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：
10216952
负责人：
Anne Searls DeGroot
金额：
$ 112.35万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10216952
关键词：
Acute Address Adjuvant Amino Acid Substitution Antibodies Antibody Formation Antibody Response Antibody titer measurement Antigens Avian Influenza Avidity Award B-Lymphocyte Epitopes B-Lymphocytes Baculovirus Expression System 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 Leukocytes Membrane Fusion Modification Molecular Conformation Mus Mutation Nature Phase Population Property Publishing Recombinants Recording of previous events Research Site Structure T cell response T-Lymphocyte Epitopes Testing Transgenic Mice Vaccination Vaccine Design Vaccine Production Vaccines Variant Virus Work adverse event risk base biophysical properties candidate selection design effector T cell human pathogen immunogenic immunogenicity improved influenza infection influenza virus strain influenza virus vaccine lead candidate manufacturability memory CD4 T lymphocyte mortality neutralizing antibody novel pandemic disease pandemic influenza peripheral blood phase I trial preservation programs protective efficacy receptor binding recruit 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.

抽象的常规影响力暴露和疫苗接种会导致跨保护免疫不足新颖的鸟类影响力。这为可能引起大量严重疾病的大流行而感到担忧和免疫学人群中的死亡。禽H7N9影响对人类健康的威胁，因为自2013年紧急情况以来，其高病例死亡率一直在一年一度的流行病中观察到。增加人类到人类传播的病毒适应的潜力引起了人们对 H7N9流感病毒大流行。 H7N9影响力在自然感染和疫苗接种中引起弱中和抗体反应。到准备H7N9影响力大流行的疫苗策略，以克服不良的免疫原性需要H7N9 HA。我们假设CD4+ T细胞对H7N9 HA的反应更强将支持改善血凝抑制（HI）抗体反应。为了解决这一假设，我们建议使用结构引导的方法将季节性HA特异性CD4+ T细胞表位引入H7N9 HA中，通过诱导CD4+ T细胞产生能够启动受保护的HI反应的新型免疫原记忆。提出的研究基于我们先前的工作，表明H3-HA306-318 CD4+ T细胞表位在H7N9 HA靴子效应T细胞和抗体免疫中引入相应位点在保留自然感染中会遇到的中和抗体表位的反应。在这里，我们建议将更多内存CD4+ T细胞表位引入现有的优化H7-HA 因为识别个体中H3-HA306-318发作的CD4+ T细胞的频率取决于他们季节性影响力的历史。 AIM 1将评估小说包括不同数量的工程CD4+ T细胞表位。一个新的HA包含最少的工程季节性HA CD4+ T细胞表位最能近似于野生型H7N9的生物物理特性 HA并展示了野生型H7N9 HA的小鼠和人类免疫回报的增强被选为AIM 2改进研究。在AIM 2中，我们将减少从AIM 1出现的免疫原以生成改进的设计，以维持增益保护性免疫，同时更紧密地保留野生型H7-的结构和生物物理特性哈。较低的突变负荷的好处将被最小化以中和抗体靶标的扰动并提高了制造性。拟议的研究将确定最小的牵头候选人突变负荷和最大免疫原性和保护效率在此合作伙伴计划结束时进行研究。