Development and testing of RSV vaccines using a computational framework of virus-host interaction

呼吸道合胞病毒（RSV）是全球儿童住院的第二大原因， 作为老年人住院和死亡的一个原因越来越受到重视。最近的研究表明 多价疫苗制剂，即来自不同病原体变体的抗原混合物， 我们假设多价抗原RSV疫苗 这些制剂将增加针对抗原之间保守区域的抗体。通过利用自然 RSV变异体之间存在的变异性，我们的目的是研究多价RSV G或F抗原 对免疫反应的影响。我们将测试抗体是否对保守区域增强 病毒蛋白质与多价制剂之间的关系。 目标1。使用ELISA测定多价RSV疫苗制剂对体液免疫的影响 计算机模拟。我们假设RSV多价疫苗制剂由不同的 G或F-蛋白抗原的组合将增加对免疫球蛋白之间的保守区域的抗体应答。 抗原我们将使用病毒/宿主的计算框架来评估不同的疫苗制剂， 相互作用（ssMod.v2）。我们将测试多价和单价之间抗体特异性的差异 在框架内制定。抗体交叉反应性和针对RSV攻击的保护也将被考虑。 评估。 目标2.小鼠中宿主对多价疫苗制剂的免疫应答的比较。我们 假设用包含多价抗原制剂mRNA-LNP疫苗免疫鼠 将诱导对抗原之间保守区域特异的抗体和免疫细胞。mRNA-LNP将 使用编码来自A2或B1 RSV的G或F的cap-1、密码子优化的、结构稳定的mRNA构建 变体，并将使用可电离的阳离子脂质包封。将用以下任一种免疫小鼠组 目标3：测试RSV多价疫苗制剂是否改善对RSV疾病的保护。我们 假设含有G或F抗原的多价混合物的疫苗制剂将增加 与单价制剂相比，使用不同的mRNA混合物- LNP，我们将测试多价疫苗的能力，以保护对疾病的严重程度，使用鼠模型， RSV攻毒。将使用原代人肺上皮细胞检测血清的中和抗体滴度。 细胞RSV-中和测定。将通过检测以下指标来比较单价和多价疫苗制剂： 感染和疾病严重程度结果之间的差异。

Respiratory Syncytial Virus (RSV) is the second leading cause of hospitalization in children worldwide and has been increasing appreciated as a cause of hospitalization and death in the elderly. Recent studies have shown that polyvalent vaccine formulations, mixture of antigens derived from distinct pathogen variants, can induce antibodies to regions conserved between those variants We hypothesize that polyvalent antigen RSV vaccine formulations will increase antibody to regions conserved between the antigens. By drawing on the natural variability that exists among RSV variants, we aim to study the effect that polyvalent RSV G or F antigen formulations have on the immune response. We will test if antibodies are enhanced towards regions conserved between the viral proteins with the polyvalent formulation. Aim 1. Determining the Effect of Polyvalent RSV Vaccine Formulations on Humoral Immunity using Computer Simulations. We hypothesize that RSV polyvalent vaccine formulations consisting of different combinations of G or F-protein antigens will increase the antibody response to conserved regions between the antigens. We will evaluate different vaccine formulations using a computational framework of virus/host- interaction (ssMod.v2). We will test for differences in antibody specificity between polyvalent and monovalent formulations in the framework. Antibody cross-reactivity and protection against RSV challenge will also be evaluated. Aim 2. Comparison of the Host Immune Response to Polyvalent Vaccine Formulations in Mice. We hypothesize that murine immunization with a mRNA-LNP vaccine comprising polyvalent antigen formulations will induce antibodies and immune cells specific to regions conserved between the antigens. mRNA-LNPs will be constructed using cap-1, codon-optimized, structure-stabilized mRNA, encoding G or F from A2 or B1 RSV variants and will be encapsulated using ionizable cationic lipids. Groups of mice will be immunized with either Aim 3. Test if RSV Polyvalent Vaccine Formulation Improves Protection from RSV Disease. We hypothesize that vaccine formulations containing polyvalent mixtures of G or F antigens will increase the extent of protection against RSV disease compared to monovalent formulations. Using different mixtures of mRNA- LNP, we will test the ability of polyvalent vaccines to protect against disease severity using a murine model of RSV challenge. The neutralizing antibody titer of the sera will be tested using a primary human lung epithelial cell RSV-neutralization assay. Monovalent and polyvalent vaccine formulations will be compared by testing for differences between infection and disease severity outcomes.