Intranasal Vaccine Against Lyme Disease

摘要 我们建议开发鼻内副流感病毒5型（PIV 5）病毒载体递送疫苗 使用初免-加强方案给药，用于美国 市场疾病预防控制中心最近对LD的新估计将新数字定为每年476，000人 病例，高于2015年的329，000例，这强烈表明受影响的美国人数量 这种病媒传播的疾病正在增加。目前还没有人类莱姆病疫苗 在市场上有售。鼻内免疫原的初免-加强疫苗接种是一种科学的 和技术上的进步，最好的疫苗接种协议的发展，LD，目前 依赖于1年内至少3剂的胃肠外接种。我们的初步研究 显示了鼻内施用由实验室递送修饰的OspA疫苗 菌株WR-PIV 5病毒载体（WR-PIV 5-OspABPBPk）通过初免-加强（2剂）产生 对蜱传播B具有100%保护性免疫应答。莱姆病感染 第一次给药后4个月激发的小鼠。PIV 5是一种安全的载体， 许多疫苗，其中一种正在进行人体临床试验。商业化 开发一种新型、安全有效的LD疫苗的潜在和社会影响， 通过非侵入性方法递送的药物是非常重要的，因为它可以诱导更持久的 免疫反应，它可以减少疫苗犹豫和增加疫苗的依从性， 能够自我施用一种或两种剂量。该疫苗的新奇， 这一直接进入第二阶段的SBIR应用涉及：1）使用改进的全长OspA 蛋白质，其中假定的自身抗原表位已被替换; 2）无针 在安全的、高免疫原性的病毒载体中的鼻内递送方法; 3）减少的 免疫接种; 4）易于施用;和5）增加免疫寿命的潜力。 我们建议在PIV 5疫苗的基础上开发一种新的表达OspABPBPk的病毒载体 菌株（CPI），并评价与WR-PIV 5- 初步结果显示ABPBPk;我们还将评估 在莱姆病的非人灵长类动物（NHP）模型中的最佳候选疫苗;最后，我们 将进行FDA研究性新药（IND）监管批准所需的研究。 一旦新型疫苗显示符合我们的研究中规定的预设性能标准， 里程碑（在小鼠和非人灵长类动物模型中>80%的疗效），它将被注册为 LymeMist™和该公司将实施一项将其商业化的计划。

ABSTRACT We propose to develop intranasal, parainfluenza 5 (PIV5) viral-vector delivered vaccines against human Lyme disease (LD) to be administered using a prime-boost schedule, for the US market. A recent new estimate of LD by the CDC places the new number at 476,000 annual cases, up from 329,000 in 2015 which strongly suggests that the number of Americans affected by this vector-borne disease is increasing. Currently, there is no human Lyme Disease vaccine available in the market. A prime-boost vaccination with an intranasal immunogen is a scientific and technologic advance over best vaccination protocols in development for LD that currently rely on parenteral inoculation of a minimum of 3 doses over 1 year. Our preliminary studies show that intranasal administration of a modified OspA vaccine delivered by the laboratory strain WR-PIV5 viral vector (WR-PIV5-OspABPBPk) via prime-boost (2 doses), produces an immune response that is 100% protective against tick transmitted B. burgdorferi infection in mice challenged 4 months after the 1st dose. PIV5 is a safe delivery vector used to develop many vaccines, one of which is undergoing a human clinical trial. The commercialization potential and societal impact of developing a novel, safe and efficacious LD vaccine that can be delivered by a non-invasive method is highly significant given that it may induce more durable immune responses, it could diminish vaccine hesitancy and increase vaccine compliance, and it could enable self-administration of one or both doses. The novelty of the vaccine proposed in this Direct to Phase II SBIR application relates to: 1) the use of a modified full length OspA protein in which the putative autoantigenic epitope has been replaced; 2) a needle-free intranasal delivery method in a safe, highly immunogenic viral vector; 3) the reduced number of immunizations; 4) ease of administration; and 5) the potential to increase immunity longevity. We propose to develop a new viral vector expressing OspABPBPk based on the PIV5 vaccine strain (CPI) and evaluate intranasal vaccine efficacy in mice as compared to the WR-PIV5- ABPBPk shown in preliminary results; we will also assess immunogenicity, safety and efficacy of the best vaccine candidate in the non-human primate (NHP) model of Lyme disease; last, we will perform studies required for Investigational New Drug (IND) regulatory approval by FDA. Once the novel vaccine is shown to meet pre-set performance criteria specified in our milestones (>80% efficacy in mice and non-human primate models), it will be trademarked as LymeMist™ and the company will implement a plan to commercialize it.