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， 越来越多的人认识到这是老年人住院和死亡的一个原因。最近的研究表明 多价疫苗配方，来自不同病原体变种的抗原混合物，可以诱导 针对这些变异体之间保守区域的抗体我们假设多价抗原RSV疫苗 配方将增加对抗原之间保守区域的抗体。通过利用自然的 存在于RSV变种之间的变异性，我们的目的是研究多价RSV G或F抗原 配方对免疫反应有影响。我们将测试抗体是否向保守区域增强 病毒蛋白与多价配方之间的关系。 目的1.确定多价RSV疫苗制剂对体液免疫的影响 计算机模拟。我们假设RSV多价疫苗配方由不同的 G蛋白或F蛋白抗原的结合将增强对 抗原。我们将使用病毒/宿主的计算框架来评估不同的疫苗配方- 交互(ssmod.v2)。我们将测试多价和单价抗体特异性的差异。 框架中的配方。抗体的交叉反应和对RSV挑战的保护也将是 已评估。 目的2.比较小鼠对多价疫苗制剂的宿主免疫应答。我们 假设用含有多价抗原制剂的mRNA-LNP疫苗免疫小鼠 将诱导针对抗原之间保守区域的抗体和免疫细胞。MRNA-LNPs将 使用CAP-1、密码子优化、结构稳定的mRNA构建，编码A2或B1 RSV的G或F 并将使用可电离阳离子脂类进行封装。多组小鼠将用其中一种方法免疫 目的3.测试RSV多价疫苗配方是否能提高对RSV疾病的保护作用。我们 假设含有多价G或F抗原混合物的疫苗配方会增加这种程度 与单价制剂相比，它对预防RSV疾病的保护作用更强。使用不同的mRNA混合物- LNP，我们将使用小鼠模型测试多价疫苗预防疾病严重程度的能力。 RSV挑战赛。血清的中和抗体效价将用原代人肺上皮细胞进行测试。 细胞RSV中和试验。单价和多价疫苗配方将通过测试 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.