Clinical Trials of Biodefense Vaccines (Dengue, West Nile Virus, TBEV)

生物防御疫苗（登革热、西尼罗河病毒、TBEV）的临床试验

• 批准号: 7964578
• 负责人: Brian Murphy
• 金额: $ 355.95万
• 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/7964578
• 关键词: Address; Adult; Alanine Transaminase; Animals; Attenuated; Attenuated Live Virus Vaccine; Cells; Clinical; Clinical Trials; Data; Dengue; Dengue Virus; Development; Dose; Drug Formulations; Enrollment; Exanthema; Goals; Hepatocyte; Human; Immune; Immunity; Immunization; Injection of therapeutic agent; Life; Macaca mulatta; Mus; Mutation; Parents; Phase I Clinical Trials; Placebos; Randomized; Reporting; Research Design; Safety; Serotyping; Serum; Site; St. Louis Encephalitis Virus; Structural Protein; Subcutaneous Injections; Symptoms; Tick-Borne Encephalitis Virus; Tick-Borne Encephalitis Viruses; Time; Translating; Untranslated Regions; Vaccines; Viremia; Virus; Virus Diseases; Virus Replication; West Nile virus; biodefense; design; immunogenic; immunogenicity; mutant; neutralizing antibody; pre-clinical; vaccine candidate; vaccine development; volunteer

Dengue serotype 1 vaccine development: The live attenuated DEN1 vaccine candidate virus rDEN1del30 has been evaluated in Phase I clinical trials and was found to be safe and immunogenic at a dose of 1000 PFU. It is a promising vaccine candidate for inclusion in a tetravalent dengue vaccine formulation. Additional studies have been fully enrolled to determine the number of doses and the timing of the two doses needed to achieve optimal immunization. The studies involve two doses of vaccine given at an interval of 4 or 6 months. The results will be fully reported pending complete analysis, but preliminary analysis indicates that the first dose is highly immunogenic but the second dose is poorly infectious at 6 months. Trials to determine the human infectious dose 50 are planned. Dengue serotype 2 vaccine development: rDEN2/4del30(ME) is an attenuated chimeric dengue virus in which the prM and E structural proteins of the DEN4 candidate vaccine, rDEN4del30, have been replaced by those of the prototypic DEN2 NGC virus. The live attenuated DEN2 vaccine candidate virus rDEN2/4del30(ME) has been evaluated in Phase I clinical trials and found to be safe and immunogenic at a dose of 1000 PFU. It is a promising vaccine candidate for inclusion in a tetravalent dengue vaccine formulation. Additional studies are in progress to address the number and timing of two doses of this vaccine candidate. Enrollment is not complete, and results of the trial will be reported pending completion. Trials to determine the human infectious dose 50 are planned. Dengue serotype 3 vaccine development; rDEN3/4del30(ME) is an attenuated chimeric dengue virus in which the prM and E structural proteins of the DEN4 candidate vaccine rDEN430 have been replaced by those of a DEN3 wild type virus. rDEN3/4del30(ME) or placebo was evaluated at a dose of 1,000 or 100,000 PFU in 28 healthy dengue-naive adult volunteers per dose. Less than 40% of vaccinees were infected with either dose indicating this vaccine candidate is not sufficiently infectious to be used as a component of a tetravalent dengue vaccine formulation. Studies have been initiated with an additional DEN3 vaccine candidate in which the DEN3-UTR (untranslated region) has been replaced with that of DEN4del30, and initial trials indicate the virus is safe and more infectious than rDEN3/4del30(ME) and that it can be used as the DEN3 component of a tetravalent vaccine. Dengue serotype 4 vaccine development: rDEN4∆30-200,201 is a live attenuated DENV-4 vaccine candidate specifically designed to further attenuate the rDEN4∆30 parent virus. In a previous study, 5 of 20 vaccinees who received rDEN4∆30 at 100,000 PFU developed moderately elevated levels of serum alanine aminotransferase (ALT). Mutational analysis of DENV-4 revealed that the 200,201 mutation of NS5 greatly restricted virus replication in human hepatocarcinoma HuH-7 cells. In pre-clinical animal studies, the vaccine candidate rDEN4∆30-200,201 was shown to be more attenuated than rDEN4∆30 in both SCID-HuH-7 mice and rhesus macaques. In the present study, twenty-eight healthy adult volunteers were randomized to receive either 100,000 PFU of vaccine (20) or placebo (8) as a single subcutaneous injection. The vaccine infected all vaccinees and was well tolerated without inducing ALT elevations. Although virus was not recovered from the serum of any vaccinee, moderate levels of neutralizing antibody were induced. The restricted replication of rDEN430-200,201 in SCID HuH-7 mice and rhesus monkeys was also observed in humans, thus validating the pre-clinical approach of selecting a mutant virus with a decreased level of replication in human liver cells. rDEN4∆30-200,201 is a promising candidate and can be considered for inclusion in a tetravalent DEN virus vaccine. We currently consider the rDEN4del30 vaccine our DEN4 leading candidate for inclusion in the tetravalent vaccine for two reasons. At a proposed dose of 1000 PFU, it is economical to produce and has an acceptable safety profile; and, rDEN4del30 appears slightly more immunogenic in humans than rDEN4del30-200,201; this greater immunogenicity likely would translate into a more durable immunity. A second candidate is rDEN4del30-4995. rDEN4∆30-4995 is a live attenuated dengue virus type 4 (DEN4) vaccine candidate specifically designed as a further attenuated derivative of the rDEN4∆30 parent virus. In a previous study, 5/20 vaccinees who received 100,000 plaque forming units (PFU) of rDEN4∆30 developed a transient serum ALT elevation and 10/20 developed an asymptomatic maculopapular rash. In the current study, 28 healthy adult volunteers were randomized to receive 100,000 PFU of rDEN4∆30-4995 (20) or placebo (8) as a single subcutaneous injection. The vaccine was safe, well-tolerated, and immunogenic. An asymptomatic generalized maculopapular rash and elevations in ALT levels were observed in 10% of the rDEN4∆30-4995 vaccinees. None of the rDEN4∆30-4995 volunteers became viremic, yet 95% developed a four-fold rise in neutralizing antibody titers. Thus rDEN4∆30-4995 was demonstrated to be safe, highly attenuated, and immunogenic. However, an asymptomatic localized erythematous rash at the injection site was seen in 17/20 rDEN4∆30-4995 vaccinees, and, therefore, alternative DEN4 vaccine strains were selected for further clinical development. Two tetravalent formulations will be evaluated in humans in the next FY. One will consist of rDEN1del30, rDEN2/4del30(ME), rDEN3-3Ddel30, and DEN4-del30 and the second will have rDEN4∆30-200,201 as the DEN4 component. An additional study designed to evaluate the safety of our DEN vaccine viruses in subjects immune to a heterologous dengue virus has been completed, and the data is being analyzed. Preliminary analysis of this trial, in which four combinations of heterologous first and second vaccines were studied, indicated that the vaccine viruses were infectious, safe, and immunogenic in the presence of preexisting heterologous immunity. Only one of the four combinations showed increased replication of vaccine virus, an expected finding in which preexisting immunity enhances virus replication, but this small increase in viremia was not accompanied by an increase in signs or symptoms of dengue virus disease. West Nile virus vaccine development trials in humans: Phase I trials are ongoing with a live attenuated West Nile virus vaccine candidate, WNVDEN4del30. Studies at 1000 and 100,000 infectious units per vaccinee indicated the vaccine was safe with low viremia, but was immunogenic in only 80% of vaccinees. To achieve a higher take rate, a study is ongoing in which two doses of 100,000 infectious units are given six months apart. The study is fully enrolled, and preliminary analysis indicates that the vaccine given as two doses is safe and immunogenic with up to 100% of vaccinees developing a rise in neutralizing antibody titer.

登革热血清型1疫苗开发：已在I期临床试验中评估了活衰减的DEN1疫苗候选病毒RDEN1DEL30，并发现以1000 PFU的剂量被发现安全且免疫原性。它是一种有前途的疫苗候选者，可纳入四龙猎犬疫苗配方。已完全注册了其他研究，以确定实现最佳免疫所需的两种剂量的数量和时间的时间。这些研究涉及两次疫苗的时间为4或6个月。结果将充分报道，直到完整分析，但初步分析表明，第一个剂量具有高度免疫原性，但第二剂量在6个月时感染不良。计划确定人类感染剂量50的试验。登革热血清型2疫苗开发：RDEN2/4DEL30（ME）是一种减弱的嵌合登革热病毒，其中DEN4候选疫苗RDEN4DEL30的PRM和E结构蛋白被原始DEN2 NGC病毒所取代。在I期临床试验中评估了活体衰减DEN2疫苗候选病毒RDEN2/4DEL30（ME），发现以1000 PFU的剂量为安全和免疫原性。它是一种有前途的疫苗候选者，可纳入四龙猎犬疫苗配方。正在进行其他研究以解决该疫苗候选两种剂量的数量和时间。 入学率尚不完整，审判结果将报告待完成。计划确定人类感染剂量50的试验。登革热血清型3疫苗开发； RDEN3/4DEL30（ME）是一种衰减的嵌合登革热病毒，其中DEN4候选疫苗RDEN430的PRM和E结构蛋白已被DEN3野生型病毒的PRM和E结构蛋白所取代。 RDEN3/4DEL30（ME）或安慰剂以1,000或100,000 pfu的剂量评估，每剂28位健康的登革热成人志愿者。少于40％的疫苗被任何剂量感染，表明该疫苗候选者的感染力不足以将其用作四位价值的登革热疫苗配方的组成部分。研究是用额外的DEN3疫苗候选者进行的，其中DEN3-UTR（未翻译区域）已被DEN4DEL30取代，初步试验表明该病毒比RDEN3/4DEL30（ME）更安全，更感染性，并且可以用作Tetravalent疫苗的DEN3组件。登革热血清型4疫苗开发：RDEN4Δ30-200,201是一种活体衰减的DENV-4疫苗候选者，专门设计用于进一步减弱RDEN4Δ30父病毒。 在先前的研究中，以100,000个PFU接收RDEN4Δ30的20个疫苗中有5例在血清丙氨酸氨基转移酶（ALT）中升高。 DENV-4的突变分析表明，NS5的200,201突变在人肝癌HuH-7细胞中极大地限制了病毒复制。 在临床前动物研究中，在SCID-HUH-7小鼠和Rhesus猕猴中，候选疫苗候选RDEN4Δ30-200,201比RDEN4Δ30更衰减。在本研究中，将28名健康的成年志愿者随机分配，以接收100,000 PFU的疫苗（20）或安慰剂（8）作为单一皮下注射。 疫苗感染了所有疫苗，并且在没有诱导ALT升高的情况下耐受耐受性。 尽管未从任何疫苗的血清中回收病毒，但仍诱导中和抗体水平。 还观察到在人类中，在SCID HUH-7小鼠和恒河猴中的RDEN430-200,201的复制受限，从而验证了在人肝细胞中选择具有降低的复制水平的突变病毒的临床前方法。 RDEN4Δ30-200,201是一个有前途的候选人，可以考虑将其纳入四位含量DEN病毒疫苗。目前，我们认为RDEN4DEL30疫苗我们的DEN4领先候选人纳入了四位价值疫苗，原因有两个。在拟议的1000 PFU剂量下，生产并具有可接受的安全性。而且，RDEN4DEL30在人类中的免疫原性比RDEN4DEL30-200,201略高。这种更大的免疫原性可能会转化为更耐用的免疫力。第二个候选人是RDEN4DEL30-4995。 RDEN4Δ30-4995是一种活的减毒登革热病毒4型（DEN4）疫苗候选者，专门设计为RDEN4Δ30父病毒的进一步减弱衍生物。 在先前的研究中，5/20疫苗接收了100,000个斑块成型单元（PFU）的RDEN4Δ30产生了短暂的血清ALT升高，10/20出现了一种无症状的大绝语皮疹。 在当前的研究中，将28名健康的成年志愿者随机分配，以获得100,000 PFU的RDEN4Δ30-4995（20）或安慰剂（8）作为单一皮下注射。 该疫苗安全，耐受性且免疫原性。在RDEN4Δ30-4995疫苗的10％中观察到无症状的广义刺皮疹和ALT水平的升高。 RDEN4Δ30-4995志愿者没有一个病毒，但95％的中和抗体滴度却增加了四倍。 因此，RDEN4Δ30-4995被证明是安全，高度衰减和免疫原性的。然而，在17/20RDEN4Δ30-4995疫苗中可以看到注射部位的无症状局部红斑皮疹，因此选择了替代的DEN4疫苗菌株以进行进一步的临床发育。 在下一个FY中，将在人类中评估两种四位数制剂。 一个将由RDEN1DEL30，RDEN2/4DEL30（ME），RDEN3-3DDEL30和DEN4-DEL30组成，第二个将以RDEN4Δ30-200,201作为DEN4组件。 一项旨在评估我们的DEN疫苗病毒在免疫异源登革热病毒的受试者中的安全性的其他研究已经完成，并且正在分析数据。对这项试验的初步分析，其中研究了异源的第一和第二疫苗的四个组合，表明在存在先前存在异源免疫的情况下，疫苗病毒具有感染性，安全和免疫原性。 这四种组合中只有一种显示出疫苗病毒的复制增加，这是一种预期的发现，即先前存在的免疫增强了病毒的复制，但是病毒血症的这种少量增加并未伴随着登革热病毒疾病的体征或症状的增加。西尼罗河病毒疫苗开发试验：I期试验正在进行中，其中有活死的西尼罗河病毒疫苗候选者WNVDEN4DEL30。每种疫苗的1000和100,000个传染单元的研究表明，该疫苗的病毒血症很低，但仅在80％的疫苗中是免疫原性的。为了达到更高的收入率，正在进行一项研究，其中两剂100,000个传染性单元相隔六个月。 这项研究已完全参与，初步分析表明，服用的两剂疫苗是安全且免疫原性的，高达100％的疫苗在中和抗体滴度上会增加。