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

使用病毒-宿主相互作用的计算框架开发和测试 RSV 疫苗

• 批准号: 10426748
• 负责人: Christopher S Anderson
• 金额: $ 10.17万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-21 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426748
• 关键词: Antibodies; Antibody Response; Antibody Specificity; Antibody titer measurement; Antigens; B-Lymphocytes; Binding; Biological Assay; Blood group antigen f; Body Weight decreased; Cations; Cells; Cessation of life; Child; Clinical Trials; Codon Nucleotides; Computer Assisted; Computer Models; Computer Simulation; Development; Disease; Elderly; Encapsulated; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Evaluation; Failure; Formulation; Hospitalization; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunize; Immunology; In Vitro; Infection; Lipids; Lung; Membrane Proteins; Messenger RNA; Monitor; Mus; Outcome; Polyvalent Vaccine; Proteins; Recording of previous events; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Severity of illness; Site; Specificity; Structure; T-Lymphocyte; Testing; Time; Vaccine Design; Vaccines; Variant; Viral Proteins; Viral load measurement; Virus; Virus Diseases; adaptive immune response; antibody test; computer framework; cross reactivity; enzyme linked immunospot assay; improved; insight; lipid nanoparticle; lung histology; mouse model; neutralizing antibody; pathogen; pulmonary function; respiratory virus; simulation; vaccine development; vaccine formulation; virus host interaction

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.

呼吸道合胞病毒（RSV）是全球儿童住院的第二大主要原因， 作为老年人住院和死亡的原因，人们受到越来越多的赞赏。最近的研究表明 多价疫苗制剂，源自不同病原体变异的抗原的混合物可以诱导 这些变体之间保守区域的抗体，我们假设多价抗原RSV疫苗 制剂将增加对抗原之间保守区域的抗体。通过绘制自然 RSV变体之间存在的可变性，我们旨在研究多价RSV G或F抗原的效果 配方具有免疫反应。我们将测试抗体是否对保存区域增强 在具有多价配方的病毒蛋白之间。 目标1。确定多价RSV疫苗制剂对使用体液免疫的影响 计算机模拟。我们假设RSV多价疫苗制剂由不同 G或F蛋白抗原的组合将增加对对抗体的抗体反应 抗原。我们将使用病毒/宿主的计算框架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的抗体特异性差异 框架中的配方。抗体交叉反应性和针对RSV挑战的保护也将是 评估。 目标2。对小鼠多价疫苗制剂的宿主免疫反应的比较。我们 假设用包含多价抗原制剂的mRNA-LNP疫苗接种鼠免疫 将诱导对抗原之间保守区域的特异性抗体和免疫细胞。 mRNA-LNP会 可以使用CAP-1，优化，结构稳定的mRNA构建，编码A2或B1 RSV的G或F 变体将使用可离子阳离子脂质封装。一组小鼠将通过任何一种 AIM 3。测试RSV多价疫苗是否可以改善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配方将增加 与单价配方相比，针对RSV疾病的保护。使用mrna-的不同混合物 LNP，我们将使用使用的鼠模型来测试多价疫苗防止疾病严重程度的能力 RSV挑战。血清中和中和抗体滴度将使用原代人肺上皮进行测试 细胞RSV中和化测定。通过测试将对单价和多价疫苗制剂进行比较 感染与疾病严重性结果之间的差异。