Immune Profiles as Markers of Safe and Protective RSV Vaccines

摘要 疾病严重程度的降低最有可能表明RSV疫苗对幼儿有效， 最优先的目标人群。然而，我们没有准确的标记物来客观地评估RSV疾病 严重程度，这使得对婴儿RSV疫苗的评估具有挑战性。通过应用一种系统 免疫学方法我们的目标是确定免疫图谱、血清抗体反应和RSV NS 轻度呼吸道合胞病毒感染婴儿中的变异，代表了理想的疫苗诱导模式 结果。根据我们的初步数据，我们假设强效干扰素(干扰素)和先天性免疫 部分与病毒NS1和/或NS2变种有关的反应，导致最佳的B细胞激活，抗体 反应(以核心C衡量)，并改善RSV感染婴儿的临床结果。身份识别 对自然RSV感染的“安全和保护性”简介将为选择候选疫苗提供信息(开发于 项目1、2、3)在棉鼠(核心B)中，应该会产生类似(或改善)的特征。此外，这些 在未来的疫苗试验中，原型配置文件将作为“安全和保护性”反应的替代标记 对本P01研制的RSV减毒活疫苗进行检测。我们将使用以下内容来验证我们的假设 具体目标：1)定义与轻度RSV感染相关的血液转录信号；2)定义 与急性和长期保护相关的特异性RSV抗体的数量和中和活性 3)确定与疾病最相关的RSV NS1和NS2基因单倍型 严肃性。

Abstract A reduction in disease severity is the most likely indicator that an RSV vaccine is effective in young infants, the highest priority target population. However, we don't have precise markers to objectively assess RSV disease severity, which has made the evaluation of RSV vaccines in infants challenging. By applying a systems immunology approach our goal is to define the immune profiles, serum antibody responses, and RSV NS variants in infants with mild RSV infection, who represent the ideal model of a desirable vaccine induced outcomes. Based on our preliminary data we hypothesize that robust interferon (IFN) and innate immune responses, related in part to viral NS1 and/or NS2 variants, result in optimal B-cell activation, antibody responses (measured in Core C), and improved clinical outcomes in RSV infected infants. Identification of the “safe and protective” profile to natural RSV infection will inform the selection of vaccine candidates (develop in Projects 1,2,3) in cotton rats (Core B) that should induce similar (or improved) profiles. In addition, these prototype profiles will serve as surrogate markers for the “safe and protective” response in future vaccine trials testing the live attenuated RSV vaccine developed in this P01. We will test our hypothesis with the following specific aims: 1) Define the blood transcriptional signatures that correlate with mild RSV infection; 2) Define quantity and neutralizing activity of specific RSV antibodies associated with acute and long-term protection from severe RSV infection; 3) Identify the RSV NS1 and NS2 gene haplotypes that best correlate with disease severity.