Clinical and Primate Paramyxovirus Vaccine Evaluation

本研究的长期目标是生产针对儿童最常见的呼吸道副病毒的有效疫苗：人副流感病毒1型、3型和呼吸道合胞病毒（RSV）。尽管这些病毒的流行病学重要性，有效的疫苗并不存在。 副粘病毒疫苗开发面临的挑战包括安全性问题以及引发持久有效的体液和细胞免疫应答的需要。鼠副流感病毒（PIV）1型（仙台病毒）是一种优秀的候选呼吸道病毒疫苗骨架，因为它在非人灵长类动物研究中引起了对人PIV 1型（hPIVl 1）的保护，并已成功进入I期人体安全性试验。此外，重组仙台病毒已被证明可以引发针对替代靶标（RSV）的保护性免疫应答，从而确立仙台病毒作为其他副粘病毒的疫苗载体。 该项目的具体目标侧重于： 目的1：评价增加剂量鼻内仙台病毒血清阳性，然后血清阴性儿童的耐受性。 目的2：描述鼻内仙台病毒在成人和儿童受者中引起的hPIV1特异性抗体应答。 目的3：确定重组SV疫苗是否可以保护非人灵长类动物免受呼吸道病毒的攻击，在预期的人类研究。 该项目将仙台病毒作为hPPV 1的新型候选疫苗以及相关副粘病毒抗原的骨架进行研究，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。儿科研究（目的1）将确定血清阴性幼儿中鼻内SV的最高耐受剂量，这对于将来使用该单次给药进行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将在此（目的3）测试在非人灵长类动物中的安全性和保护性，这是临床试验的重要前体。 问题研究因此，该项目代表了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.