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: 10014018
• 负责人: PETER LEON COLLINS
• 金额: $ 154.41万
• 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/10014018
• 关键词: 1 year old; 5 year old; Acute; Adolescence; Adult; Age; Age-Months; Amino Acids; Antibodies; 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; Effectiveness; Elements; Experimental Models; Genes; Genetic Transcription; Genome; Goals; Head; Health; Hospitalization; Human; Human Metapneumovirus; Immune response; Immunity; 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; Pathogenesis; Patients; Phase; Phase I Clinical Trials; Phenotype; Placebos; Play; Pneumovirus; Polymerase; Population; Positioning Attribute; Proteins; Publishing; RNA chemical synthesis; RNA replication; Reporting; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Reverse Transcriptase Polymerase Chain Reaction; Role; Safety; Seasons; Serotyping; Serum; System; Time; Up-Regulation; Vaccine Clinical Trial; Vaccine Design; Vaccines; Viral; Viral Antigens; Viral Genes; Viral Pathogenesis; Virus; Virus Diseases; attenuation; base; efficacy study; head-to-head comparison; immunogenic; immunogenicity; improved; infancy; lead candidate; mortality; neutralizing antibody; parainfluenza virus; particle; pathogen; phase 1 study; 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. (i) 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 PIV strains (primarily PIV3 and secondarily PIV1) as vectors to express RSV antigen (primarily the fusion F protein) which provide live bivalent HPIV/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 a PIV-vectored vaccine in the clinic in 2020. 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 delM2-2 candidates called RSV MEDI/delM2-2 and RSV LID/delM2-2 were evaluated and reported upon in past years. Based on these results, a number of derivatives were constructed and are in small Phase 1 pediatric clinical trials. These viruses are: RSV D46/cp/delM2-2 (ClinicalTrials.gov identifier NCT02601612), RSV LID/delM2-2/1030s (NCT02794870 and NCT0252339), RSV LID/cp/delM2-2 (NCT02890381 and NCT02948127), RSV D46/NS2/N/delM2-2 (NCT03099291 and NCT03102034), and RSV 276 (NCT03227029, NCT03422237, and NCT03916185). The relatively large number of candidates is because of incongruities in some of the results, making it necessary to make and evaluate a greater number of derivatives. This year, a report on a single delM2-2 candidate was published, namely RSV LID/cp/delM2-2 (NCT02890381 and NCT02948127). This virus is attenuated through deletion of M2-2 combined with five cold passage (cp) missense mutations present in the N, F, and L proteins. RSV-seronegative children ages 6-24 months received a single intranasal dose of 5.0 log10 plaque forming units (PFU) of LID/cp/delM2-2 (n=11) or placebo (n=6). RSV serum antibodies, vaccine infectivity, and reactogenicity were assessed. Vaccine virus was shed by 36% of vaccinees at low levels, and 45% had 4-fold rise in serum neutralizing antibodies. LID/cp/M2-2 was well-tolerated. However, infectivity and immunogenicity were lower than desired, suggesting over-attenuation. Therefore, the study was closed early, prior to full accrual. 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 delNS2/del1313/I1314L contains the delNS2 mutation combined with a mutation called del1313/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), A single intranasal dose of RSV/NS2/1313/I1314L was administered at 6.0 log10 plaque-forming units (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. Therefore, the virus was administered at a dose of 5.0 log10 PFU to 15 vaccinees (with 6 placebo recipients). However, shedding was detected in only 11/15 (73%) recipients, and thus the vaccine was too attenuated at this dose. When given at a 10-fold higher dose (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 presently being evaluated in a Phase 1 study in a head-to-head comparison with a delM2-2 virus called RSV 276 (NCT03227029 and NCT03422237). A second delNS2-based vaccine candidate, RSV delNS2/1030s, combines the delNS2 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 del1313/I1314L mutation, and therefore RSV delNS2/1030s should be less attenuated than RSV/NS2/1313/I1314L. The RSV delNS2/1030s, RSV/NS2/1313/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/delNS1 and 6120/F1G2/delNS1, 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. These preliminary observations are very encouraging. cDNA-derived RSV strain A2 is presently being evaluated in an in-patient setting for infectivity, replication, pathogenesis, and immunogenicity 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 that is presently 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 response.

我们正在遵循两种策略来开发活体衰减的儿科RSV疫苗。 （i）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是在L聚合酶中稳定在L聚合酶中的几种非必需基因之一，并且已通过去稳定稳定而进行了衰减。使用反向遗传学。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衰减的PIV菌株（主要是PIV3，其次是PIV1）作为表达RSV抗原（主要是融合F蛋白）的向量，该抗原（主要是融合F蛋白）提供了实时的二价HPIV/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2020年评估诊所中的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/DELM2-2和RSV LID/DELM2-2的原型Delm2-2候选者。基于这些结果，构建了许多衍生物，并在小儿科临床试验中进行。这些病毒为：RSV D46/CP/DELM2-2（临床Trials.gov标识符NCT02601612），RSV LID/DELM2-2/1030S（NCT02794870和NCT0252339），RSV LID/CP/CP/CP/CP/CP/CP/CP/CP/CP/CP/CP/CP/CP/CP/CP/CP/cp/cp/cp/ccp/cp/ccp/cp/ccp/ccp/ccp/ccp/ccp/ccp/ccp/ccp/ccp/ccp/ccp/ccp/ccp/ccp/ccp/ccp/delm2-2712890289038990389990 and rid d。 /ns2/n/delm2-2（NCT03099291和NCT03102034）和RSV 276（NCT03227029，NCT03422237和NCT03916185）。相对较大的候选人是由于某些结果不一致，因此有必要制造和评估更多的衍生物。 今年，发表了有关单个Delm2-2候选人的报告，即RSV LID/CP/DELM2-2（NCT02890381和NCT02948127）。该病毒通过缺失M2-2与N，F和L蛋白中存在的五个冷通道（CP）错义突变相结合而减弱。 6-24岁的RSV副作用儿童接受了单次鼻内剂量为5.0 Log10斑块形成单元（PFU），盖子/CP/DELM2-2（n = 11）或安慰剂（n = 6）。评估了RSV血清抗体，疫苗感染性和反应生成性。疫苗病毒被低水平的36％的疫苗脱落，45％的血清中和抗体的增长4倍。盖子/CP/M2-2的耐受性良好。但是，感染力和免疫原性低于所需的，表明过度衰减。因此，该研究在全额应计之前很早就关闭。 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 DELNS2/DEL1313/I1314L包含Delns2突变，结合了一个称为DEL1313/I1314L的突变，其中包含L LOLYSER酶中密码子1313的删除，加上邻近的遗漏突变I1314L，稳定稳定抗DE-ATCATENATIENATION。该病毒在一项1期儿科临床试验（NCT01893554）中进行了评估，将单个鼻内剂量的RSV/NS2/NS2/1313/I1314L以6.0 Log10 log10 plaque-forming-forming单位（PFU）至15 RSV Seropoptist阳性儿童的年龄为12-59个月，以6.0 log10 log10 log10 log10 log10。 ，其中疫苗受到极大限制。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。因此，该病毒以5.0 log10 pfu至15个疫苗（有6个安慰剂接受者）的剂量给药。但是，仅在11/15（73％）的受体中检测到脱落，因此该剂量过于减弱疫苗。当以10倍的剂量（6.0 log10 pfu）给20疫苗（有10个安慰剂接受者）时，该疫苗的耐受性良好，90％的受体脱离了疫苗病毒，85％的疫苗患有血清RSV特异性抗体反应，，，，是100％是根据疫苗脱落和/或血清抗体反应感染的。现在，该疫苗被认为是领先的候选者，目前正在1阶段研究中评估与称为RSV 276（NCT03227029和NCT03422237）的Delm2-2病毒的头对头比较。 第二个基于DELNS2的疫苗候选RSV DELNS2/1030S将Delns2突变与L Polymerase中由Y1321K和S1313（TCA）突变组成的稳定的错义突变结合在一起。该病毒目前正在1阶段的小儿临床研究（NCT03387137）中进行评估。与DEL1313/I1314L突变相比，1030S突变的减弱程度要小得多，因此RSV Delns2/1030s的减弱应低于RSV/NS2/1313/I1314L。 RSV DELNS2/1030S，RSV/NS2/1313/I1314L和RSV 276候选人目前在血清神经和幼儿的1/2阶段临床试验中对正面进行评估（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，它编码了一种使宿主干扰素和凋亡反应拮抗的蛋白质，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。有两个病毒被称为每个delns1缺失作为唯一衰减元件，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，以增加其表达/delns1分别）。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，并通过鼻腔洗涤和鼻腔清洗和识别导致药物RT-PCR。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。这些初步观察非常令人鼓舞。 目前，在健康的成人志愿者中，在住院环境中评估了cDNA衍生的RSV菌株A2，以进行感染，复制，发病机理和免疫原性（NCT024844417）中的感染率，复制，发病机理和免疫原性。我们还评估了最近的临床分离型RSV A/Maryland/001/11，我们已经开发了一个反向遗传系统，并恢复了一种重组病毒，该病毒目前正在健康的成人志愿者中（NCT03624790）中。这些研究将提供一种感染模型，可用于评估RSV治疗候选者和成年RSV疫苗候选物，并研究病毒发病机理和宿主反应。