Universal epitopes-based recombinant influenza vaccines

基于通用表位的重组流感疫苗

• 批准号: 9979495
• 负责人: SANG-MOO KANG
• 金额: $ 19.39万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979495
• 关键词: Active Sites; Affinity; Amino Acids; Antibodies; Antigens; Antiviral Agents; Attenuated; Cell fusion; Chickens; Clinical Trials; Collaborations; Data; Development; Drug Targeting; Epidemic; Epitopes; Exhibits; Extracellular Domain; Ferrets; Flu virus; Glycoproteins; Hemagglutinin; Immune; Immune response; Immunity; Immunization; Immunoglobulin G; Inactivated Vaccines; Influenza; Influenza A virus; Influenza A virus M2 protein; Influenza B Virus; Influenza vaccination; Membrane Fusion; Monoclonal Antibodies; Morbidity - disease rate; Mus; Neuraminidase; Peptides; Proteins; Public Health; Recombinants; Role; Tandem Repeat Sequences; Testing; Vaccination; Vaccine Design; Vaccines; Viral Hemagglutinins; Virus; Virus-like particle; base; cross reactivity; flu; follow-up; immunogenic; immunogenicity; improved; influenza virus vaccine; influenzavirus; mortality; novel strategies; novel virus; pandemic disease; peptide based vaccine; polyclonal antibody; preclinical study; protein aminoacid sequence; recombinant virus; stem; universal influenza vaccine; universal vaccine; vaccine candidate; vaccine-induced immunity

PROJECT SUMMARY Current influenza vaccination inducing strain-specific immunity against variable hemagglutinin (HA) proteins is not effective in providing cross protection against antigenically different epidemic strains and unanticipated new pandemic viruses. Development of universal vaccines improving cross protection against antigenically different influenza viruses is a high priority. The fusion peptide (FP) located in the N-terminus of the stalk domain of HA is universally conserved in both influenza (flu) A and B viruses. Monoclonal and polyclonal antibodies against FP were shown to exhibit broad neutralizing activity. In preliminary data, we discovered a new HA2 stem domain near to the FP, which could generate poly IgG antibodies highly cross reactive to different subtype flu A viruses and both lineage flu B viruses. A neuraminidase (NA) epitope (NA2e) near to the enzymatic active site was also identified to be universally conserved in all flu A and B viruses. NA2e specific monoclonal antibody was used to quantitate the NA contents in different flu vaccine lots. NA immunity is considered an independent protective correlate in addition to HA. Influenza A virus M2 protein extracellular domain (M2e), which is highly conserved among flu A viruses, has been shown to be a promising target for developing universal flu A vaccines. However, M2e immunity alone would not provide sufficiently high efficacy of cross protection. No vaccines incorporating universally conserved multi epitopes including M2e, FP, stem domains and NA2e have been developed. Virus-like particle (VLP) platform has been demonstrated to be a promising delivery vehicle for poor immunogenic but cross protective epitopes. Preliminary data showed that NA2e monoclonal antibody was able to provide protection after passive inoculation. We hypothesize that new VLP vaccine constructs inducing antibodies to universal FP-stem domain epitopes and NA2e epitopes in addition to M2e will enhance the efficacy of cross protection against different strains of flu A and B viruses. In the aim 1, we will determine whether new recombinant VLP vaccine constructs containing FP-stem, NA2e (or NA), and M2e epitopes as a standalone vaccine or in combination with HA-based vaccine will enhance the cross protection against influenza A viruses. In the aim 2, we will determine whether vaccines inducing antibodies to FP-stem and NA2e epitopes as a standalone vaccine or when supplemented in inactivated virus vaccines will enhance cross protection against influenza B viruses. This proof-of-concept of two-year project on developing cross protective vaccines inducing immunity universally conserved new epitopes in both flu A and B viruses would provide supporting data warranting further advanced preclinical studies.

项目概要 目前的流感疫苗接种可诱导针对可变血凝素 (HA) 蛋白的毒株特异性免疫力 不能有效地针对抗原不同的流行毒株和意外的新病毒提供交叉保护 流行性病毒。开发通用疫苗，提高针对不同抗原的交叉保护 流感病毒是重中之重。位于HA茎结构域N端的融合肽(FP) 在甲型流感病毒和乙型流感病毒中普遍保守。单克隆和多克隆抗体 FP 显示出广泛的中和活性。在初步数据中，我们发现了一个新的HA2茎 靠近 FP 的结构域，可产生与不同亚型流感高度交叉反应的多聚 IgG 抗体 A 型流感病毒和 B 型流感病毒均属谱系。接近酶活性的神经氨酸酶 (NA) 表位 (NA2e) 该位点还被确定在所有甲型和乙型流感病毒中普遍保守。 NA2e特异性单克隆 使用抗体来定量不同批次流感疫苗中的 NA 含量。 NA 免疫被认为是 除 HA 外还有独立的保护相关性。甲型流感病毒M2蛋白胞外结构域（M2e）， 在甲型流感病毒中高度保守，已被证明是开发有希望的目标 通用甲型流感疫苗。然而，单独的 M2e 免疫并不能提供足够高的交叉功效 保护。 没有包含普遍保守的多表位（包括 M2e、FP、干结构域和 NA2e）的疫苗 已被开发出来。病毒样颗粒（VLP）平台已被证明是一种有前途的交付方式 免疫原性差但交叉保护性表位的载体。初步数据显示 NA2e 单克隆 被动接种后抗体能够提供保护。我们假设新的 VLP 疫苗 除了 M2e 之外，构建体还可诱导针对通用 FP 干结构域表位和 NA2e 表位的抗体 增强针对不同甲型和乙型流感病毒株的交叉保护功效。在目标1中，我们将 确定新的重组 VLP 疫苗构建体是否含有 FP-stem、NA2e（或 NA）和 M2e 表位作为独立疫苗或与基于 HA 的疫苗组合将增强交叉保护 对抗甲型流感病毒。在目标 2 中，我们将确定疫苗是否能诱导 FP-stem 抗体 和 NA2e 表位作为独立疫苗或在灭活病毒疫苗中补充时将增强 针对乙型流感病毒的交叉保护。这个为期两年的交叉开发项目的概念验证 诱导免疫的保护性疫苗在甲型和乙型流感病毒中普遍保留新表位 提供支持进一步高级临床前研究的数据。