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开发小儿呼吸道合胞病毒减毒活疫苗。主要策略是开发活减毒RSV菌株，其衰减主要是通过删除几个非必需基因中的一个以及主要在L聚合酶中的错义和密码子缺失突变来实现的，并且通过反向遗传学已经稳定了抗去衰减。当前的目标是确定一种或两种适合进一步开发的鼻内儿科RSV疫苗。（ii）二级疫苗策略是使用PIV3减毒版本作为载体表达RSV抗原（主要是融合F蛋白），从而提供二价HPIV3/RSV活疫苗。随附的报告“副流感病毒的实验室和临床前研究”描述了这些piv载体疫苗的临床前开发情况。这两种疫苗策略都是根据与赛诺菲巴斯德公司的合作研究与开发协议（CRADA）开发的。迄今为止，我们的临床试验主要集中在RSV减毒活株上。我们将于2021年在临床评估两种piv载体疫苗。