在 ChAd63 和 MVA 疫苗载体中评估恶性疟原虫血期抗原 AMA1 的安全性和免疫原性的 I 期临床研究。

Phase Ia clinical evaluation of the safety and immunogenicity of the Plasmodium falciparum blood-stage antigen AMA1 in ChAd63 and MVA vaccine vectors.

机构信息

Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, United Kingdom.

出版信息

PLoS One. 2012;7(2):e31208. doi: 10.1371/journal.pone.0031208. Epub 2012 Feb 21.

BACKGROUND

Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question.

METHODOLOGY

We conducted a Phase Ia, non-randomized clinical trial in 16 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding two alleles (3D7 and FVO) of the P. falciparum blood-stage malaria antigen; apical membrane antigen 1 (AMA1). ChAd63-MVA AMA1 administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to both alleles 3D7 (median 2036 SFU/million PBMC) and FVO (median 1539 SFU/million PBMC), with a mixed CD4(+)/CD8(+) phenotype, as well as substantial AMA1-specific serum IgG responses (medians of 49 µg/mL and 41 µg/mL for 3D7 and FVO AMA1 respectively) that demonstrated growth inhibitory activity in vitro.

CONCLUSIONS

ChAd63-MVA is a safe and highly immunogenic delivery platform for both alleles of the AMA1 antigen in humans which warrants further efficacy testing. ChAd63-MVA is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where strong cellular and humoral immune responses are required for protection.

TRIAL REGISTRATION

ClinicalTrials.gov NCT01095055.

背景

传统上，针对恶性疟原虫血期感染的疫苗开发一直集中在重组蛋白-佐剂制剂上，以诱导高滴度的生长抑制抗体反应。然而，迄今为止，没有任何一种编码单一血期抗原的疫苗在设计用于评估疫苗疗效的 IIa/b 期临床试验的主要终点中诱导出针对红细胞期感染的显著保护效力。细胞介导的反应与功能性抗体一起作用，可能是针对血期疟原虫免疫所必需的。开发一种既能诱导细胞介导免疫又能诱导体液免疫的疫苗，将能够进行重要的概念验证疗效研究来解决这个问题。

方法

我们在 16 名健康的、无疟疾的成年人中进行了一项 I 期、非随机临床试验，这些成年人接受了编码恶性疟原虫血期疟原虫抗原；顶膜抗原 1（AMA1）的两种等位基因（3D7 和 FVO）的 chimpanzee 腺病毒 63（ChAd63）和改良痘苗病毒 Ankara（MVA）复制缺陷病毒载体疫苗的异源初免-加强免疫。在异源初免-加强免疫方案中给予 ChAd63-MVA AMA1 是安全且具有免疫原性的，诱导高水平的针对两种等位基因 3D7（中位数 2036SFU/百万 PBMC）和 FVO（中位数 1539SFU/百万 PBMC）的 T 细胞反应，表现为混合的 CD4(+)/CD8(+)表型，以及大量的 AMA1 特异性血清 IgG 反应（3D7 和 FVO AMA1 的中位数分别为 49μg/mL 和 41μg/mL），在体外显示出生长抑制活性。