Structure-Guided Design of CD4 T cell Memory-Enhanced rHA H7N9 Influenza Vaccine

CD4 T细胞记忆增强rHA H7N9流感疫苗的结构引导设计

基本信息

批准号：
9362529
负责人：
Anne Searls DeGroot
金额：
$ 122.12万
依托单位：
EPIVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9362529
关键词：
Acute Address Adjuvant Adverse event Amino Acid Substitution Antibodies Antibody Formation Antibody Response Antibody titer measurement Antigens Avian Influenza Avidity Award B-Lymphocyte Epitopes B-Lymphocytes Baculovirus Expression System Biological Preservation Biophysics Birds CD4 Positive T Lymphocytes Case Fatality Rates Cessation of life Clinical Trials Engineering Epidemic Epitopes Evolution Exhibits Face Frequencies Goals Health Hemagglutination Hemagglutinin Human Immune Immune response Immunity Immunologics Individual Infection Influenza Influenza A Virus, H7N9 Subtype Kinetics Lead Leukocytes Membrane Fusion Modification Molecular Conformation Mus Mutation Nature Phase Population Property Publishing Recombinants Recording of previous events Recruitment Activity Research Risk Site Structure T-Lymphocyte T-Lymphocyte Epitopes Testing Transgenic Mice Vaccination Vaccine Design Vaccines Variant Virus Work base biophysical properties candidate selection design immunogenic immunogenicity improved influenza virus vaccine influenzavirus memory CD4 T lymphocyte mortality neutralizing antibody novel pandemic disease pandemic influenza pathogen peripheral blood phase I trial programs protective efficacy receptor binding response seasonal influenza vaccine efficacy

项目摘要

ABSTRACT Routine influenza exposure and vaccination generate inadequate cross-protective immunity against novel avian influenza. This fuels concerns for pandemics that may cause high numbers of severe illness and deaths in immune naïve populations. Avian H7N9 influenza poses a threat to human health because of its high case fatality rate consistently observed in annual epidemic waves since it emergence in 2013. The potential for virus adaptations that increase human-to-human transmissibility raises concern for an H7N9 influenza virus pandemic. H7N9 influenza HA elicits weak neutralizing antibody responses in natural infection and vaccination. To prepare for an H7N9 influenza pandemic, vaccine strategies that overcome the poor immunogenicity of H7N9 HA are needed. We hypothesize that a stronger CD4+ T cell response to H7N9 HA will support an improved hemagglutination inhibition (HI) antibody response. To address this hypothesis, we propose to introduce seasonal HA-specific CD4+ T cell epitopes into H7N9 HA, using a structure-guided approach, to produce a novel immunogen capable of priming protective HI responses by inducing CD4+ T cell memory. The proposed studies are grounded in our prior work showing that the H3-HA306-318 CD4+ T cell epitope introduced into the corresponding site in H7N9 HA boosts effector T cell and antibody immune responses while preserving neutralizing antibody epitopes that would be encountered in natural infection. Here, we propose to introduce more memory CD4+ T cell epitopes into the existing optimized H7-HA because the frequency of CD4+ T cells that recognize the H3-HA306-318 epitope varies among individuals depending on their history of seasonal influenza exposure. Aim 1 will evaluate novel HAs composed of different numbers of engineered CD4+ T cell epitopes. A new HA containing the fewest engineered seasonal HA CD4+ T cell epitopes that best approximates the biophysical properties of wild type H7N9 HA and demonstrates enhanced mouse and human immune responses over wild type H7N9 HA will be selected to go forward to Aim 2 refinement studies. In Aim 2, we will reduce the mutational load of the immunogen that emerges from Aim 1 to generate an improved design that maintains the gain in protective immunity while more closely preserving structural and biophysical properties of wild type H7- HA. The benefits of a lower mutational load will be minimized perturbation to neutralizing antibody targets and improved manufacturability. The proposed studies will identify a lead candidate with minimum mutational load and maximal immunogenicity and protective efficacy that is ready for IND enabling studies by the end of this Partnerships program.

抽象的常规流感暴露和疫苗接种产生的交叉保护免疫力不足新型禽流感加剧了人们对可能导致大量严重疾病的流行病的担忧。禽 H7N9 流感对人类健康构成威胁，因为自 2013 年出现以来，每年的流行病浪潮中一直观察到其高病死率。病毒适应增加人际传播能力的潜力引起了人们的担忧 H7N9 流感病毒大流行。 H7N9 流感 HA 在自然感染和疫苗接种中引起微弱的中和抗体反应。为H7N9流感大流行做好准备，克服H7N9流感免疫原性差的疫苗策略我们认为对 H7N9 HA 更强的 CD4+ T 细胞反应将支持 H7N9 HA。改善血凝抑制（HI）抗体反应为了解决这一假设，我们建议：使用结构引导方法将季节性 HA 特异性 CD4+ T 细胞表位引入 H7N9 HA 中，产生一种能够通过诱导 CD4+ T 细胞引发保护性 HI 反应的新型免疫原拟议的研究基于我们之前的工作，表明 H3-HA306-318 CD4+ T 细胞。将表位引入 H7N9 HA 的相应位点可增强效应 T 细胞和抗体免疫反应，同时保留自然感染中会遇到的中和抗体表位。在这里，我们建议在现有优化的H7-HA中引入更多的记忆CD4+ T细胞表位因为识别 H3-HA306-318 表位的 CD4+ T 细胞的频率在个体之间存在差异目标 1 将评估由以下组成的新型 HA 不同数量的工程 CD4+ T 细胞表位，包含最少的工程改造的新 HA。最接近野生型 H7N9 生物物理特性的季节性 HA CD4+ T 细胞表位 HA 并证明小鼠和人类对野生型 H7N9 HA 的免疫反应增强选择继续进行目标 2 细化研究在目标 2 中，我们将减少突变负荷。从目标 1 中产生的免疫原可产生改进的设计，从而保持增益保护性免疫，同时更紧密地保留野生型 H7- 的结构和生物物理特性 HA。较低突变负荷的好处是可以最大限度地减少对中和抗体靶标的干扰。并提高可制造性。拟议的研究将确定一个具有最低限度的主要候选者。突变负荷、最大免疫原性和保护功效，为 IND 做好准备在该伙伴关系计划结束时进行研究。