Clinical Trials of Vaccines for Respiratory Syncytial Virus and Related Viruses

呼吸道合胞病毒及相关病毒疫苗的临床试验

• 批准号: 10272020
• 负责人: Ursula Buchholz
• 金额: $ 125.84万
• 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/10272020
• 关键词: 1 year old; 5 year old; Acute; Adolescence; Adult; Age; Age-Months; Amino Acids; Antibody Response; Antibody titer measurement; Antigens; Antiviral Agents; Apoptosis; Asthma; Attenuated; Attenuated Live Virus Vaccine; Cessation of life; Child; Childhood; Clinic; Clinical; Clinical Research; Clinical Trials; Codon Nucleotides; Collaborations; Complementary DNA; Complication; Conduct Clinical Trials; Cooperative Research and Development Agreement; Deletion Mutation; Development; Dose; Elements; Evaluation; Experimental Models; Fever; Genes; Genetic; Genetic Transcription; Genome; Goals; Head; Health; Hospitalization; Human; Human Metapneumovirus; Immune response; Immunity; Immunization; Immunoglobulin G; Infant; Infection; Interferons; Laboratories; Laboratory Study; Lower Respiratory Tract Infection; Lung diseases; Malaria; Maryland; Measures; Medical; Missense Mutation; Modeling; Monitor; Mutation; Nose; Open Reading Frames; Para-Influenza Virus Type 1; Para-Influenza Virus Type 3; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Phenotype; Placebos; Play; Pneumovirus; Polymerase; Population; Positioning Attribute; Preparation; Proteins; Publishing; RNA chemical synthesis; RNA replication; Reporting; Research; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Reverse Transcriptase Polymerase Chain Reaction; Role; Safety; Seasons; Serotyping; Serum; Symptoms; System; Universities; Up-Regulation; Upper respiratory tract; Vaccine Clinical Trial; Vaccine Design; Vaccines; Viral; Viral Antigens; Viral Genes; Viral Pathogenesis; Virus; Virus Diseases; aged; attenuation; base; effectiveness evaluation; efficacy study; head-to-head comparison; immunogenic; immunogenicity; improved; infancy; lead candidate; mortality; neutralizing antibody; parainfluenza virus; particle; pathogen; phase 1 study; phase I trial; preclinical development; preclinical study; prototype; recombinant virus; respiratory; response; reverse genetics; seropositive; therapeutic candidate; vaccine candidate; vector; vector vaccine; viral RNA; virology; volunteer

We are following two strategies to develop a live-attenuated pediatric RSV vaccine. The primary strategy is to develop live-attenuated RSV strains, with attenuation provided mainly by deletion of one of several nonessential genes and by missense and codon-deletion mutations that are mainly in the L polymerase and have been stabilized against de-attenuation using reverse genetics. The immediate goal is to identify one or two lead candidates suitable for further development as an intranasal pediatric RSV vaccine. (ii) A secondary vaccine strategy is to use attenuated versions of PIV3 as vectors to express RSV antigen (primarily the fusion F protein) which provide live bivalent HPIV3/RSV vaccines. The pre-clinical development of these PIV-vectored vaccines is described in the accompanying report "Laboratory and Pre-Clinical Studies of Parainfluenza Viruses". Both vaccine strategies are being developed under a Cooperative Research and Development Agreement (CRADA) with Sanofi Pasteur, Inc. To date, our clinical trials have focused on live-attenuated RSV strains. We will evaluate two PIV-vectored vaccines in the clinic in 2021. One lineage of live-attenuated RSV vaccine candidates involves deletion of the ORF encoding the small (90 amino acids) viral M2-2 protein. The M2-2 protein plays a role in regulating RSV RNA synthesis, and its deletion results in down-regulated viral RNA replication (causing viral attenuation) and a global up-regulation of viral gene transcription and antigen synthesis. Increased antigen expression per genome raises the possibility of increased immunogenicity per infectious particle. Prototype deltaM2-2 candidates called RSV MEDI/deltaM2-2 and RSV LID/deltaM2-2 were evaluated and reported upon in past years. Based on these results, a number of derivatives were constructed and evaluated in small Phase 1 pediatric clinical trials. This year, two reports on delM2-2 candidates were published, RSV LID/deltaM2-2/1030s (NCT02794870 and NCT0252339) and D46/NS2/N/deltaM2-2-HindIII (NCT03099291 and NCT03102034). D46/NS2/N/deltaM2-2-HindIII is based on previous candidate LID/deltaM2-2 but incorporates prominent differences from MEDI/deltaM2-2, which was more restricted in replication than LID/deltaM2-2 in phase 1. RSV-seronegative children aged 6 to 24 months received 1 intranasal dose 5 log10 plaque-forming units (PFU) of D46/NS2/N/deltaM2-2-HindIII (n=21) or placebo (n=11) and were monitored for vaccine shedding, reactogenicity, RSV-antibody responses. All 21 vaccinees were infected with vaccine; 20 (95%) shed vaccine, and serum RSV-neutralizing antibodies and anti-RSV fusion immunoglobulin G increased 4-fold in 95% and 100% of vaccines, respectively. Mild upper respiratory tract symptoms and/or fever occurred in vaccinees (76%) and placebo recipients (18%). Overall, D46/NS2/N/deltaM2-2-HindIII had excellent infectivity and immunogenicity and primed vaccine recipients for anamnestic responses, encouraging further evaluation of this attenuation strategy. For larger studies, a vaccine candidate with a slightly lower level of shedding might be preferable. LID/deltaM2-2/1030s is also attenuated through deletion of M2-2, combined with a stabilized missense mutation called 1030s that consists of Y1321K and S1313(TCA) mutations in the L polymerase. RSV-seronegative children ages 6 to 24 months received 1 intranasal dose of 5 log10 PFU of LID/deltaM2-2/1030s (n=21) or placebo (n=11) and were monitored as described above. Eighty-five percent of vaccinees shed vaccine at low or moderate levels and had a 4-fold rise in serum RSV neutralizing antibodies. LID/deltaM2-2/1030s was well tolerated, had excellent infectivity without evidence of genetic instability, induced durable immunity, and primed for strong anamnestic antibody responses to wildtype RSV infection, making it an attractive candidate for further evaluation. A larger study in RSV seronegative children is in preparation. A second lineage of RSV vaccine candidates contains deletion of the NS2 gene, whose encoded protein antagonizes host interferon and apoptosis responses to viral infection. The candidate RSV deltaNS2/delta1313/I1314L contains the delNS2 mutation combined with a mutation called delta1313/I1314L comprising deletion of codon 1313 in the L polymerase plus an adjacent missense mutation I1314L that stabilizes against de-attenuation. This virus was evaluated in a Phase 1 pediatric clinical trial (NCT01893554). In this study, a single intranasal dose of RSV/deltaNS2/delta1313/I1314L was administered at 6.0 log10 PFU to 15 RSV-seropositive children ages 12-59 months, in whom the vaccine was very highly restricted. This indicated that this candidate was sufficiently attenuated to evaluate in seronegative infants and children 6-24 months of age. When given at a dose of 6.0 log10 PFU to 20 vaccinees (with 10 placebo recipients), the vaccine was well-tolerated, 90% of recipients shed vaccine virus, 85% had a serum RSV-specific antibody response, and 100% were infected based on vaccine shedding and/or a serum antibody response. This vaccine is now considered to be a leading candidate, and is being evaluated in a Phase 1 study in a head-to-head comparison with a deltaM2-2 virus called RSV 276 (NCT03227029 and NCT03422237). A second deltaNS2-based vaccine candidate, RSV deltaNS2/1030s, combines the deltaNS2 mutation with a stabilized missense mutation called 1030s that consists of Y1321K and S1313(TCA) mutations in the L polymerase. This virus presently is being evaluated in a Phase 1 pediatric clinical study (NCT03387137). The 1030s mutation is somewhat less attenuating than the delta1313/I1314L mutation, and therefore RSV deltaNS2/1030s should be less attenuated than RSV/NS2/1313/I1314L. The RSV deltaNS2/1030s, RSV/deltaNS2/delta1313/I1314L, and RSV 276 candidates are presently being evaluated head-to-head in a Phase 1/2 clinical trial in seronegative infants and young children (NCT03916185). A third lineage of RSV vaccine candidates contains deletion of the NS1 gene that, like NS2, encodes a protein that antagonizes host interferon and apoptosis responses, but does so more efficiently than NS2 and thus might confer a phenotype that is more attenuated and immunogenic. Two viruses were made that each contain the delNS1 deletion as the sole attenuating element, but in one virus the F and G genes have been moved to the first and second genome positions in order to increase their expression (RSV 6120/deltaNS1 and 6120/F1G2/deltaNS1 respectively). These viruses presently are being compared head-to-head in a Phase 1 clinical trial (NCT03596801). The subjects in a number of Phase 1 studies were surveilled during the subsequent winter RSV season to measure serum RSV-neutralizing antibody titers at the beginning and end of the winter, and to monitor respiratory illness during the winter and identify causative agents by nasal wash and RT-PCR. Without going into detail, this surveillance has provided presumptive evidence of protection against wild-type RSV infection, as well as strong anamnestic RSV-specific antibody responses. RSV serum neutralizing antibody responses were identified as the most suitable correlate of vaccine take and possible predictors of efficacy. These preliminary observations are very encouraging. cDNA-derived RSV strain A2 is presently being evaluated in healthy adult volunteers in a dose-escalation study (NCT02484417). We also are evaluating a recent clinical isolate RSV A/Maryland/001/11 for which we have developed a reverse genetic system and recovered a recombinant virus in a Phase 1 trial in healthy adult volunteers (NCT03624790). These studies will provide an infection model that can be used to evaluate RSV therapeutic candidates and adult RSV vaccine candidates, and to study viral pathogenesis and the host

我们正在遵循两种策略来开发活体衰减的儿科RSV疫苗。主要策略是开发实时衰减的RSV菌株，主要是通过删除几个非必需基因之一，以及主要在L聚合酶中的错义和密码子删除突变，并且使用反向遗传学进行了去衰减，这些基因和密码子删除突变已稳定。直接的目标是确定一两个适合进一步发展的主要候选者作为鼻内小儿RSV疫苗。 （ii）一种次级疫苗策略是使用PIV3的减毒版本作为向量表达RSV抗原（主要是融合F蛋白），该抗原提供了实时的二价HPIV3/RSV疫苗。这些PIV载体疫苗的临床前发育在随附的报告“副菌病毒的实验室和临床前研究”中描述了。两种疫苗策略都在与赛诺菲Pasteur，Inc。的合作研究与开发协议（CRADA）下制定，迄今为止，我们的临床试验集中在实时衰减的RSV菌株上。我们将在2021年在诊所评估两种PIV循环疫苗。 一个活体衰减的RSV疫苗候选者的一个谱系涉及编码小（90个氨基酸）病毒M2-2蛋白的ORF。 M2-2蛋白在调节RSV RNA合成中起作用，其缺失导致病毒RNA复制下调（导致病毒衰减）和病毒基因转录和抗原合成的全局上调。每个基因组的抗原表达增加增加了每个感染粒子免疫原性增加的可能性。 在过去几年中评估并报告了称为RSV MEDI/Deltam2-2和RSV盖/Deltam2-2的原型Deltam2-2候选者。基于这些结果，在小儿科临床试验中构建和评估了许多衍生物。今年，发表了有关DELM2-2候选人的两份报告，RSV LID/DELTAM2-2/1030S（NCT02794870和NCT0252339）和D46/NS2/NS2/NS2/NS2/NS2/DELTAM2-2-2-HINDIII（NCT03099291和NCT03102034）。 D46/NS2/NS2-2-2-HINDIII基于先前的候选盖/Deltam2-2，但与Medi/Deltam2-2合并了显着差异，复制中的复制限制比第1阶段的LID/Deltam2-2在1阶段1中更限制。RSV-SERONEGATION儿童Aged 6至24个月接受1 intanasas dose dose dose 5 logignits d logigrun fort（ D46/NS2/N/deltam2-2-hindiii（n = 21）或安慰剂（n = 11），并受到监测的疫苗脱落，反应生成，RSV抗体反应。所有21种疫苗都被疫苗感染； 20（95％）脱离疫苗和血清RSV中和抗体和抗RSV融合免疫球蛋白G分别在95％和100％的疫苗中增加了4倍。疫苗（76％）和安慰剂接受者（18％）发生轻度上呼吸道症状和/或发烧。总体而言，D46/NS2/NS2/N/Deltam2-2-Hindiii具有出色的感染性和免疫原性，并引发了疫苗接种者的植入疫苗，从而鼓励对这种衰减策略进行进一步评估。对于较大的研究，脱落水平略低的疫苗候选者可能是可取的。 盖子/deltam2-2/1030s也通过缺失M2-2衰减，并结合稳定的错义突变，称为1030S，由L1321K和S1313和S1313（TCA）突变组成。 6至24个月的RSV-Seronegative儿童接受了1个lid/deltam2-2/1030s（n = 21）或安慰剂（n = 11）的鼻内剂量1 log10 pfu，并如上所述进行监测。百分之八十五的疫苗以低或中等水平脱离疫苗，血清RSV中和抗体的增长4倍。盖子/Deltam2-2/1030s的耐受性良好，具有出色的感染性，没有遗传不稳定性，诱发耐用的免疫力，并用于对Wildtype RSV感染的强吞噬抗体反应，使其成为进一步评估的有吸引力的候选者。在准备RSV血清神经儿童中进行的一项更大的研究正在准备。 RSV疫苗候选物的第二个谱系包含NS2基因的缺失，NS2基因的编码蛋白会拮抗宿主干扰素和对病毒感染的凋亡反应。候选RSV deltans2/delta1313/i1314L包含Delns2突变，并结合了一个称为Delta1313/I1314L的突变，其中包含CODON 1313在L Polymerase中删除的突变，以及邻近的Missense Just突变I1314L，可稳定抗DE-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-te-nity。该病毒在1期的小儿临床试验（NCT01893554）中进行了评估。在这项研究中，将单个鼻内剂量的RSV/Deltans2/delta1313/i1314L以6.0 log10 pfu至15个RSV静脉阳性儿童为12-59个月，其中疫苗受到了极为巨大的限制。这表明该候选人足够衰减以评估6-24个月大的血清传记婴儿和儿童。 当以6.0 log10 PFU的剂量至20个疫苗（有10个安慰剂接受者）时，该疫苗的耐受性良好，90％的受体脱离疫苗病毒，85％的疫苗病毒患有血清RSV特异性抗体反应，并基于疫苗的脱水和/或血清抗体反应感染了100％的血清RSV特异性抗体。现在，该疫苗被认为是领先的候选人，并且正在与1阶段研究中评估与称为RSV 276（NCT03227029和NCT03422237）的Deltam2-2病毒的头对对比较。 第二个基于DELTANS2的疫苗候选疫苗RSV Deltans2/1030s将Deltans2突变与稳定的错义突变结合在一起，称为1030S，该突变称为1030S，该突变由L聚合酶中的Y1321K和S1313（TCA）突变组成。该病毒目前正在1阶段的小儿临床研究（NCT03387137）中进行评估。与Delta1313/I1314L突变相比，1030S突变的减弱程度要小得多，因此RSV Deltans2/1030s的减弱应低于RSV/NS2/NS2/NS2/1313/I1314L。 RSV Deltans2/1030s，RSV/Deltans2/delta1313/i1314L和RSV 276候选人目前在血清神经婴儿和幼儿中的1/2期临床试验中正在评估头对头试验（NCT03916185）。 RSV疫苗候选物的第三个谱系包含NS1基因的缺失，与NS2一样，它编码了一种蛋白质，该蛋白质可以拮抗宿主干扰素和凋亡反应，但比NS2更有效，因此可能会赋予一种更衰减和免疫原性的表型。有两种病毒称每个病毒包含Delns1缺失作为唯一的衰减元件，但在一种病毒中，F和G基因已移至第一个和第二个基因组位置以增加表达（RSV 6120/Deltans1和6120/6120/F1G2/Deltans1）。这些病毒目前正在1期临床试验（NCT03596801）中进行比较。 在随后的冬季RSV季节中，对许多1期研究中的受试者进行了监视，以测量冬季开始和结束时血清RSV中和抗体滴度，并在冬季监测呼吸系统疾病，并通过鼻腔洗涤和RT-PCR识别导致剂。这种监视无需详细介绍，就可以推定防止野生型RSV感染以及强烈的吞咽RSV特异性抗体反应的证据。 RSV血清中和抗体反应被确定为疫苗服用的最合适相关性和功效的可能预测因子。这些初步观察非常令人鼓舞。 在剂量降低研究（NCT02484417）中，目前在健康的成人志愿者中评估了cDNA来源的RSV菌株A2。我们还评估了近期的临床分离株RSV A/MARYLAND/001/11，我们已经开发了反向遗传系统，并在健康的成人志愿者的1期试验中回收了重组病毒（NCT03624790）。这些研究将提供一个感染模型，可用于评估RSV治疗候选物和成人RSV疫苗候选物，并研究病毒发病机理和宿主