随机 I 期临床试验 HIV-CORE 003：血清淀粉样蛋白 P 成分耗竭与 HIV-1 DNA 疫苗免疫原性。

Randomized phase I trial HIV-CORE 003: Depletion of serum amyloid P component and immunogenicity of DNA vaccination against HIV-1.

机构信息

The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

Centre for Amyloidosis and Acute Phase Proteins, University College London, London, United Kingdom.

出版信息

PLoS One. 2018 May 17;13(5):e0197299. doi: 10.1371/journal.pone.0197299. eCollection 2018.

DOI:10.1371/journal.pone.0197299

PMID:29772028

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5957335/

Abstract

BACKGROUND

The failure of DNA vaccination in humans, in contrast to its efficacy in some species, is unexplained. Observational and interventional experimental evidence suggests that DNA immunogenicity may be prevented by binding of human serum amyloid P component (SAP). SAP is the single normal DNA binding protein in human plasma. The drug (R)-1-[6-[(R)-2-carboxypyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, miridesap), developed for treatment of systemic amyloidosis and Alzheimer's disease, depletes circulating SAP by 95-99%. The proof-of-concept HIV-CORE 003 clinical trial tested whether SAP depletion by CPHPC would enhance the immune response in human volunteers to DNA vaccination delivering the HIVconsv immunogen derived from conserved sub-protein regions of HIV-1.

METHODS

Human volunteers received 3 intramuscular immunizations with an experimental DNA vaccine (DDD) expressing HIV-1-derived immunogen HIVconsv, with or without prior depletion of SAP by CPHPC. All subjects were subsequently boosted by simian (chimpanzee) adenovirus (C)- and poxvirus MVA (M)-vectored vaccines delivering the same immunogen. After administration of each vaccine modality, the peak total magnitudes, kinetics, functionality and memory subsets of the T-cell responses to HIVconsv were thoroughly characterized.

RESULTS

No differences were observed between the CPHPC treated and control groups in any of the multiple quantitative and qualitative parameters of the T-cell responses to HIVconsv, except that after SAP depletion, there was a statistically significantly greater breadth of T-cell specificities, that is the number of recognized epitopes, following the DDDC vaccination.

CONCLUSIONS

The protocol used here for SAP depletion by CPHPC prior to DNA vaccination produced only a very modest suggestion of enhanced immunogenicity. Further studies will be required to determine whether SAP depletion might have a practical value in DNA vaccination for other plasmid backbones and/or immunogens.

TRIAL REGISTRATION

Clinicaltrials.gov NCT02425241.

摘要

背景

DNA 疫苗在人类中的失败与在某些物种中的疗效形成鲜明对比，其原因尚不清楚。观察性和干预性实验证据表明，人血清淀粉样蛋白 P 成分（SAP）的结合可能会阻止 DNA 的免疫原性。SAP 是人类血浆中唯一的正常 DNA 结合蛋白。为治疗系统性淀粉样变性和阿尔茨海默病而开发的药物（R）-1-[6-（R）-2-羧基吡咯烷-1-基]-6-氧代-己酰基]吡咯烷-2-羧酸（CPHPC，miridesap）可使循环 SAP 减少 95-99%。概念验证性 HIV-CORE 003 临床试验测试了 CPHPC 通过耗尽 SAP 是否会增强人类志愿者对 DNA 疫苗的免疫反应，该疫苗接种了来自 HIV-1 保守亚蛋白区的 HIVconsv 免疫原。

方法

人类志愿者接受了 3 次肌肉内免疫接种，使用表达 HIV-1 衍生免疫原 HIVconsv 的实验性 DNA 疫苗（DDD），其中一些志愿者在接受 CPHPC 治疗前先耗尽 SAP。所有受试者随后均接受了携带相同免疫原的猴（黑猩猩）腺病毒（C）和痘病毒 MVA（M）载体疫苗的加强接种。在接种每种疫苗后，对 HIVconsv 的 T 细胞反应的峰值总量、动力学、功能和记忆亚群进行了全面描述。