with 0 participants receiving placebo. In addition, a greater increase was observed in plasma Aβ1-40 and Aβ1-42 levels among individuals receiving ACI-24. Conclusions and Relevance In this study, the ACI-24 vaccine was safe and well tolerated in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target engagement were observed, and anti-Aβ antibody titers were not associated with any adverse findings. These results support progression to clinical trials using an optimized formulation of the ACI-24 vaccine among individuals with DS. Trial Registration ClinicalTrials.gov Identifier: NCT02738450.

中文翻译：

---

ACI-24 疫苗在成人唐氏综合症患者中的安全性、耐受性和免疫原性：1b 期随机临床试验。


重要性唐氏综合症 (DS) 患者由于淀粉样前体蛋白基因 APP 剂量增加，导致全长 APP 及其产物（包括淀粉样蛋白-β (Aβ)）水平增加，因此患阿尔茨海默病的风险很高。 ）。基于脂质体的抗淀粉样蛋白 ACI-24 疫苗旨在治疗由错误折叠的 Aβ 病理蛋白引起的神经系统疾病。然而，ACI-24 疫苗在成人 DS 中的安全性、耐受性和免疫原性尚未得到充分检验。目的 评估 ACI-24 疫苗在成人 DS 中的安全性和耐受性，以及通过抗 Aβ 免疫球蛋白 G 滴度测量其诱导免疫原性的能力。设计、设置和参与者 这项多中心双盲安慰剂对照剂量递增 1b 期随机临床试验于 2016 年 3 月 30 日至 2020 年 6 月 29 日在拥有附属唐氏综合症诊所的 3 个美国学术医疗中心进行。对 20 名患有 DS 的成年人进行了筛查；其中，16 名成年人有资格参加。资格标准包括年龄 25 至 45 岁、细胞遗传学诊断为 21 三体或 21 号染色体完全不平衡易位的男性或女性。2016 年 4 月 27 日至 2018 年 7 月 2 日期间，参与者按 3:1 随机分为 2 个剂量水平组（每组 8 名参与者，其中 6 名参与者接受 ACI-24 疫苗，2 名参与者接受安慰剂）在一项为期 96 周的研究中。参与者接受了 48 周的治疗，随后又进行了 48 周的安全随访。干预措施 参与者随机接受 7 次皮下注射 ACI-24（300 μg 或 1000 μg）或安慰剂。主要结果和措施 主要结果是安全性和耐受性以及抗体滴度的测量。 结果 16 名登记参与者的平均 (SD) 年龄为 32.6 (4.4) 岁； 9 名参与者是女性，7 名是男性。所有参与者均为白人，其中 1 名参与者为西班牙裔或拉丁裔。治疗依从率为100%。没有发生脑膜脑炎、死亡或其他严重不良事件 (AE) 的病例，也没有因 AE 导致退出的病例。大多数治疗中出现的 AE 均为轻度（132 起事件中的 110 起 [83.3%]），与 ACI-24 疫苗无关或不太可能相关（132 起事件中的 113 起 [85.6%]）。磁共振成像扫描未观察到淀粉样蛋白相关的成像异常（伴有水肿或脑微出血），也未观察到中枢神经系统炎症的证据。与接受安慰剂的 0 名参与者相比，接受 ACI-24 的 12 名参与者中有 4 名（33.3%）（2 名接受 300 μg，2 名接受 1000 μg）抗 Aβ 免疫球蛋白 G 滴度增加。此外，在接受 ACI-24 的个体中，观察到血浆 Aβ1-40 和 Aβ1-42 水平有更大的增加。结论和相关性 在这项研究中，ACI-24 疫苗对于患有 DS 的成人来说是安全的且耐受性良好。观察到免疫原性以及药效学和靶点参与的证据，并且抗 Aβ 抗体滴度与任何不良结果无关。这些结果支持在 DS 个体中使用优化的 ACI-24 疫苗配方进行临床试验。试验注册 ClinicalTrials.gov 标识符：NCT02738450。