Clinical Trials of Parainfluenza and Respiratory Syncytial Virus Vaccines

副流感和呼吸道合胞病毒疫苗的临床试验

• 批准号: 7592132
• 负责人: Brian Murphy
• 金额: $ 316.15万
• 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/7592132
• 关键词: Age; Age-Months; Antigens; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Bos taurus; Cattle; Child; Clinical Trials; Complementary DNA; Data; Development; Disease; Dose; Formalin; Future; Genes; Genome; Goals; Human; Immune response; Immunization; Infant; Infection; Kidney; Life; Lower respiratory tract structure; Lung diseases; Medical Surveillance; Monkeys; Nasal Lavage Fluid; Para-Influenza Virus Type 3; Parainfluenza; Placebos; Prevention; Purpose; Rate; Recombinants; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Sampling; Seasons; Seeds; Serological; Serum; Subgroup; Target Populations; Therapeutic Equivalency; Upper respiratory tract; Vaccinated; Vaccination; Vaccines; Vertebral column; Virus; Virus Shedding; base; design; efficacy trial; experience; immunogenic; parainfluenza virus; preclinical study; recombinant virus; respiratory; response; trend; vaccine development; vaccine efficacy

RSV vaccine development Early in the development of respiratory syncytial virus (RSV) vaccines severe disease occurred in some children after receipt of formalin-inactivated RSV vaccine. The illnesses occurred in children who had not previously experienced RSV infection but had wild-type RSV infection in the winter season subsequent to vaccination. Live attenuated, intranasally administered vaccines offer the potential for a broadly based immune response and, by mimicking the response to natural infection, are unlikely to result in potentiated disease. The continuing efforts to develop an appropriately attenuated and immunogenic live RSV vaccine have provided an opportunity to give assurances that live vaccines are a safe approach to RSV immunization and to provide useful data on the optimal design of subsequent vaccine efficacy trials. Between 1996 and 2003 7 different RSV vaccines were given to 113 6-24 month old children seronegative to RSV at immunization and 2 vaccines to 62 RSV-nave infants 1-3 months of age. In total, 388 vaccinees, placebo recipients and age-matched controls were followed for respiratory illness during the subsequent winter. Nasal wash samples were cultured for RSV with each episode of respiratory disease. For purposes of analysis we focused on: 1) a comparison between all vaccinees and controls - an intent to treat analysis, and 2) for two vaccines given to both 6-24 month olds and 1-3 month olds - a comparison of those who had a response to vaccination (evidence of virus shedding or an immune response) versus controls - a vaccine efficacy analysis. Pre and post-season sera available on 122 of the infants and 143 of the children were examined for serologic evidence of RSV infection. In the intent to treat analysis the rate of RSV-associated upper respiratory tract illness was lower in vaccinated children than in controls (14% versus 20% in the 6-24 month old group and 16% versus 25% in infants). RSV-associated lower respiratory tract illness was infrequent and there was no evidence that vaccination predisposed to more severe illness. The vaccine efficacy analysis of the two leading vaccine candidates (cpts 248404 and rA2cp 2484041030SH) revealed similar trends towards efficacy. RSV serologic rises over the ensuing winter were common in children (31%) and infants (21%) regardless of receipt of vaccine or placebo. This surveillance clearly demonstrated that infection with a live attenuated RSV vaccine did not result in enhanced disease upon infection with wild type RSV. The information on the impact of RSV in the young infants and children during the period of surveillance will assist in designing future efficacy studies with RSV vaccines. Parainfluenza virus (PIV) vaccine development HPIV3cp45 - Studies have been initiated with a human (H) recombinant(r) vaccine virus, designated rHPIV3cp45. Previously, biologically-derived HPIV3cp45 was shown to be satisfactorily attenuated, immunogenic, and genetically stable in the target population of HPIV3 nave subjects. Deriving a virus from a cDNA copy of the HPIV3 genome using defined materials and media generates a virus seed that is free of adventitious contaminants from the previous 45 passages of the virus in primary monkey kidney cultures. The present study was done to demonstrate the bioequivalence of the rHPIV3cp45 and the biologically-derived HPIV3cp45 and to define a dose of vaccine that is safe, infectious, and immunogenic in older and younger HPIV3 nave subjects. These studies are in progress and preliminary results indicate that the two versions of HPIV3cp45 vaccine are comparable. BHPIV3 Studies have been initiated with the chimeric recombinant virus that contains the HPIV3 HN and F protective antigens on a bovine (B) PIV3 backbone that contains multiple attenuating BPIV3 genes. HPIV1 and HPIV2 Live attenuated HPIV1 and HPIV2 vaccine candidates have been identified in preclinical studies and clinical trial materials are being prepared. Trials with this vaccine should be initiated this coming year.

RSV疫苗开发 在收到福尔马林失活的RSV疫苗后，一些儿童发生了呼吸道合胞病毒（RSV）疫苗的发生早期。这些疾病发生在以前从未经历过RSV感染但在疫苗接种后冬季感染野生型RSV感染的儿童中。现场衰减，鼻内给药的疫苗为广泛的免疫反应提供了潜力，并且通过模仿对自然感染的反应，不太可能导致增强的疾病。不断开发适当衰减和免疫原性的现场RSV疫苗的努力为保证实时疫苗是一种安全的RSV免疫方法，并提供有关随后疫苗效能试验的最佳设计的有用数据。 在1996年至2003年之间，将7种不同的RSV疫苗送给了113个6-24个月大的儿童，可在免疫接收到RSV，并在1-3个月大的62个RSV纳维婴儿时对RSV和2次疫苗至62个疫苗。 在随后的冬季，总共遵循388名疫苗，安慰剂接受者和年龄匹配的对照。 每发呼吸道疾病，将鼻洗样品用于RSV。 为了进行分析目的，我们重点介绍：1）所有疫苗和对照组之间的比较 - 一种治疗分析的意图，以及2）两种疫苗对6-24个月大和1-3个月大的疫苗进行了比较 - 对那些对疫苗有反应的人进行了比较（病毒脱落或免疫反应的证据）与疫苗的效果分析。 检查了122名婴儿和143名儿童的季前和季前血清是否有RSV感染的血清学证据。 为了治疗分析，接种疫苗的儿童中与RSV相关的上呼吸道疾病的发生率低于对照组（在6-24个月大的组中为14％，为20％，在婴儿中为16％，在婴儿中为25％）。 与RSV相关的下呼吸道疾病很少见，没有证据表明疫苗接种易于更严重的疾病。两种主要候选疫苗的疫苗疗效分析（CPTS 248404和RA2CP 2484041030SH）显示出类似的效力趋势。 在随后的冬季，RSV血清学升高在儿童中很常见（31％）和婴儿（21％），而不管接收疫苗或安慰剂。该监视清楚地表明，通过野生型RSV感染后，带有活衰减的RSV疫苗感染并不会导致疾病增强。在监视期间，RSV对年轻婴儿和儿童的影响的信息将有助于通过RSV疫苗设计未来的功效研究。 Parainfluenza病毒（PIV）疫苗开发 HPIV3CP45-研究已使用人（H）重组（R）疫苗病毒，指定为RHPIV3CP45。 以前，在HPIV3中神中含有的目标群体中，生物学衍生的HPIV3CP45被证明是令人满意的减弱，免疫原性和遗传稳定的。 使用定义的材料和培养基从HPIV3基因组的cDNA副本中得出病毒，从而在原代猴肾脏培养物中没有前45个病毒通道中没有不良污染物的病毒种子。 本研究是为了证明RHPIV3CP45和生物学衍生的HPIV3CP45的生物等效性，并定义了在老年人和年轻的HPIV3中含有安全，感染性和免疫原性的疫苗剂量。 这些研究正在进行中，初步结果表明HPIV3CP45疫苗的两个版本是可比的。 BHPIV3研究已从嵌合在牛（B）PIV3骨架上的嵌合重组病毒开始，该病毒包含HPIV3 HN和F保护性抗原，其中包含多种衰减BPIV3基因。 HPIV1和HPIV2活减弱的HPIV1和HPIV2疫苗候选物已在临床前研究中鉴定出来，并且正在制备临床试验材料。该疫苗的试验应在今年开始。