Randomized phase I trial HIV-CORE 003: Depletion of serum amyloid P component and immunogenicity of DNA vaccination against HIV-1.
Randomized phase I trial HIV-CORE 003: Depletion of serum amyloid P component and immunogenicity of DNA vaccination against HIV-1.
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DOI：
10.1371/journal.pone.0197299
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Pepys MB
中科院分区：
文献类型：
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作者：
Borthwick NJ;Lane T;Moyo N;Crook A;Shim JM;Baines I;Wee EG;Hawkins PN;Gillmore JD;Hanke T;Pepys MB
DNA疫苗在人类中的失败，与其在某些物种中的功效相反，是无法解释的。观察和干预性实验证据表明，DNA免疫原性可以通过结合人血清淀粉样蛋白P组分（SAP）来预防。SAP是人血浆中唯一的正常DNA结合蛋白。开发用于治疗系统性淀粉样变性和阿尔茨海默病的药物（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）使循环SAP消耗95- 99%。概念验证HIV-CORE 003临床试验测试了通过CPHPC消耗SAP是否会增强人类志愿者对DNA疫苗接种的免疫应答，所述DNA疫苗接种递送来自HIV-1的保守亚蛋白区域的HIVconsv免疫原。人类志愿者接受了3次肌内免疫接种，使用表达HIV-1衍生免疫原HIVconsv的实验DNA疫苗（DDD），预先通过CPHPC消耗或不消耗SAP。所有受试者随后通过递送相同免疫原的猿（黑猩猩）腺病毒（C）和痘病毒MVA（M）载体疫苗加强。在施用每种疫苗形式后，彻底表征了对HIVconsv的T细胞应答的峰值总量、动力学、功能性和记忆子集。在CPHPC处理组和对照组之间，在对HIVconsv的T细胞应答的任何多个定量和定性参数中均未观察到差异，除了在SAP耗尽后，在DDDC疫苗接种后，T细胞特异性的宽度（即识别的表位的数量）在统计学上显著更大。此处使用的在DNA接种之前通过CPHPC消耗SAP的方案仅产生非常适度的增强免疫原性的暗示。将需要进一步的研究，以确定是否SAP耗尽可能有实际价值的DNA疫苗接种其他质粒骨架和/或免疫原。Clinicaltrials.gov www.example.com
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. 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. 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. 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. Clinicaltrials.gov NCT02425241