A vaccine for hypertension based on virus-like particles:: preclinical efficacy and phase I safety and immunogenicity
A vaccine for hypertension based on virus-like particles:: preclinical efficacy and phase I safety and immunogenicity
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DOI：
10.1097/hjh.0b013e32800ff5d6
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发表时间：
2007-01-01
影响因子：
4.9
通讯作者：
Bachmann, Martin F.
中科院分区：
文献类型：
--
作者：
Ambuehl, Patrice M.;Tissot, Alain C.;Bachmann, Martin F.
背景尽管有有效的药物可供使用，但治疗高血压的成功受到患者和药物摄入不一致的限制。针对血管紧张素 II 的免疫可能为治疗高血压的传统药物提供有价值的替代方案，因为疫苗会产生相对持久的效果，并且不需要每天给药。在此，我们描述了基于病毒样颗粒 (VLP) 的抗高血压疫苗的临床前开发和 I 期临床试验测试。方法和结果将血管紧张素 II 衍生肽与 VLP Q beta (AngQb) 缀合。 AngQb 在小鼠和大鼠中具有高度免疫原性。为了测试功效，用400μg AngQb或单独的VLP对自发性高血压大鼠(SHR)进行免疫。与 VLP 对照组相比，组平均收缩压 (SBP) 降低高达 21 mmHg（159 +/- 2 对比 180 +/- 5 mmHg，P < 0.001），总血管紧张素 II 水平（抗体结合的和游离的）增加九倍（85 +/- 20 对比 9 +/- 1 pmol/l，P = 0.002）。用血管紧张素转换酶 (ACE) 抑制剂雷米普利（每天口服 1 mg/kg）治疗的 SHR 达到了 155 +/- 2 mmHg 的 SBP。一项安慰剂对照随机 I 期试验的 12 名健康志愿者被注射一次 100 μg AngQb。所有受试者均产生血管紧张素 II 特异性抗体（应答率 100%），AngQb 耐受性良好。结论 AngQb 将 SHR 中的血压降低至 ACE 抑制剂获得的水平，并且在人类中具有免疫原性和良好耐受性。因此，针对血管紧张素 II 的疫苗接种有可能成为一种有用的抗高血压治疗方法，提供持久的效果并提高患者的依从性。
Background Despite the availability of efficacious drugs, the success of treating hypertension is limited by patients, inconsistent drug intake. Immunization against angiotensin II may offer a valuable alternative to conventional drugs for the treatment of hypertension, because vaccines induce relatively long-lasting effects and do riot require daily dosing. Here we describe the preclinical development and the phase I clinical trial testing of a viruis-like particle (VLP)based anti hypertensive vaccine.Methods and results An angiotensin II-derived peptide was conjugated to the VLP Q beta (AngQb). AngQb was highly immunogenic in mice and rats. To test for efficacy, spontaneously hypertensive rats (SHR) were immunized with 400 mu g AngQb or VLP alone. Group mean systolic blood pressure (SBP) was reduced by up to 21 mmHg (159 +/- 2 versus 180 +/- 5 mmHg, P < 0.001), and total angiotensin II levels (antibody-bound and free) were, increased ninefold (85 +/- 20 versus 9 +/- 1 pmol/l, P = 0.002) compared with VLP controls. SHR treated with the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg per day by mouth) reached an SBP of 155 +/- 2 mmHg. Twelve healthy volunteers of a placebo-controlled randomized phase I trial were injected once with 100 mu g AngQb. Angiotensin II-specific antibodies were raised in all subjects (100% responder rate) and AngQb was well tolerated.Conclusions AngQb reduces blood pressure in SHR to levels obtained with an ACE inhibitor, and is immunogenic and well tolerated in humans. Therefore, vaccination against angiotensin II has the potential to become a useful anti hypertensive treatment providing long-lasting effects and improving patient compliance.