Universal epitopes-based recombinant influenza vaccines

基于通用表位的重组流感疫苗

• 批准号: 10092937
• 负责人: SANG-MOO KANG
• 金额: $ 23.37万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092937
• 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 Hemagglutinin; 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; Virus; Virus-like particle; base; cross reactivity; flu; follow-up; immunogenic; immunogenicity; improved; influenza virus strain; 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 antibodies; 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.

项目总结 目前的流感疫苗诱导对可变血凝素(HA)蛋白的毒株特异性免疫 对抗原性不同的流行毒株和意外的新病毒提供交叉保护效果不佳 大流行病毒。提高对不同抗原的交叉保护的通用疫苗的开发 流感病毒是一个高度优先的问题。位于HA茎结构域N端的融合肽(FP) 在甲型和乙型流感病毒中都是普遍保守的。抗肿瘤单抗和多克隆抗体 结果表明，FP具有广泛的中和活性。在初步数据中，我们发现了一种新的HA2茎 FP附近的结构域，可产生与不同亚型流感高度交叉反应的多聚免疫球蛋白抗体 甲型流感病毒和两种B型流感病毒。一个接近酶活性的神经氨酸酶(NA)表位(NA2e) 在所有甲型和乙型流感病毒中也发现了普遍保守的位点。Na2E特异性单抗 用抗体定量检测不同批次流感疫苗中NA的含量。NA豁免权被认为是 除了HA之外，还有独立的保护性关联。甲型流感病毒M2蛋白胞外区(M2e)， 它在甲型流感病毒中高度保守，已被证明是一个有希望的开发目标 通用甲型流感疫苗。然而，仅有M2e免疫并不能提供足够高的CROSS疗效。 保护。 没有包含包括M2E、FP、茎结构域和NA2E在内的通用保守多表位的疫苗 已经被开发出来了。病毒样颗粒(VLP)平台已被证明是一种很有前途的传输方式 免疫原性差但交叉保护表位的载体。初步数据显示，NA2E单抗 被动免疫后抗体可提供保护作用。我们假设新的VLP疫苗 除M2e外还能诱导针对通用FP-干区表位和NA2e表位的抗体的构建 增强对不同甲型和乙型流感病毒株的交叉保护效力。在目标1中，我们将 确定新的含有FP-STEM、NA2E(或NA)和M2E的重组VLP疫苗构建体 表位作为单独疫苗或与基于HA的疫苗联合使用将增强交叉保护 对抗甲型流感病毒。在目标2中，我们将确定疫苗是否诱导针对FP-干细胞的抗体 而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B型流感病毒的交叉保护。这是为期两年的十字开发项目的概念验证 诱导免疫的保护性疫苗将普遍保守甲型和乙型流感病毒的新表位 为进一步的高级临床前研究提供支持数据。