Antigenicity and Immunogenicity of Stabilized prefusion F protein

RSV F糖蛋白是疫苗诱导的中和抗体的关键靶标。我们的假设是，通过定义F的结构和与中和相关的表位的结构，将有助于理解抗体中和的机制。这将允许新的抗原设计。表征F中的化学和翻译后修饰也将促进改进的疫苗抗原设计。 我们已经在1期临床试验VRC 317中测试了我们的稳定的融合前F蛋白的临床评价。 在这项试验中，我们正在评估我们的稳定的融合前F蛋白（DS-Cav 1）与或与明矾佐剂在健康成人中的安全性，耐受性和免疫原性。 我们已经评估了人类对单剂量DS-Cav 1的免疫应答，发现DS-Cav 1疫苗接种使中和活性增加7-15倍。 对抗体应答的分析表明，DS-Cav 1免疫引发了与融合前形式的蛋白质结合的抗体和与融合前和融合后构象结合的抗体。 由DS-Cav 1疫苗接种引起的中和活性高于由RSV感染引起的中和活性，并且比由F后或未确定的F结构引起的中和活性高2-5倍。 这项工作是基于结构的疫苗设计的临床概念验证。 除了中和抗体之外，在疫苗候选物中还需要诱导保护性的、疾病保留的CD 8 + T细胞应答。这些研究包括评价表达稳定的Pre-F蛋白或野生型F蛋白的基于基因和载体的疫苗与可溶性Pre-F蛋白的疫苗接种。我们还与合作者一起评估表达我们稳定的Pre-F蛋白的其他载体的免疫原性。

The RSV F glycoprotein is a key target for vaccine-induced neutralizing antibody. Our hypothesis is that understanding the mechanism of antibody neutralization will be facilitated by defining the structure of F and the structure of epitopes associated with neutralization. This will allow novel antigen design. Characterizing the chemistry and post-translational modifications in F will also promote improved vaccine antigen design. We have tested our stabilized prefusion F protein into clinical evaluation in a Phase 1 clinical trial, VRC 317. In this trial, we are evaluating safety, tolerability, and immunogenicity of our stabilized prefusion F protein (DS-Cav1) with or with alum adjuvant in healthy adults. We have assessed the immune response to a single dose of DS-Cav1 in humans and found that DS-Cav1 vaccination elicits a 7-15-fold increase in neutralizing activity. Dissection of the antibody response showed that DS-Cav1 immunization elicited both antibodies that bind to the prefusion form of the protein and antibodies that bind to both the prefusion and postfusion conformation. The neutralizing activity elicited by DS-Cav1 vaccination is higher than that elicited by RSV infection, and 2-5 fold higher than neutralizing activity elicited by post-F or non-determined F structure. This work serves as a clinical proof-of-concept for structure-based vaccine design. In addition to neutralizing antibodies, the induction of both protective, disease-sparing CD8+ T cell responses are desirable in a vaccine candidate. These studies include evaluation of gene and vector-based vaccines expressing either the stabilized Pre-F protein or the wildtype F protein to vaccination with soluble Pre-F protein. We are also working with collaborators to assess immunogenicity of other vectors expressing our stabilized Pre-F protein.