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; 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.

项目摘要 当前的流感疫苗接种诱导针对可变血凝素（HA）蛋白的应变特异性免疫力为 无效地提供抗原上不同的流行病和意外的新的新的新的 大流行病毒。开发通用疫苗，改善抗原上不同的交叉保护 流感病毒是高度优先级。位于HA茎结构域的N末端的融合肽（FP） 在流感（流感）A和B病毒中都是普遍保守的。单克隆和多克隆抗体抗体 表明FP表现出广泛的中和活性。在初步数据中，我们发现了一个新的HA2茎 FP附近的域，该域可能会产生高度交叉反应到不同亚型流感 病毒和谱系流感B病毒。神经氨酸酶（Na）表位（Na2e）接近酶活性 位点在所有流感A和B病毒中也被确定为普遍保守。 Na2e特异性单克隆 抗体用于定量不同流感疫苗批次中的Na含量。 NA免疫被认为是 独立的保护性除了HA之外。流感A流感病毒M2蛋白细胞外域（M2E）， 在流感A病毒中高度保守，已被证明是发展的有希望的目标 通用流感A疫苗。但是，仅M2E免疫力将无法提供足够高的交叉功效 保护。 无疫苗，其中包括普遍保守的多个表位，包括M2E，FP，STEM结构域和NA2E 已经开发了。病毒样粒子（VLP）平台已被证明是有希望的传递 免疫原性但交叉保护表位的载体。初步数据显示Na2e单克隆 抗体能够在被动接种后提供保护。我们假设新的VLP疫苗 除M2E之外，还将诱导通用FP-Tem域表位的抗体和Na2e表位的抗体 增强对不同菌株流感A和B病毒的跨保护功效。在目标1中，我们将 确定新的重组VLP疫苗是否包含FP-STEM，Na2e（或Na）和M2E 作为独立疫苗的表位或与基于HA的疫苗结合使用将增强交叉保护 反对流感病毒。在目标2中，我们将确定疫苗是否诱导了FP茎的抗体 NA2E表位为独立疫苗，或者在灭活病毒疫苗中补充时会增强 交叉保护对流感B病毒。这项为期两年的杂志概念证明 诱导流感A和B病毒中普遍保守的新表位免疫的保护性疫苗将 提供支持的数据保证，以进一步的高级临床前研究。