Clinical and Primate Paramyxovirus Vaccine Evaluation

这项研究的长期目标是生产针对儿童最常见的呼吸道副粘液病毒的有效疫苗：人类副流感病毒1型、3型和呼吸道合胞病毒(RSV)。尽管这些病毒具有重要的流行病学意义，但目前尚不存在有效的疫苗。 开发副粘病毒疫苗面临的挑战包括对安全性的担忧，以及引发持久和有效的体液和细胞免疫反应的必要性。小鼠副流感病毒(PIV)1型(仙台病毒)是一种很好的候选呼吸道病毒疫苗骨架，因为它在非人类灵长类动物研究中获得了对人PIV 1型(HPIVl1)的保护，并成功地进入了I期人类安全性试验。此外，重组仙台病毒已被证明能诱导针对交替靶标(RSV)的保护性免疫反应，从而使仙台病毒成为其他副粘病毒的疫苗载体。 本项目的具体目标集中在： 目的1：评估血清阳性和阴性儿童对鼻腔注射仙台病毒的耐受性。 目的：研究仙台病毒鼻腔感染成人和儿童受者的hPIV1特异性抗体应答。 目的3：确定重组SV疫苗是否能保护非人类灵长类动物免受呼吸道病毒的攻击，以期进行人体研究。 该项目研究Sendal病毒作为hPIV1的新候选疫苗和相关副粘病毒抗原的骨架，是该计划的基本组成部分，也是疫苗设计和评估的实验室和临床要素之间的重要桥梁。这项儿科研究(目标1)将确定血清阴性幼儿中鼻腔内SV的最高耐受量，这对于未来进行该单剂的安慰剂对照研究至关重要。在项目1和2中制备和表征的重组SV将在这里测试(目标3)在非人类灵长类动物中的安全性和保护，这是临床的重要前驱 学习。因此，该项目代表着所有项目工作的高潮，重点是为儿童最常见的呼吸道病毒开发有效的儿科疫苗。

The long term objective of this research is to produce effective vaccines against the most common respiratory paramxyoviruses of childhood: human parainfiuenza virus types 1, 3 and respiratory syncytial virus (RSV). Despite the epidemiologic importance of these viruses, effective vaccines do not exist. Challenges facing the development of paramyxovirus vaccines include concerns regarding safety and the need to elicit durable and effective humoral and cellular immune responses. The murine parainfluenza virus (PIV) type 1 (Sendai virus) is an excellent candidate respiratory virus vaccine backbone as it has elicited protection against human PIV type 1 (hPIVl1) in a non-human primate study and has successfully entered Phase I human safety trials. Additionally, recombinant Sendal virus has been shown to elicit protective immune responses against alternate targets (RSV), thus establishing Sendai virus as a vaccine vector for other Paramyxoviruses. Specific Aims in this Project are focused on: AIM 1: Evaluating the tolerability of increasing doses of intranasal Sendai virus among seropositive and then seronegative children. AIM 2: Characterizing hPIV1-specific antibody responses elicited by intranasal Sendai virus among adult and pediatric recipients. AIM 3: Determining whether recombinant SV vaccines can protect non-human primates from respiratory virus challenge, in anticipation of human studies. This project examining Sendal virus as a novel vaccine candidate for hPIV1 and as a backbone for related paramyxoviral antigens is a fundamental component of this Program and an essential bridge between the laboratory and clinical elements of vaccine design and evaluation. The pediatric study (Aim 1) will identify the highest tolerated dose of intranasal SV among seronegative toddlers, essential to conduct future placebocontrolled studies with this single dose. Recombinant SV prepared and characterized in Projects 1 and 2, will be tested here (Aim 3) for safety and protection in non-human primates, an essential precursor to clinical studies. Accordingly, this Project represents the culmination of work across all Projects, focused on developing effective pediatric vaccines for the most common respiratory viruses of childhood.