HIV Preventive Vaccine and Monoclonal Antibody Studies

HIV预防疫苗和单克隆抗体研究

• 批准号: 8745624
• 负责人: Barney Graham
• 金额: $ 556.21万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745624
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Active immunity; Adenovirus Vector; Adenoviruses; Affect; Antibodies; Binding Sites; Biological Assay; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; DNA; DNA Vaccines; Development; Devices; Dose; Enrollment; Epidemic; Evaluation; Futility; Gagging; HIV; HIV Infections; HIV Vaccine Trials Network; HIV vaccine; HIV-1; Immune; Immune response; Injection of therapeutic agent; Intramuscular; Kinetics; Manuscripts; Methods; Monoclonal Antibodies; Needles; Participant; Passive Immunity; Pattern; Phase; Phase I Clinical Trials; Placebos; Plasmids; Polyproteins; Prevention; Preventive; Protocols documentation; Public Health; Publishing; Recombinants; Recommendation; Regimen; Research Personnel; Research Project Grants; Route; Safety; Schedule; Secondary Immunization; Serotyping; Site; Syringes; United States National Institutes of Health; Vaccination; Vaccines; Viral Load result; base; design; dosage; env Glycoproteins; follow-up; gag Gene Products; immunogenicity; meetings; nef Protein; neutralizing monoclonal antibodies; novel; novel strategies; phase 1 study; plasmid DNA; pol Gene Products; programs; prototype; subcutaneous; vaccine evaluation

Summary: This clinical research project is for clinical trials related to active immunity (preventive vaccines) and passive immunity (monoclonal antibodies) directed against HIV that are conducted by the VRC Clinic at the NIH Clinical Center. The clinical trials to evaluate candidate preventive HIV-1 vaccines include: 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. Beginning in FY13, we are also investigating the use of highly neutralizing monoclonal antibodies directed against HIV. A brief summary of each study to date follows. 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) was 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. A manuscript describing results from VRC 008 study was published: PLoS One, 2013; 8(4):e59340. VRC 009 (05-I-0081) was 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) was 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) was 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 FY10; long-term follow-up is ongoing. 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 FY10; long-term follow-up is ongoing. VRC 016 (11-I-0197) is a Phase Ib descriptive study to evaluate the kinetics and pattern of early innate and adaptive immune responses to the rAd5 vaccine, VRC-HIVADV014-00-VP, alone and after priming with DNA vaccine. This study was developed and initiated in FY11 and remains ongoing during FY12. HVTN 505 (09-I-0163) is a multicenter Phase 2b efficacy 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 1/2 safety and immunogenicity evaluations of the vaccines were completed, this study was developed in collaboration with the Division of AIDS and HVTN and designed to see whether or not the vaccines have efficacy in prevention of HIV or an effect on HIV viral load in vaccine recipients as compared to placebo recipients who acquire HIV infection during 2 years of follow-up. Study enrollments were completed in FY13. Study vaccinations were discontinued in April 2013 based on DSMB recommendations when study results showed that prospectively defined efficacy futility criteria had been met. Long term follow-up is ongoing. VRC 602 is under development as the first Phase 1 study to evaluate a highly neutralizing monoclonal antibody directed at the CD4 binding site on HIV. The study is on track to open in 4th quarter 2014.

摘要：该临床研究项目是针对与主动免疫（预防性疫苗）和针对HIV的被动免疫（预防性疫苗）有关的临床试验，该试验由NIH临床中心的VRC诊所进行。评估候选HIV-1疫苗的临床试验包括：DNA疫苗构建体，重组腺病毒载体血清型5（RAD5）疫苗以及重组腺病毒载体血清型35（RAD35）疫苗。研究旨在评估剂量，免疫原性，给药途径，用于给药的装置和原始方案。从2013财年开始，我们还研究了针对HIV的高度中和单克隆抗体的使用。 迄今为止的每项研究的简要摘要如下。 在建立VRC诊所之前，I阶段研究的VRC 001（01-I-I-0079）通过VRC开发的单质粒DNA疫苗是通过与其他室内研究人员的合作进行的。 一个描述结果WSS的手稿在07财年发表在J获取免疫缺陷症状，2007。44（5）：p。 601-5。 VRC 004（03-I-0022）是多层4质粒DNA疫苗的第一阶段临床试验，VRC-HIVDNA009-00-VP，该试验表达了来自进化核武器B HIV-1和ENK糖蛋白的GAG-POL-NEF多蛋白，该研究来自Callades A，B and b and b and b and C.该研究。在07财年，描述结果的手稿发表了J Infect Dis，2006。194（12）：p。 1650-60。该协议的长期随访于2008财年完成。 VRC 006（04-I-0128）是研究重组血清型5腺病毒载体（RAD5）疫苗，VRC-HIVADV014-00-VP的第一阶段临床试验，用于预防HIV感染。该疫苗由4个腺病毒载体（在3：1：1：1的比例中）组成，该疫苗分别从进化枝A，B和C分别编码了来自进化枝B和HIV-1 ENV糖蛋白的HIV-1 GAG/POL多蛋白。这项研究评估了三种剂量。在07财年，描述结果的手稿发表了J Infect Dis，2006。194（12）：p。 1638-49。该协议的长期随访于2009财年完成。 VRC 007（04-I-I-0254）是多层6-质量HIV-1 DNA疫苗的第一阶段临床试验，VRC-HIVDNA016-00-VP，该试验表达了从进化枝BHIV-1和C. b and b and b and b and b and b and b and b and b and b and b and b and b and b and b and b and b and b and C.在2007财年，描述研究结果的手稿发表了疫苗，2007年。25（20）：p。 4085-92。 VRC 008（05-I-0148）是对促进疫苗接种方案的第一阶段研究，该研究由3种疫苗和6质子剂DNA疫苗组成，然后用RAD5疫苗促进。这项研究评估了生物体和针/注射器作为DNA疫苗的注射装置的安全性和免疫原性，以及RAD5助推器的两种不同剂量的安全性和免疫原性。该研究旨在注册对腺病毒血清型5的低抗体滴度的相等数量的受试者，以便更好地了解既有抗体是否影响RAD5助推器的安全性和免疫原性。在08周期间，完成了94次长期随访评估，并完成了主要免疫原性测定法。描述VRC 008研究结果的手稿发表了：PLOS One，2013年； 8（4）：E59340。 VRC 009（05-I-0081）是对RAD5疫苗的I期研究，作为先前用4毫克或8 mg剂量在VRC 004研究中用4 mg或8 mg剂量的4倍剂多叶片DNA疫苗接种的受试者。十个主题被录取。同样，VRC 010（05-I-0140）是对RAD5疫苗作为I阶段研究，作为先前用4 mg的6倍磷酸多层多层DNA疫苗接种的受试者的促进疫苗接种，在VRC 007研究中。只有少数受试者有资格参加； 4个受试者招收并完成了24周的随访。 发表了描述VRC 009和010结果的手稿：PLOS ONE，2010年2月，第5（2）页：p。 1-15 VRC 011（06-I-0149）是一项I期研究，用于评估肌肉内，皮下和内部给药途径，用于对6倍峰DNA疫苗的三种注射或一种注射Rad5疫苗的三种注射。 在所有时间表中，对RAD5助推器注入均被施用IM。六十名受试者被录取；相等数量的受试者在入学时具有对腺病毒血清型5的阴性和阳性抗体滴度，以便更好地了解既有抗体是否影响该方案的安全性和免疫原性。在09财年期间完成了研究参与者的随访。 VRC 012（07-I-0167）是一项I阶段研究，用于评估一项研究的三个剂量的新型原型腺病毒载体血清型35疫苗35疫苗（RAD 35-ENVA），在研究的第一部分中，然后在研究的第二部分中，在研究的第二部分中，具有RAD5-ENVA疫苗的异源原料时间表。在2008财年期间，I部分入学率和疫苗接种完成。 该研究的第二部分的入学疫苗和研究疫苗在FY10完成；长期随访正在进行中。 VRC 015（08-I-0171）是一项I期研究，旨在评估生物体和针/注射器的安全性和免疫原性，作为重组血清型5腺病毒载体（RAD5）疫苗的注射装置，VRC-HIVADV014-00-VP。 入学疫苗和研究疫苗在FY10完成；长期随访正在进行中。 VRC 016（11-I-0197）是一项IB期描述性研究，用于评估对RAD5疫苗的早期先天和适应性免疫反应的动力学和模式，即VRC-HIVADV014-00-VP，单独和使用DNA疫苗进行启动后。 这项研究是在FY11开发和发起的，并在2012财年期间仍在进行中。 HVTN 505（09-I-0163）是VRC候选DNA Prime-Rad5促进HIV疫苗方案的多中心2B效力研究，VRC临床试验核心正在作为站点参与该方案。在完成了疫苗的1/2阶段安全性和免疫原性评估后，该研究是与AIDS和HVTN的部门合作开发的，旨在查看疫苗是否在预防HIV或对HIV接受者的HIV病毒载荷的影响中与接受HIV受体的疫苗接收者相比，在2年期间获得HIV HIV感染的人是否具有功效。研究入学率在2013财年完成。 根据DSMB的建议，研究结果表明已达到前瞻性确定的效力徒劳标准，于2013年4月在2013年4月停止研究疫苗。 长期随访正在进行中。 VRC 602作为第一阶段的研究正在开发中，旨在评估针对HIV上CD4结合位点的高度中和单克隆抗体。 这项研究有望在2014年第四季度开放。