HIV Preventive Vaccine Studies

摘要：该临床研究项目是在美国国立卫生研究院临床中心的VRC诊所进行的与预防性HIV疫苗相关的临床试验。这些包括评估候选预防性HIV-1疫苗的筛选方案和临床试验，包括：DNA疫苗构建体、重组腺病毒载体血清型5(RAd5)疫苗和重组腺病毒载体血清型35(RAd35)疫苗。已经设计了评估剂量、免疫原性、给药途径、给药装置和主要增强方案的研究。以下是迄今为止每项研究的简要摘要。 筛查方案VRC 000(02-I-0127)促进招募和筛查健康的、艾滋病毒阴性的受试者进行研究性预防性艾滋病毒疫苗临床试验。在登记参加研究之前，与受试者一起审查和提供有关疫苗的教育材料。 在VRC诊所建立之前，VRC与其他内部研究人员合作进行了VRC 001(01-I-0079)的I期研究，该疫苗是由VRC开发的B分支单质粒DNA疫苗。描述结果的手稿发表在2007财年J Acquir免疫缺陷综合征杂志上。44(5)：第601-5页。 VRC 004(03-I-0022)是多分支4质粒DNA疫苗VRC-HIVDNA009-00-VP的第一阶段临床试验，该疫苗表达B分支HIV-1的Gag-Pol-Nef多蛋白以及A、B和C分支的包膜糖蛋白。在2007财年，一份描述研究结果的手稿发表在2006年的传染病杂志上。194(12)：1650-60页。该议定书的长期后续行动在2008财年期间完成。 VRC 006(04-I-0128)是用于预防HIV感染的研究性重组血清型5型腺病毒载体疫苗VRC-HIVADV014-00-VP的第一阶段临床试验。该疫苗由4个腺病毒载体(3：1：1：1)组成，分别编码B分支的HIV-1 Gag/Pol多蛋白和A、B、C分支的HIV-1包膜糖蛋白。这项研究评估了三种剂量。在2007财年，一份描述研究结果的手稿发表在2006年的传染病杂志上。194(12)：1638-49页。该议定书的长期后续行动在09财年期间完成。 VRC 007(04-I-0254)是多分支6质粒HIV-1 DNA疫苗VRC-HIVDNA016-00-VP的第一阶段临床试验，该疫苗表达B分支HIV-1的Gag、Pol和Nef蛋白以及A、B和C分支的Env糖蛋白。2007财年，Vaccine出版了一份描述研究结果的手稿。25(20)：第4085-92页。 VRC 008(05-I-0148)是第一阶段加强免疫方案的研究，包括3次接种6质粒DNA疫苗，然后加强接种rAd5疫苗。本研究评估了生物注射器和针头/注射器作为DNA疫苗注射装置的安全性和免疫原性，以及两种不同剂量的rAd5佐剂的安全性和免疫原性。这项研究的目的是在登记时招募同等数量的对腺病毒血清5型抗体效价低和高的受试者，以便更好地了解先前存在的抗体是否影响rAd5启动子的安全性和免疫原性。在08财年的一周内，完成了94项长期随访评估，并完成了初级免疫原性分析。 VRC 009(05-I-0081)是在VRC 004研究中，将rAd5疫苗作为加强疫苗接种于先前用4 mg或8 mg剂量的4质粒多分支DNA疫苗免疫的受试者的I期研究。共有10名受试者报名参加。同样，VRC010(05-I-0140)是VRC007研究中rAd5疫苗的I期研究，作为以前用4毫克6质粒多分支DNA疫苗免疫的受试者的加强疫苗。只有一小部分受试者有资格参与；4名受试者入选并完成了24周的随访。一份描述VRC 009和010综合结果的手稿发表：《公共科学图书馆·综合》，2010年2月，5(2)：第1-15页 VRC 011(06-I-0149)是一项I期研究，旨在评估肌肉内、皮下和皮内注射疫苗的途径，即三次注射6质粒DNA疫苗或一次注射rAd5疫苗。在所有方案中，肌注rAd5增强剂。60名受试者入选；相同数量的受试者在登记时对腺病毒血清5型抗体效价为阴性和阳性，以更好地了解先前存在的抗体是否影响方案的安全性和免疫原性。在09财年完成了对研究参与者的跟踪调查。 VRC012(07-I-0167)是一项第一阶段研究，在研究的第一部分评估三种剂量的新型原型腺病毒载体血清型35型疫苗(rAd35-ENVA)，然后在研究的第二部分评估使用rAd5-ENVA疫苗的异种Prime-Boost方案。在2008财年期间，完成了第一部分的注册和疫苗接种。第二部分研究的登记和研究疫苗接种是在去年完成的。 VRC 015(08-I-0171)是一项I期研究，旨在评估作为重组血清型5型腺病毒载体(RAd5)疫苗VRC-HIVADV014-00-VP的生物注射器和针头/注射器的安全性和免疫原性。在过去的一年里完成了注册和研究疫苗接种。 HVTN 505(09-I-0163)是VRC候选DNA Prime-rAd5 Boost HIV疫苗方案的多中心第二阶段研究，VRC临床试验核心作为一个站点参与其中。在完成第一/第二阶段疫苗的安全性和免疫原性评估后，开展这项研究，以开始新的评估阶段。它的设计是为了观察疫苗接受者与安慰剂接受者相比，疫苗接受者在大约3年的随访中是否对HIV病毒载量产生影响。

Summary: This clinical research project is for clinical trials related to preventive HIV vaccines conducted at the VRC Clinic at the NIH Clinical Center. These consist of a screening protocol and clinical trials to evaluate candidate preventive HIV-1 vaccines including: DNA vaccine constructs, a recombinant adenoviral vector serotype 5(rAd5) vaccine, and a recombinant adenoviral vector serotype 35 (rAd35) vaccine. Studies have been designed to evaluate dose, immunogenicity, route of administration, device for administration and prime-boost regimens. A brief summary of each study to date follows. The screening protocol, VRC 000 (02-I-0127), facilitates recruitment and screening of healthy, HIV-negative subjects for investigational preventive HIV vaccine clinical trials. Educational materials on vaccines are reviewed with and provided to subjects before enrollment into a study. Prior to the establishment of the VRC Clinic, a Phase I study VRC 001 (01-I-0079) of a clade B, single plasmid DNA vaccine developed by VRC was conducted through collaboration with other intramural investigators. A manuscript describing results wss published in FY07 J Acquir Immune Defic Syndr, 2007. 44(5): p. 601-5. VRC 004 (03-I-0022) was the first Phase I clinical trial of a multiclade 4-plasmid DNA vaccine, VRC-HIVDNA009-00-VP, which expresses a Gag-Pol-Nef polyprotein from clade B HIV-1 and Env glycoproteins from clades A, B and C. This study evaluated the 2 mg, 4 mg and 8 mg dosage. In FY07 a manuscript describing results was published J Infect Dis, 2006. 194(12): p. 1650-60. The long-term follow-up for the protocol was completed during FY08. VRC 006 (04-I-0128) was the first Phase I clinical trial of an investigational recombinant serotype 5 adenoviral vector (rAd5) vaccine, VRC-HIVADV014-00-VP, for the prevention of HIV infection. This vaccine is composed of 4 adenoviral vectors (in a 3:1:1:1 ratio) that encode for the HIV-1 Gag/Pol polyprotein from clade B and HIV-1 Env glycoproteins from clades A, B, and C, respectively. This study evaluated three dosages. In FY07 a manuscript describing results was published J Infect Dis, 2006. 194(12): p. 1638-49. The long-term follow-up for the protocol was completed during FY09. VRC 007 (04-I-0254) was the first Phase I clinical trial of a multiclade 6-plasmid HIV-1 DNA vaccine, VRC-HIVDNA016-00-VP, which expresses Gag, Pol and Nef proteins from clade B HIV-1 and Env glycoproteins from clades A, B and C. The 4 mg dosage was evaluated. In FY07 a manuscript describing study results was published Vaccine, 2007. 25(20): p. 4085-92. VRC 008 (05-I-0148) is a Phase I study of the prime-boost vaccination regimen consisting of 3 vaccinations with the 6-plasmid DNA vaccine followed by a boost with the rAd5 vaccine. This study evaluated the safety and immunogenicity of both Biojector and needle/syringe as injection devices for the DNA vaccine, as well as safety and immunogenicity of two different dosages for the rAd5 booster. The study was designed to enroll equal numbers of subjects with low and high antibody titers to adenovirus serotype 5 at enrollment in order to gain a better understanding of whether pre-existing antibody affects the safety and immunogenicity of the rAd5 booster. During FY08 week 94 long-term follow-up evaluations were completed and analysis of the primary immunogenicity assays were completed. VRC 009 (05-I-0081) is a Phase I study of the rAd5 vaccine as a booster vaccination in subjects previously immunized with the 4 mg or 8 mg dose of the 4-plasmid multiclade DNA vaccine in the VRC 004 study. Ten subjects enrolled. Similarly, VRC 010 (05-I-0140) is a Phase I study of the rAd5 vaccine as a booster vaccination in subjects previously immunized with 4 mg of the 6-plasmid multiclade DNA vaccine in the VRC 007 study. Only a small number of subjects were eligible to participate; 4 subjects enrolled and completed the 24 weeks of follow-up. A manuscript describing results from VRC 009 and 010 combined was published: PLOS One, Feb 2010, 5(2):p. 1-15 VRC 011 (06-I-0149) is a Phase I study to evaluate the intramuscular, subcutaneous and intradermal routes of administration for priming vaccinations with either three injections of the 6-plasmid DNA vaccine or one injection of the rAd5 vaccine. In all schedules a rAd5 booster injection is administered IM. Sixty subjects were enrolled; equal numbers of subjects had negative and positive antibody titers to adenovirus serotype 5 at enrollment in order to gain a better understanding of whether pre-existing antibody affects the safety and immunogenicity of the regimens. Follow-up of study participants was completed during FY 09. VRC 012 (07-I-0167) is a Phase I study to evaluate a novel prototype adenoviral vector serotype 35 vaccine (rAd 35-EnvA) at three dosages in Part I of the study and then in Part II of the study heterologous prime-boost schedules with an rAd5-EnvA vaccine will be evaluated. During FY08 the Part I enrollments and vaccinations were completed. The enrollments and study vaccinations for Part II of the study were completed in teh past year. VRC 015 (08-I-0171) is a Phase I study to evaluate the safety and immunogenicity of both Biojector and needle/syringe as injection devices for the recombinant serotype 5 adenoviral vector (rAd5) vaccine, VRC-HIVADV014-00-VP. The enrollments and study vaccinations were completed in the past year. HVTN 505 (09-I-0163) is a multicenter Phase II study of the VRC candidate DNA prime-rAd5 boost HIV vaccine regimen for which the VRC Clinical Trials Core is participating as a site. After Phase I/II safety and immunogenicity evaluations of the vaccines were completed, this study was developed to begin a new phase of evaluation. It is designed to see whether or not the vaccines have an effect on HIV viral load in vaccine recipients as compared to placebo recipients who later acquire HIV infection during about 3 years of follow-up.