HIV Preventive Vaccine Studies

总结：该临床研究项目是在NIH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。这些包括筛选方案和临床试验，以评估候选的预防性HIV-1疫苗，包括：DNA疫苗构建体，重组腺病毒载体血清型5（rAd 5）疫苗和重组腺病毒载体血清型35（rAd 35）疫苗。设计研究以评价剂量、免疫原性、给药途径、给药装置和初免-加强方案。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）有助于招募和筛查健康的HIV阴性受试者进行研究性预防性HIV疫苗临床试验。在入组研究之前，与受试者一起审查疫苗教育材料并提供给受试者。 在建立VRC诊所之前，通过与其他内部研究者合作，对VRC开发的进化枝B、单质粒DNA疫苗进行了I期研究VRC 001（01-I-0079）。 描述结果的手稿发表在FY 07 J Acquir Immune Defic Syndr，2007。44（5）：p.601 -5. VRC 004（03-I-0022）是多分支4质粒DNA疫苗VRC-HIVDNA 009 -00-VP的首次I期临床试验，该疫苗表达来自分支B HIV-1的Gag-Pol-Nef多聚蛋白和来自分支A、B和C的Env糖蛋白。本研究评价了2 mg、4 mg和8 mg剂量。在2007财年，描述结果的手稿发表在J Infect Dis，2006。194（12）：p. 1650-60.在2008财年完成了方案的长期随访。 VRC 006（04-I-0128）是研究重组血清型5腺病毒载体（rAd 5）疫苗VRC-HIVADV 014 -00-VP预防HIV感染的第一个I期临床试验。该疫苗由4种腺病毒载体（以3：1：1：1的比例）组成，其分别编码来自进化枝B的HIV-1 Gag/Pol多聚蛋白和来自进化枝A、B和C的HIV-1 Env糖蛋白。这项研究评估了三种剂量。在2007财年，描述结果的手稿发表在J Infect Dis，2006。194（12）：p. 1638-49.在2009财年完成了方案的长期随访。 VRC 007（04-I-0254）是多分支6质粒HIV-1 DNA疫苗VRC-HIVDNA 016 -00-VP的首次I期临床试验，该疫苗表达来自分支B HIV-1的Gag、Pol和Nef蛋白以及来自分支A、B和C的Env糖蛋白。对4 mg剂量进行了评价。在2007财年，描述研究结果的手稿发表于Vaccine，2007。25（20）：第4085-92页。 VRC 008（05-I-0148）是一项初免-加强免疫方案的I期研究，包括3次接种6质粒DNA疫苗，随后加强接种rAd 5疫苗。本研究评价了Biojector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rAd 5加强剂的安全性和免疫原性。本研究旨在入组相同数量的受试者，入组时血清5型腺病毒抗体滴度低和高，以便更好地了解既存抗体是否影响rAd 5加强剂的安全性和免疫原性。在2008财年，完成了94项长期随访评价，并完成了主要免疫原性试验的分析。 VRC 009（05-I-0081）是一项在先前在VRC 004研究中接受4 mg或8 mg剂量4质粒多分支DNA疫苗免疫的受试者中进行rAd 5疫苗作为加强疫苗接种的I期研究。10例受试者入组。类似地，VRC 010（05-I-0140）是一项在先前在VRC 007研究中接受4 mg 6质粒多分支DNA疫苗免疫的受试者中进行rAd 5疫苗作为加强疫苗接种的I期研究。只有少数受试者有资格参加; 4例受试者入组并完成了24周随访。 发表了描述VRC 009和010合并结果的手稿：PLOS One，2010年2月，5（2）：第1-15页 VRC 011（06-I-0149）是一项I期研究，旨在评价肌内、皮下和皮内给药途径，用于注射三次6质粒DNA疫苗或注射一次rAd 5疫苗进行初免接种。 在所有时间表中，均通过IM给予rAd 5加强注射。60例受试者入组;为了更好地了解预先存在的抗体是否影响方案的安全性和免疫原性，在招募时相同数量的受试者具有针对腺病毒血清型5的阴性和阳性抗体滴度。研究参与者的随访在2009财年完成。 VRC 012（07-I-0167）是一项I期研究，在研究的第I部分评价三种剂量的新型原型腺病毒载体血清型35疫苗（rAd 35-EnvA），然后在研究的第II部分评价rAd 5-EnvA疫苗的异源初免-加强方案。在2008财年，完成了第I部分的入组和疫苗接种。 研究第II部分的入组和研究疫苗接种已于去年完成。 VRC 015（08-I-0171）是一项I期研究，旨在评价Biojector和针头/注射器作为重组血清5型腺病毒载体（rAd 5）疫苗VRC-HIVADV 014 -00-VP注射器械的安全性和免疫原性。 去年完成了入组和研究疫苗接种。 HVTN 505（09-I-0163）是一项VRC候选DNA初免-rAd 5加强HIV疫苗方案的多中心II期研究，VRC临床试验中心作为研究中心参与了该研究。在完成疫苗的I/II期安全性和免疫原性评价后，开发本研究以开始新的评价阶段。它的目的是观察疫苗接种者与安慰剂接种者相比，疫苗是否对HIV病毒载量有影响，后者在约3年的随访期间感染HIV。

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.