Development of VLP vaccine for RSV

RSV VLP 疫苗的开发

• 批准号: 9897525
• 负责人: JORGE C BLANCO
• 金额: $ 100万
• 依托单位: SIGMOVIR BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897525
• 关键词: Acute; Age; Animals; Antibodies; Antibody Response; Antibody titer measurement; Baculoviruses; Cell Line; Child; Clinical Trials; Complication; Cotton Rats; Data; Developing Countries; Development; Disease; Dose; Drops; Effectiveness; FDA approved; Family member; Fetus; GTP-Binding Proteins; Goals; Hospitalization; Human; Immune response; Immune system; Immunity; Immunization; Immunize; Infant; Infection; Life; Lung; Maternal antibody; Measures; Methods; Mothers; Pathology; Phase; Placenta; Plasmids; Population; Pregnancy; Process; Production; Proteins; Protocols documentation; Publishing; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Tract Infections; Respiratory syncytial virus; Role; Safety; Small Business Technology Transfer Research; Testing; Time; Transfection; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccine Production; Vaccines; Virus; Virus-like particle; Vulnerable Populations; cost effective; experience; human model; human pathogen; improved; in utero; large scale production; maternal vaccination; mortality; neonatal infection; neonate; neutralizing antibody; novel; novel virus; offspring; preclinical development; pregnant; protective effect; protocol development; pup; respiratory; response; sex; vaccine candidate; vaccine efficacy; vaccine safety; vector; viral transmission; virus development

Respiratory syncytial virus (RSV) is a significant human pathogen severely impacting neonates and young children, but no vaccine exists to protect this vulnerable population. Furthermore, direct vaccination of neonates is likely ineffective due to the immaturity of their immune system, and neonate immunization is potentially unsafe. The current view is that maternal vaccination is the best and safest approach to protection of neonates through the passive transfer of maternal neutralizing antibodies in utero to the fetus after maternal immunization. However, a complicating issue is that most people have experienced RSV infections during their lifetimes. Thus, any maternal vaccine must induce high levels of protective antibodies in the presence of pre-existing, but very poorly neutralizing, anti-RSV antibodies. In our STTR phase IIa project, we tested our novel RSV VLP vaccine candidates in pregnant cotton rats, a surrogate human model, to determine the effect of prior RSV exposure on induction of protective immune responses in these animals and to assess maternal antibody transfer, protection, and safety in offspring of the immunized dams. Our results showed that a single VLP immunization of RSV primed cotton rats stimulated high titers of NA. Furthermore, VLP immunization of dams protected their offspring from RSV challenge and decreased pathology in pups' lungs compared to pathology observed after RSV infection of offspring of unimmunized dams. We also found that maternal immunizations with VLPs containing different versions of the pre-fusion F protein varied significantly in the extent of protection of offspring of vaccinated dams. We identified one version of pre-fusion F VLPs that improved protection of offspring ten-fold compared to the originally tested pre-F VLP. It is our goal to move our VLP vaccine candidates toward clinical trials as a maternal vaccine. To this end, we propose three specific tasks using cotton rats as human surrogates. Task 1: Develop protocols and processes for production and purification of cost effective GMP VLP vaccine candidates on a large scale. Task 2: Refine parameters of protection of neonates after maternal immunization. Task 3: Assess and improve protective responses in mothers post-delivery.

呼吸道合胞病毒（RSV）是一种严重的人类病原体 影响新生儿和幼儿，但没有疫苗可以保护这一弱势群体 人口。此外，直接给新生儿接种疫苗可能无效，因为 他们的免疫系统不成熟，新生儿免疫接种可能不安全。这 目前的观点是，孕产妇接种疫苗是最好、最安全的保护方法。 新生儿通过母体中和抗体在子宫内被动转移到子宫 母亲免疫后的胎儿。然而，一个复杂的问题是，大多数人 一生中经历过 RSV 感染。因此，任何母体疫苗 必须在预先存在但非常严重的情况下诱导高水平的保护性抗体 中和性较差的抗 RSV 抗体。 在我们的 STTR IIa 期项目中，我们测试了新型 RSV VLP 候选疫苗 在怀孕棉鼠（一种替代人类模型）中，以确定先前 RSV 的效果 暴露在这些动物中诱导保护性免疫反应并评估 免疫母鼠后代的母源抗体转移、保护和安全。 我们的结果表明，RSV 引发的棉鼠的单次 VLP 免疫刺激 高滴度 NA。此外，母鼠的 VLP 免疫可以保护它们的后代免受感染 与病理相比，RSV 攻击和幼犬肺部病理减少 未免疫母鼠的后代感染 RSV 后观察到的结果。我们还发现 使用含有不同版本融合前 F 的 VLP 进行母体免疫 蛋白质对接种疫苗的母鼠后代的保护程度存在显着差异。我们 确定了融合前 F VLP 的一种版本，可将后代的保护提高十倍 与最初测试的 pre-F VLP 相比。 我们的目标是将我们的 VLP 候选疫苗作为 母体疫苗。为此，我们提出了利用棉鼠作为三项具体任务 人类代理人。 任务 1：制定生产和净化成本的协议和流程 大规模有效的 GMP VLP 候选疫苗。 任务 2：完善孕产妇免疫后新生儿保护参数。 任务 3：评估和改善母亲产后的保护反应。