Modeling Mechanisms of Adjuvanted Influenza Vaccine Induced IgG Repertoire Diversity and Heterosubtypic Immunity

佐剂流感疫苗诱导 IgG 库多样性和异亚型免疫的建模机制

• 批准号: 10092077
• 负责人: Ollivier Hyrien
• 金额: $ 67.58万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092077
• 关键词: Address; Adjuvant; Affinity; Age-Years; Antibodies; Antibody Affinity; Antibody Diversity; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Biological Assay; Clone Cells; Complementarity Determining Regions; Cytoprotection; DNA; DNA Sequence; DNA Sequence Alteration; Data; Development; Epithelial Cells; Evolution; FDA approved; Family; Ferrets; Frequencies; Generations; Genomics; Germ-Line Mutation; Goals; Heavy-Chain Immunoglobulins; Hemagglutinin; Human; Human Volunteers; Immune; Immune response; Immune system; Immunity; Immunization; Immunize; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Immunoglobulins; In Vitro; Individual; Infection prevention; Influenza; Influenza Hemagglutinin; Influenza vaccination; International; Intramuscular; Light; Lymphocyte; MF59; Measures; Mediating; Methods; Modeling; Molecular; Mus; Mutation; Oils; Peptide Sequence Determination; Phylogenetic Analysis; Phylogeny; Plasmablast; Process; Production; Proteins; Public Health; Publishing; Reaction; Serum; Sialic Acids; Site; Somatic Mutation; Source; Structure of germinal center of lymph node; Surface; Surface Plasmon Resonance; Testing; Trees; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccine Production; Vaccines; Viral; Virus; Virus Diseases; Work; age related; anti-IgG; anti-influenza; base; cross reactivity; cytokine; flu; human old age (65+); human subject; in vivo; influenza infection; influenza virus strain; influenza virus vaccine; influenzavirus; insight; lymph nodes; mathematical model; molecular modeling; novel vaccines; pandemic disease; prevent; reconstruction; recruit; seasonal influenza; success; transcriptome sequencing; vaccination strategy; vaccine response; vaccine-induced antibodies

Annual immunization against influenza infection is one of the largest coordinated international public health efforts. Current flu vaccination strategies primarily elicit protection by the generating long lasting type-specific neutralizing IgG anti-hemagglutinin (HA) antibodies that bind to molecularly similar influenza subtypes. This phenomenon is termed antibody mediated heterosubtypic immunity (amHSI), and a major reason for the success of seasonal influenza vaccination. MF59 is a squaline-oil adjuvant recently approved for seasonal influenza vaccination in indivduals ≥65 years of age. Our preliminary data suggests that MF59 increases amHSI in mice, ferrets and human subjects. Thus the primary goal of this Project is to elucidate and model the mechanisms of by which MF59 adjuvanted seasonal influenza vaccine increase B cell mediated amHSI at the immunoglobulin heavy chain DNA and protein repertoire level. Aim 1: To test the hypothesis that MF59 adjuvant increases the breadth, depth and molecular sequence diversity in the IgG repertoire after influenza vaccination. Aim 2: To build and validate an age-dependent branching process model of heterosubtypic immunity coverage induced by adjuvanted influenza vaccine. Aim 3: To model and identify the mechanisms responsible for MF59 adjuvanted influenza vaccine induced anti-HA IgG repertoire evolution and amHSI generation in human vaccine recipients. This proposal addresses a highly significant issue in public health, how to optimize the protection of the influenza vaccine using vaccine adjuvants to increase the cross-strain reactivity of the resulting mixture of IgG anti-HA antibodies. It also addresses a significant gap in scientific methods for reconstructing Ig sequence lineages resulting from hyperaccellerated somatic mutation within germinal center reactions. We will create age dependent branching process models that will provide mechanistic insight into how the adjuvant and intradermal vaccination alter the molecular diversity of antibody-mediated HSI. These models will be first developed using mice vaccinated with MF59 adjuvanted influenza vaccine in Aim 1, and then extended to human subjects in Aim 2. If successful, this work will provide a general framework for modeling the molecular processes involved in the generation of amHSI.

预防流感感染的年度免疫接种是最大的国际公共卫生协调之一

项目成果

Highly Accurate and Robust Absolute Quantification of Target Proteins in Formalin-Fixed Paraffin-Embedded (FFPE) Tissues by LC-MS.

• DOI: 10.1021/acs.analchem.2c03473
• 发表时间: 2023-01-17
• 期刊: ANALYTICAL CHEMISTRY
• 影响因子: 7.4
• 作者: Pu, Jie;Xue, Chao;Huo, Shihan;Shen, Qingqing;Qu, Yang;Yang, Xinxin;An, Bo;Angel, Thomas E.;Chen, Zhuo;Mehl, John T.;Tang, Huaping;Yang, Eric;Sikorski, Timothy W.;Qu, Jun
• 通讯作者: Qu, Jun

A Multiplex Microsphere IgG Assay for SARS-CoV-2 Using ACE2-Mediated Inhibition as a Surrogate for Neutralization.

使用ACE2介导的抑制作用作为中和替代的SARS-COV-2的多重微球IgG分析。

• DOI: 10.1128/jcm.02489-20
• 发表时间: 2021-01-21
• 期刊: Journal of clinical microbiology
• 影响因子: 9.4
• 作者: Cameron A;Porterfield CA;Byron LD;Wang J;Pearson Z;Bohrhunter JL;Cardillo AB;Ryan-Muntz L;Sorensen RA;Caserta MT;Angeloni S;Hardy DJ;Zand MS;Pecora ND
• 通讯作者: Pecora ND

Continuous Readout versus Titer-Based Assays of Influenza Vaccine Trials: Sensitivity, Specificity, and False Discovery Rates.

流感疫苗试验的连续读数与基于滴度的测定：敏感性、特异性和错误发现率。

• DOI: 10.1155/2019/9287120
• 发表时间: 2019
• 期刊: Computational and mathematical methods in medicine
• 作者: Li,Dongmei;Wang,Jiong;Garigen,Jessica;Treanor,JohnJ;Zand,MartinS
• 通讯作者: Zand,MartinS

Highly Reproducible Quantitative Proteomics Analysis of Pancreatic Cancer Cells Reveals Proteome-Level Effects of a Novel Combination Drug Therapy That Induces Cancer Cell Death via Metabolic Remodeling and Activation of the Extrinsic Apoptosis Pathway.

• DOI: 10.1021/acs.jproteome.3c00463
• 发表时间: 2023-10
• 期刊: Journal of proteome research
• 影响因子: 4.4
• 作者: Sailee Rasam;Q. Lin;S. Shen;R. Straubinger;Jun Qu

Broad Cross-Reactive IgA and IgG against Human Coronaviruses in Milk Induced by COVID-19 Vaccination and Infection.

• DOI: 10.3390/vaccines10060980
• 发表时间: 2022-06-20
• 期刊: VACCINES
• 影响因子: 7.8
• 作者: Wang, Jiong;Young, Bridget E.;Li, Dongmei;Seppo, Antti;Zhou, Qian;Wiltse, Alexander;Nowak-Wegrzyn, Anna;Murphy, Katherine;Widrick, Kaili;Diaz, Nicole;Cruz-Vasquez, Joseline;M. Jarvinen, Kirsi;Zand, Martin S.
• 通讯作者: Zand, Martin S.