Rapid Manufacturing of a Universal Flu Vaccine Using TMV-conjugated Centralized Antigens

使用 TMV 结合的集中抗原快速生产通用流感疫苗

基本信息

批准号：
10633131
负责人：
Alison Anne McCormick
金额：
$ 66.18万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633131
关键词：
Affect Antibody-mediated protection Antigens Biotechnology Cellular Immunity Centers for Disease Control and Prevention (U.S.)Characteristics Clinical Trials Computing Methodologies Consensus Consensus Sequence Data Development Discipline Disease Progression Disease model Dose Ferrets Fluzone Foundations Future Genes Goals Human Humoral Immunities Immune Immune response Immunity Immunization Immunologics Inactivated Vaccines Influenza Influenza A Virus, H3N2 Subtype Influenza A virus Intramuscular Kentucky Methods Modeling Mus Pathogenicity Peptide Vaccines Peptides Persons Plants Plasmid Cloning Vector Production Proteins Public Health Recombinants Research Route Safety Schedule Series Speed Subunit Vaccines Surface System Technology Testing Tobacco Mosaic Virus Tobacco use Translating United States National Institutes of Health Vaccination Vaccine Production Vaccines Variant Virus Work World Health Organization age group anti-influenza bioprocess chemical conjugate combat comparative efficacy cross reactivity design experimental study immunogenicity improved infection rate influenza infection influenza outbreak influenza virus strain influenza virus vaccine influenzavirus innovation interdisciplinary approach manufacture meetings mouse model novel pandemic disease pandemic influenza pathogen practical application pre-clinical protein expression protein purification rational design research clinical testing scale up seasonal influenza translational potential universal influenza vaccine universal vaccine vaccine candidate vaccine efficacy vaccine formulation

项目摘要

Project Abstract This interdisciplinary proposal brings together three highly successful but independent technologies to create an effective and broadly neutralizing universal influenza vaccine. Our approach combines breath of immunity, by using a consensus HA strategy, production speed and capacity by working with Kentucky BioProcessing (KBP), who can express HA protein in plants, and vastly improved subunit vaccine potency using a TMV-HA conjugation approach to create a candidate universal influenza virus vaccine. Based on our preclinical data on three influenza A strains, we expect our approach will drive long term immunity that is balanced between antibody and cellular immunity, providing potential for overlapping mechanisms of immune protection. We bring together a strong team of different disciplines with a combined goal to quickly show proof of concept with H1, H3, H5, and M2e antigens. Our Specific Aims are as follows: 1) Production of TMV-HA conjugates of centralized H1, H3, H5 genes and M2e peptide, 2) Immune response analysis, murine challenge studies and 3) Translational and ferret studies of TMV-HAc and TMV-M2e vaccines. Dr. Weaver has developed a computational method to express an ancestral sequence of HA, representing a consensus of sequences within an Influenza subtype. These vaccines protect against drifted seasonal influenza variants better than a traditional trivalent inactivated virus vaccine. In partnership with KBP, we will use established plant expression methods to produce centralized HA proteins, with the capacity to produce protein for the planned studies and for future clinical trial development. HA consensus protein will be fused to the surface of Tobacco Mosaic virus (TMV) by chemical conjugation, a method developed by Dr. McCormick to improve HA subunit vaccine potency. TMV-HA vaccines will also be combined with a highly conserved M2e peptide vaccine, to broaden protection and reduce vaccine dose. Immunological analysis will be used to confirm vaccine potency, in order to optimize dose, schedule and route of administration. Vaccine efficacy and broadly protective immunity will be confirmed by lethal influenza challenge using 9 divergent virus types in a murine model of disease. Finally, vaccine formulations will be re-tested in ferrets, a models of influenza infection which more closely mimics the progress of disease in humans. Our vaccine is designed to drive local and systemic immunity after either intranasal or intramuscular routes of administration, and we will use immunogenicity and pathogen challenge data to define an optimized single dose vaccine formulation. Our goal is to generate an effective universal vaccine against influenza that can be manufactured at scale, with significant potential for translation into a universal vaccine product that is ready for clinical testing.

项目摘要这个跨学科的提案汇集了三种非常成功但独立的技术来创造一种有效且广泛中和的通用流感疫苗。我们的方法结合了免疫力的呼吸，通过使用共识 HA 策略、生产速度和产能与 Kentucky BioProcessing 合作 (KBP)，可以在植物中表达 HA 蛋白，并使用 TMV-HA 大大提高了亚单位疫苗的效力结合方法创建候选通用流感病毒疫苗。根据我们的临床前数据三种甲型流感毒株，我们预计我们的方法将推动长期免疫，在三种甲型流感毒株之间取得平衡抗体和细胞免疫，提供了免疫保护重叠机制的潜力。我们汇集不同学科的强大团队，共同目标是快速展示概念验证 H1、H3、H5 和 M2e 抗原。我们的具体目标如下： 1) 生产 TMV-HA 缀合物集中的 H1、H3、H5 基因和 M2e 肽，2) 免疫反应分析、小鼠攻击研究和 3) TMV-HAc 和 TMV-M2e 疫苗的转化和雪貂研究。韦弗博士开发了一种表达 HA 祖先序列的计算方法，代表内部序列的共识流感亚型。这些疫苗比流感疫苗更好地预防季节性流感变异。传统的三价灭活病毒疫苗。与 KBP 合作，我们将使用已建立的植物表达生产集中HA蛋白的方法，具有生产用于计划研究的蛋白质的能力，以及以供未来临床试验开发。 HA共有蛋白将融合到烟草花叶病毒的表面 (TMV) 通过化学缀合，麦考密克博士开发的一种改进 HA 亚单位疫苗的方法效力。 TMV-HA 疫苗还将与高度保守的 M2e 肽疫苗结合使用，以拓宽保护并减少疫苗剂量。将使用免疫学分析来确认疫苗的效力，以便优化剂量、时间表和给药途径。疫苗功效和广泛的保护性免疫力将通过在小鼠疾病模型中使用 9 种不同病毒类型的致命流感攻击来证实。最后，疫苗配方将在雪貂身上进行重新测试，雪貂是一种更接近于模拟流感病毒感染的模型人类疾病的进展。我们的疫苗旨在在以下任一情况后驱动局部和全身免疫：鼻内或肌内给药途径，我们将利用免疫原性和病原体攻击数据来定义优化的单剂量疫苗配方。我们的目标是建立一个有效的通用可以大规模生产的流感疫苗，具有转化为疫苗的巨大潜力准备进行临床测试的通用疫苗产品。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adenoviral-Vectored Centralized Consensus Hemagglutinin Vaccine Provides Broad Protection against H2 Influenza a Virus.

DOI：
10.3390/vaccines10060926
发表时间：
2022-06-10
期刊：
VACCINES
影响因子：
7.8
作者：
Petro-Turnquist, Erika M.;Bullard, Brianna L.;Pekarek, Matthew J.;Weaver, Eric A.
通讯作者：
Weaver, Eric A.

Adenoviral-vectored epigraph vaccine elicits robust, durable, and protective immunity against H3 influenza A virus in swine.