Development of live attenuated respiratory syncytial virus vaccines with novel thermal stable fusion protein

呼吸道合胞病毒（RSV）可导致其他健康儿童的下呼吸道疾病（LRI） 开发一种有效的预防性疫苗来减轻婴儿RSV疾病是一个公共和全球性的问题。 根据世界卫生组织的健康优先。该项目的总体目标是开发一个安全的 和有效的RSV疫苗，用于免疫血清阴性的4个月至2岁的婴儿，他们超过了 保护性RSV母体抗体的覆盖范围，以防止RSV住院治疗和医疗护理的LRI。 在全球范围内，每年有3400万例新的RSV感染，其中340万例住院治疗，66，000例 199，000人死亡尽管大多数人在出生后的第一年就被感染， 在生活中。据估计，在美国，200万5岁以下儿童需要RSV护理 每年有78%的人感染，78%的人超过一岁。在美国，管理RSV疾病的医疗费用 估计每年婴儿的死亡率为11.5亿美元，估计额外的收入损失和护理费用为 每年6.25亿元。用对以下疾病有50%有效性和保护性的RSV疫苗接种出生队列 据估计，12个月将减少2.36亿美元的医疗费用，减少1.34亿美元的收入和生产力损失 每年在美国。 减毒活RSV疫苗模拟天然RSV感染。RSV流行病学和自然史 研究已经证明自然感染导致对严重RSV疾病的持久保护。的 摩尔实验室最近发表了一种候选疫苗，这种疫苗经过独特的工程改造，可以像野生型一样复制 病毒在受感染的细胞中传播，但由于毒力基因的下调，其传播能力较低。的 减毒表型是稳定的，因为它由RSV基因组中的数百个突变赋予。的 另一个区别性特征是一种专有的融合蛋白，其富含免疫原性更强的前体， 融合构象这些特性的结合导致了棉鼠高水平的衰减 具有几乎wtRSV水平的中和抗体和对wtRSV攻击的完全保护， 一种很有前途的候选疫苗用于临床开发。 在第1阶段，目标是产生两种减毒活RSV疫苗的研究储备 名为OE4和DB1Quad的候选人，并建立一个可以转移到cGMP的预种子过程 启动疫苗生产的设施。在第2阶段，我们将评估OE4和DB1Quad的衰减， 人气道上皮细胞离体和棉鼠体内，并在棉鼠中进行研究以证实 它们不引起RSV疫苗增强的疾病。这些研究的结果将使Meissa完成 IND使药理学研究，并优先考虑临床开发的主要候选人。

Respiratory syncytial virus (RSV) can cause lower respiratory illness (LRI) in otherwise healthy children and developing an effective prophylactic vaccine to mitigate RSV disease in infants is a public and global health priority according to the World Health Organization. The overall goal of this project is to develop a safe and efficacious RSV vaccine for immunizing sero-negative 4 months to 2 years old infants, who are beyond the reach of protective RSV maternal antibodies, against RSV hospitalizations and medically attended LRI. Globally, there are 34 million new RSV infections annually with 3.4 million hospitalizations and 66,000 to 199,000 deaths. Although most people are infected in the first year of life, recurring RSV infections occur throughout life. It was estimated that in the US, 2 million children under the age of 5 required care for RSV infections annually and 78% are over the age of one year. In the US, medical costs for managing RSV disease in infants were estimated at $1.15 billion annually with additional lost income and caregiver costs estimated at $625 million annually. Vaccinating the birth cohort with a RSV vaccine that has 50% efficacy and protection for 12 months was estimated to reduce medical costs by $236 million and income and productivity losses by $134 million annually in the US. A live attenuated RSV vaccine mimics natural RSV infection. RSV epidemiology and natural history studies have demonstrated that natural infection results in lasting protection against severe RSV disease. The Moore lab recently published on a vaccine candidate that was uniquely engineered to replicate like wild-type virus in infected cells and yet is less able to spread because of the down-regulation of virulence genes. The attenuation phenotype is stable because it is conferred by hundreds of mutations in the RSV genome. The other distinguishing characteristic is a proprietary fusion protein that is enriched for the more immunogenic pre- fusion conformation. The combination of these properties resulted in high levels of attenuation in cotton rats with almost wtRSV level neutralizing antibodies and complete protection against wtRSV challenge making this a promising vaccine candidate for clinical development. In Phase 1 the objectives are to generate research stocks of two live attenuated RSV vaccine candidates called OE4 and DB1Quad and establish a pre-seed process that can be transferred to a cGMP facility for initiation of vaccine production. In Phase 2, we will evaluate attenuation of OE4 and DB1Quad in human airway epithelial cells ex vivo and in cotton rats in vivo and perform studies in cotton rats to verify that they do not cause RSV vaccine-enhanced disease. The outcome of these studies will allow Meissa complete IND-enabling pharmacology studies and to prioritize a lead candidate for clinical development.