HIV Vaccine Studies

HIV疫苗研究

• 批准号: 10696776
• 负责人: Lesia Dropulic
• 金额: $ 581.79万
• 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/10696776
• 关键词: AIDS Vaccines; AIDS prevention; Acquired Immunodeficiency Syndrome; Adenovirus Vector; Adenoviruses; Adjuvant; Adult; Antibody Response; Antibody titer measurement; Binding; Biological Assay; Clinic; Clinical Research; Clinical Trials; Clinical Trials Network; Collaborations; Conjugate Vaccines; DNA; DNA Vaccines; Data; Development; Devices; Dose; Enrollment; Epidemic; Epitopes; Evaluation; Follow-Up Studies; Futility; Future; HIV; HIV Infections; HIV Vaccine Trials Network; HIV prevention trials network; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Immune; Immunize; Injections; Intramuscular; Investigation; Kinetics; Longterm Follow-up; Methods; Multicenter Trials; Needles; Participant; Pattern; Peptides; Phase; Phase I Clinical Trials; Physicians; Placebos; Plasmids; Polyproteins; Polysaccharides; Preventive; Preventive vaccine; Protocols documentation; Public Health; Publishing; Randomized; Recombinants; Recommendation; Regimen; Research Personnel; Route; Safety; Schedule; Secondary Immunization; Serotyping; Site; Syringes; Therapeutic Studies; Vaccination; Vaccine Research; Vaccines; Viral Load result; adaptive immune response; aluminum sulfate; base; clinical center; clinical development; design; dosage; efficacy study; env Glycoproteins; follow-up; gag Gene Products; i(19); immunogenicity; meetings; member; nef Protein; neutralizing antibody; novel; novel strategies; open label; pharmacovigilance; phase 1 study; plasmid DNA; pol Gene Products; programs; prospective; prototype; research study; response; subcutaneous; therapeutic vaccine; vaccine candidate; vaccine development; vaccine evaluation; vaccine evaluation center; vaccine trial; vector vaccine

This Vaccine Research Center (VRC) Clinical Trials Program (CTP) project is for clinical research related to preventive and therapeutic vaccines directed against HIV. Preventive HIV-1 vaccine candidates have included: DNA vaccine constructs, a recombinant adenoviral vector serotype 5(rAd5) vaccine, a recombinant adenoviral vector serotype 35 (rAd35) vaccine, and a trimer based vaccine with alum. Therapeutic vaccine candidates have included: DNA vaccine constructs and a recombinant adenoviral vector vaccine. Studies have been designed to evaluate dose, immunogenicity, route and device of administration, and prime-boost regimens. VRC 001 (01-I-0079) evaluated a clade B, single plasmid DNA vaccine developed by the VRC in collaboration with other intramural investigators. Published: 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. Results published: J Infect Dis, 2006. 194(12):p.1650-60. Long-term follow-up was completed in 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. Results published: J Infect Dis, 2006. 194(12):p.1638-49. Long-term follow-up was completed in 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. 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. During FY08 week 94 long-term follow-up evaluations and analysis of the primary immunogenicity assays was completed. 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. Published: PLoS One, Feb 2010, 5(2):p.1-15 VRC 101 (06-I-0056) was the first Phase I therapeutic study of two candidate HIV-1 vaccines developed by the VRC and administered in a prime-boost regimen. Published: J Infect Dis. 2013 Jun 15;207(12):1829-40. 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 3 injections of the 6-plasmid DNA vaccine or one injection of the rAd5 vaccine. In all schedules a rAd5 booster injection was administered IM. Sixty subjects were enrolled; equal numbers of subjects had negative and positive antibody titers to adenovirus serotype 5 at enrollment. Follow-up of study participants was completed in FY 09. Published: PLoS One, 2014 Mar 12;9(3). VRC 012 (07-I-0167) was 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, Part I enrollments and vaccinations were completed. The enrollments and study vaccinations for Part II of the study were completed in FY10. Published: PLoS One. 2016 Nov 15;11(11). VRC 015 (08-I-0171) was 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. Enrollments and study vaccinations were completed in FY10; long-term follow-up was completed in FY14. Published: PLoS One. 2014 Sep 29;9(9). VRC 016 (11-I-0197) was 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 a DNA vaccine. This study was initiated in FY11 and follow-up completed in FY14. HVTN 505 (09-I-0163) was 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. Published: N Engl J Med. 2013 Nov 28;369(22):2083-92. VRC 018 (19-I-0031) is a phase 1 dose escalation, randomized, open-label clinical trial to evaluate dose, safety, tolerability, and immunogenicity of an HIV-1 Env Vaccine, VRC-HIVRGP096-00-VP, (Trimer 4571) with alum in healthy adults. The trial was initiated in FY19 and enrollment was completed in FY 20. Trimer 4571 is the first prefusion-closed, stabilized HIV-1 Env trimer evaluated in humans. It was determined to be safe and well tolerated when adjuvanted with alum and administered by subcutaneous and intramuscular routes. Trimer-specific antibody responses detected two weeks after administration primarily focused on the glycan-free trimer base with no detectable responses to CD4 binding epitopes. Limited neutralizing antibody was detected which was also primarily directed to the glycan-free base of the trimer. This study informed future HIV vaccine efforts to determine how to induce effective neutralizing antibody responses against HIV in humans. EClinicalMedicine. 2022 Jun 1;48:101477. doi: 10.1016/j.eclinm.2022.101477. PMID: 35783486; PMCID: PMC9249552. HVTN 303 is a Phase 1, open-label, dose escalation study to evaluate the dose, safety, tolerability, and immunogenicity of an adjuvanted HIV-1 Fusion Peptide (FP) conjugate vaccine (FP8v1-rTTHC) alone or in prime-boost regimens with adjuvanted HIV-1 Trimer 4571 and adjuvanted HIV-1 Trimer 6931 opened in July 2022. This is a multicenter trial sponsored by the Division of AIDS (DAIDS) and conducted by the HIV Vaccine Trials Network (HVTN) using vaccine products developed by the VRC. VRC Clinical Trials Program (CTP) physicians are members of the HVTN 303 protocol team, serve as VRC product representatives, and participate in protocol safety review team meetings.

该疫苗研究中心（VRC）临床试验计划（CTP）项目针对针对针对HIV的预防和治疗疫苗有关的临床研究。预防性HIV-1疫苗候选物包括：DNA疫苗构建体，重组腺病毒载体血清型5（RAD5）疫苗，一种重组腺病毒载体35（RAD35）疫苗以及基于Alum的三聚体疫苗。候选治疗疫苗包括：DNA疫苗构建体和重组腺病毒载体疫苗。研究旨在评估剂量，免疫原性，途径和给药手段以及原始方案。 VRC 001（01-I-0079）评估了VRC与其他壁内研究者合作开发的进化枝B，即单质质粒DNA疫苗。已发表：J Acquir免疫缺陷综合症，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。结果发表：J Infect Dis，2006。194（12）：P.1650-60。长期随访于08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。结果发表：J Infect Dis，2006。194（12）：P.1638-49。长期随访于09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.发表：疫苗，2007。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。该研究旨在招募对腺病毒血清型5的低抗体滴度和高抗体滴度的受试者。在08周期间，94财年的长期随访评估和对主要免疫原性测定法的分析。发布：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。发布：PLOS One，2010年2月，第5（2）：P.1-15 VRC 101（06-I-0056）是VRC开发的两种候选HIV-1疫苗的第一阶段治疗研究，并在原始方案中施用。发表：J Infect Dis。 2013年6月15日； 207（12）：1829-40。 VRC 011（06-I-0149）是一项I期研究，用于评估肌肉内，皮下和皮内给药途径，用于启动疫苗接种疫苗，3次注射6-铂DNA疫苗或一种注射RAD5疫苗。在所有时间表中，对IM进行了RAD5助推器注入。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。研究参与者的随访于09财年完成。发表：PLOS ONE，2014年3月12日； 9（3）。 VRC 012（07-II-0167）是一项I阶段研究，用于评估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I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08财年期间，第一部分的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中完成。出版：PLOS ONE。 2016年11月15日； 11（11）。 VRC 015（08-I-0171）是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。 入学率和研究疫苗在FY10完成；长期随访于2014财年完成。出版：PLOS ONE。 2014年9月29日； 9（9）。 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开始的，并于2014财年完成。 HVTN 505（09-I-0163）是VRC候选DNA Prime-RAD5促进HIV疫苗方案的多中心2B疗效研究，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。出版：N Engl J Med。 2013年11月28日； 369（22）：2083-92。 VRC 018（19-I-0031）是1阶段剂量升级，随机，开放标签的临床试验，用于评估HIV-1 ENV疫苗的剂量，安全性，耐受性和免疫原性，VRC-HIVRGP096-00-VP（Trimer 4571）（Trimer 4571）与健康成人的Alum。 该试验于19财年启动，并在20财年完成了入学率。Trimer4571是在人类中评估的第一个封闭的，稳定的HIV-1 Env Trimer。 当与明矾辅助并通过皮下和肌内路线给药时，它被确定为安全且耐受性。给药后两周检测到的三聚体特异性抗体反应主要集中在无聚糖的三聚体碱基上，而没有对CD4结合表位的可检测反应。检测到有限的中和抗体，这也主要针对三聚体的无聚糖碱。这项研究告知未来的HIV疫苗为确定如何在人类中诱导对HIV的有效中和抗体反应的努力。 Eclinicalmedicine。 2022 Jun 1; 48：101477。 doi：10.1016/j.eclinm.2022.101477。 PMID：35783486; PMCID：PMC9249552。 HVTN 303是一项1阶段的开放标签，剂量升级研究，可评估辅助的HIV-1融合肽（FP）共轭疫苗（FP8V1-RTTHC）的剂量，安全性，容忍性和免疫原性这是由AIDS（DAIDS）发起的，由HIV疫苗试验网络（HVTN）进行的多中心试验，该试验使用VRC开发的疫苗产品进行。 VRC临床试验计划（CTP）医师是HVTN 303协议团队的成员，担任VRC产品代表，并参加协议安全审查团队会议。