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: 10927725
• 负责人: Ursula Buchholz
• 金额: $ 129.09万
• 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/10927725
• 关键词: 5 year old; Active Immunization; Active immunity; Acute; Adolescence; Adult; Age Months; Amino Acids; Antibody Response; Antigens; Antiviral Agents; Apoptosis; Asthma; Attenuated; Attenuated Vaccines; Cessation of life; Child; Childhood; Clinic; Clinical; Clinical Trials; Codon Nucleotides; Collaborations; Complementary DNA; Complication; Conduct Clinical Trials; Cooperative Research and Development Agreement; Deletion Mutation; Development; Dose; Elements; Enrollment; Evaluation; Experimental Models; Genes; Genetic; Genetic Transcription; Genome; Goals; Half-Life; Head; Health; Hospitalization; Human; Human Metapneumovirus; Immune response; Immunity; Immunization; Infant; Infection; Interferons; Laboratories; Laboratory Study; Lower Respiratory Tract Infection; Maryland; Medical; Missense Mutation; Modeling; Monoclonal Antibodies; Mutation; Open Reading Frames; Para-Influenza Virus Type 1; Para-Influenza Virus Type 3; Passive Immunity; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Phenotype; Pneumovirus; Polymerase; Population; Positioning Attribute; Proteins; Publishing; RNA chemical synthesis; RNA replication; Reporting; Research; Respiratory Disease; Respiratory Mucosa; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Respiratory syncytial virus RSV F proteins; Safety; Seasons; Serotyping; Side; Subunit Vaccines; System; Toddler; Universities; Up-Regulation; Vaccine Clinical Trial; Vaccine Design; Vaccines; Viral; Viral Antigens; Viral Genes; Viral Pathogenesis; Virus; Virus Diseases; age group; attenuation; effectiveness evaluation; efficacy study; follow-up; immunogenic; immunogenicity; improved; infancy; lead candidate; maternal vaccination; mucosal site; parainfluenza virus; particle; passive immunoprophylaxis; pathogen; phase 1 study; phase I trial; preclinical development; preclinical study; prototype; recombinant virus; respiratory; response; reverse genetics; therapeutic candidate; vaccine candidate; vaccine evaluation; vaccine strategy; vector; vector vaccine; viral RNA; virology; volunteer

We are following two strategies to develop a live-attenuated pediatric RSV vaccine. (i) Our 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. To date, our clinical trials have focused on live-attenuated RSV strains. We will evaluate two PIV-vectored vaccines in the clinic in 2023. 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; two reports on delM2-2 candidates were recently published, RSV LID/delM2-2/1030s (NCT02794870 and NCT0252339) and D46/NS2/N/delM2-2-HindIII (NCT03099291 and NCT03102034). Among these candidates, LID/delM2-2/1030s emerged as the most promising virus. It is 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. In a Phase 1 study in 6-24 months-old RSV seronegative children, LID/delM2-2/1030s 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. Over the 2022 and 2023 fiscal years, a larger study to further evaluate the safety and immunogenicity of LID/delM2-2/1030s in RSV seronegative children has been ongoing. This study is now fully enrolled, and follow-up will continue through the early spring of 2024. A second lineage of RSV vaccine candidates contains a 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 vaccine is being evaluated in a Phase 1/2 study in a side-by-side comparison with a second delNS2-based vaccine candidate, RSV delNS2/1030s. This virus combines the delNS2 mutation with a stabilized missense mutation called 1030s that consists of Y1321K and S1313(TCA) mutations in the L polymerase. The 1030s mutation is somewhat less attenuating than the del1313/I1314L mutation, and therefore RSV delNS2/1030s should be less attenuated than RSV/delNS2/del1313/I1314L. The RSV delNS2/1030s and RSV/delNS2/del1313/I1314L 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 a 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 cDNA-derived version of the wildtype 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 response.

我们遵循两种策略来开发减毒活小儿RSV疫苗。(i)我们的主要策略是开发减毒活RSV毒株，减毒主要通过缺失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缺失突变来提供，并且已经使用反向遗传学针对减毒稳定。目前的目标是确定一个或两个主要候选人适合进一步发展为鼻内小儿RSV疫苗。(ii)第二种疫苗策略是使用减毒形式的PIV 3作为载体来表达RSV抗原（主要是融合F蛋白），其提供活的二价HPIV 3/RSV疫苗。这些PIV载体疫苗的临床前开发描述见随附报告“副流感病毒的实验室和临床前研究”。这两种疫苗策略都是根据与赛诺菲的合作研究和开发协议（CRADA）开发的。迄今为止，我们的临床试验主要集中在减毒活RSV毒株上。我们将在2023年在临床上评估两种PIV载体疫苗。 减毒活RSV疫苗候选物的一个谱系涉及编码小（90个氨基酸）病毒M2-2蛋白的ORF的缺失。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（导致病毒减毒）和病毒基因转录和抗原合成的整体上调。每个基因组抗原表达的增加提高了每个感染性颗粒免疫原性增加的可能性。 在过去几年中评价并报道了称为RSV MEDI/delM 2 -2和RSV LID/delM 2 -2的原型delM 2 -2候选物;最近发表了两份关于delM 2 -2候选物的报告，RSV LID/delM 2 -2/1030 s（NCT 02794870和NCT 0252339）和D46/NS 2/N/delM 2 -2-HindIII（NCT 03099291和NCT 03102034）。在这些候选者中，LID/delM 2 -2/1030 s成为最有希望的病毒。它通过M2-2的缺失，结合称为1030 s的稳定错义突变（由L聚合酶中的Y1321 K和S1313（TCA）突变组成）而减毒。在6-24月龄RSV血清阴性儿童中进行的1期研究中，LID/delM 2 -2/1030 s耐受性良好，具有优异的感染性而没有遗传不稳定性的证据，诱导持久的免疫力，并引发了对野生型RSV感染的强回忆抗体应答，使其成为进一步评价的有吸引力的候选物。在2022和2023财政年度，一项更大规模的研究正在进行中，以进一步评估LID/delM 2 -2/1030在RSV血清阴性儿童中的安全性和免疫原性。这项研究现已全部入组，随访将持续到2024年早春。 RSV疫苗候选物的第二谱系含有NS 2基因的缺失，其编码的蛋白质拮抗宿主对病毒感染的干扰素和细胞凋亡应答。候选RSV delNS 2/del 1313/I1314 L含有与称为del 1313/I1314 L的突变组合的delNS 2突变，所述突变包括L聚合酶中密码子1313的缺失加上针对减毒稳定的相邻错义突变I1314 L。该疫苗正在1/2期研究中与第二种基于delNS 2的候选疫苗RSV delNS 2/1030进行并行比较。该病毒将delNS 2突变与称为1030 s的稳定错义突变相结合，该错义突变由L聚合酶中的Y1321 K和S1313（TCA）突变组成。1030 s突变比dell 313/I1314 L突变的减毒性稍低，因此RSV delNS 2/1030 s的减毒性应低于RSV/delNS 2/dell 313/I1314 L。RSV delNS 2/1030 s和RSV/delNS 2/del 1313/I1314 L候选物目前正在血清阴性婴儿和幼儿的1/2期临床试验中进行头对头评价（NCT 03916185）。 RSV候选疫苗的第三谱系含有NS 1基因的缺失，其与NS 2一样编码拮抗宿主干扰素和细胞凋亡应答的蛋白质，但比NS 2更有效，因此可能赋予更减毒和免疫原性的表型。制备了两种病毒，其各自含有delNS 1缺失作为唯一的减毒元件，但在一种病毒中，F和G基因已被移动到第一和第二基因组位置以增加其表达（分别为RSV 6120/delNS 1和6120/F1 G2/delNS 1）。这些病毒目前正在1期临床试验（NCT 03596801）中进行头对头比较。 目前正在一项剂量递增研究（NCT 02484417）中，在健康成人志愿者中评价野生型RSV毒株A2的cDNA衍生版本。我们还正在评估最近的临床分离株RSV A/马里兰州/001/11，我们已开发了反向遗传系统，并在健康成人志愿者的I期试验中回收了重组病毒（NCT 03624790）。这些研究将提供一种感染模型，可用于评价RSV候选治疗药物和成人RSV候选疫苗，并研究病毒发病机制和宿主反应。

项目成果

Progress in the development of human parainfluenza virus vaccines.

• DOI: 10.1586/ers.11.32
• 发表时间: 2011-08
• 期刊: Expert review of respiratory medicine
• 影响因子: 3.9
• 作者: Schmidt AC;Schaap-Nutt A;Bartlett EJ;Schomacker H;Boonyaratanakornkit J;Karron RA;Collins PL
• 通讯作者: Collins PL

Live-attenuated respiratory syncytial virus vaccines.

活衰减的呼吸道合胞病毒疫苗。

• DOI: 10.1007/978-3-642-38919-1_13
• 发表时间: 2013
• 期刊: Current topics in microbiology and immunology
• 作者: Karron RA;Buchholz UJ;Collins PL
• 通讯作者: Collins PL

Pathogenesis of acute respiratory illness caused by human parainfluenza viruses.

• DOI: 10.1016/j.coviro.2012.02.001
• 发表时间: 2012-06
• 期刊: CURRENT OPINION IN VIROLOGY
• 影响因子: 5.9
• 作者: Schomacker, Henrick;Schaap-Nutt, Anne;Collins, Peter L.;Schmidt, Alexander C.
• 通讯作者: Schmidt, Alexander C.

Evaluation of a Live Attenuated Human Metapneumovirus Vaccine in Adults and Children.

• DOI: 10.1093/jpids/pix006
• 发表时间: 2018-02-19
• 期刊: Journal of the Pediatric Infectious Diseases Society
• 影响因子: 3.2
• 作者: Karron RA;San Mateo J;Wanionek K;Collins PL;Buchholz UJ
• 通讯作者: Buchholz UJ

WHO consultation on Respiratory Syncytial Virus Vaccine Development Report from a World Health Organization Meeting held on 23-24 March 2015.

• DOI: 10.1016/j.vaccine.2015.05.093
• 发表时间: 2016-01-04
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Modjarrad K;Giersing B;Kaslow DC;Smith PG;Moorthy VS;WHO RSV Vaccine Consultation Expert Group
• 通讯作者: WHO RSV Vaccine Consultation Expert Group