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: 10549828
• 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/10549828
• 关键词: Antibodies; Antibody Response; Antibody Specificity; Antibody titer measurement; Antigens; B-Lymphocytes; Binding; Biological Assay; Blood group antigen f; Body Weight decreased; 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原因