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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

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.