Development of a Non-adjuvanted VLP Vaccine against Stealth H7N9 Influenza

针对隐形 H7N9 流感的无佐剂 VLP 疫苗的开发

基本信息

批准号：
9304958
负责人：
Anne Searls DeGroot
金额：
$ 29.05万
依托单位：
EPIVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304958
关键词：
Acute Address Adjuvant Adverse effects Antibodies Antibody Response Antibody titer measurement Antigens Avidity Birds CD4 Positive T Lymphocytes Cell Culture Techniques China Clinical Clinical Trials Collaborations Development Disease Dose Engineering Epitopes Event Excision Exhibits Formulation Frequencies Goals Hemagglutinin Human Immunization Immunize Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H7N9 Subtype Influenza A virus Influenza vaccination Intramuscular Methods Modification Monitor Mucosal Immunity Mus Outcome Phase Phenotype Production Publishing Regulatory T-Lymphocyte Research Risk Route Running Safety Small Business Innovation Research Grant T-Lymphocyte T-Lymphocyte Epitopes T-Lymphocyte Subsets Techniques Technology Testing Toxic effect Transgenic Mice Universities Vaccination Vaccine Design Vaccine Production Vaccines Viral Viral Load result Virus Virus-like particle Work Writing design experience global health immunogenic immunogenicity improved in vivo influenza virus vaccine influenzavirus neutralizing antibody novel pandemic disease pathogen programs prototype public health relevance response seasonal influenza vaccine candidate vaccine development vaccine efficacy vaccine evaluation

项目摘要

DESCRIPTION (provided by applicant): The avian-origin H7N9 influenza virus that emerged in humans in China in 2013 presents a unique challenge to vaccine development because it is poorly immunogenic. Neutralizing antibodies are not detected in acute-phase infection. Anti-H7 antibody responses are significantly delayed and exhibit low avidity, in comparison with antibodies generated following seasonal influenza vaccination and infection. Furthermore, unadjuvanted H7N9 vaccines developed using conventional approaches elicit weak hemagglutinin-inhibition (HAI) antibody titers in clinical trials. Adjuvanted formulations may overcome this limitation but present significant regulatory challenges because adverse effects have recently been associated with adjuvanted influenza vaccines. Alternative vaccine approaches are needed to redress the low immunogenicity of H7N9 and circumvent safety risks. Because HAI titers are directly related to effector CD4+ T cell frequencies induced by vaccination, we hypothesize that a vaccine strategy that enhances effector CD4+ T cell activation will improve H7N9 vaccine efficacy without requiring adjuvant formulation. In published studies, we observed that the T cell epitope content of H7N9 virus differs significantly from more immunogenic influenza subtypes. H7N9 contains fewer T cell epitopes and some epitopes stimulate regulatory T cells (Tregs) that may help the virus evade effector responses needed for protection. These findings suggest that H7N9 vaccine design that carefully addresses the T cell subsets primed by immunization will overcome limitations of conventional vaccine approaches. The goal of this research program is to produce an unadjuvanted, influenza H7N9 virus-like particle (VLP) vaccine that augments effector CD4+ T cell responses and diminishes Treg effects for enhanced protection against disease. This new SBIR program will apply cutting edge computational and experimental methods that EpiVax has successfully applied against influenza and other viral and bacterial pathogens, as well as deep experience in influenza VLP production and vaccine testing in collaboration with Dr. Ted Ross at the University of Georgia. Two different engineered VLP strategies will be tested: (i) addition of effector epitopes and (ii) removal of Treg epitopes. Using these prototype effector T cell epitope-enhanced VLP vaccines in the proof-of-concept program described here, we will evaluate the vaccines for immunogenicity and efficacy and move forward in a Phase II program to further optimize efficacy and complete safety/toxicity studies in the run up to clinical trial.

描述（申请人提供）：2013 年在中国出现的禽源 H7N9 流感病毒对疫苗开发提出了独特的挑战，因为它在急性期感染中未检测到中和抗体。与季节性流感疫苗接种和感染后产生的抗体相比，反应显着延迟并且表现出较低的亲和力。此外，使用传统方法开发的未佐剂的 H7N9 疫苗引起的反应较弱。临床试验中的血凝素抑制 (HAI) 抗体滴度可能会克服这一限制，但会带来重大的监管挑战，因为最近发现与佐剂流感疫苗相关的副作用需要替代疫苗方法来纠正 H7N9 的低免疫原性并规避安全性。由于 HAI 滴度与疫苗接种诱导的效应 CD4+ T 细胞频率直接相关，因此我们认为增强效应 CD4+ T 细胞激活的疫苗策略将会改善。在已发表的研究中，我们观察到 H7N9 病毒的 T 细胞表位含量与免疫原性更强的流感亚型显着不同，其中 T 细胞表位较少，一些表位可能有助于刺激调节性 T 细胞 (Treg)。这些发现表明，仔细处理免疫引发的 T 细胞亚群的 H7N9 疫苗设计将克服传统疫苗方法的局限性。该研究计划的目标是生产一种无佐剂的 H7N9 流感病毒样颗粒 (VLP) 疫苗，该疫苗可增强效应 CD4+ T 细胞反应并减少 Treg 效应，从而增强对疾病的保护。这一新的 SBIR 计划将应用尖端的计算和实验方法。 EpiVax 已成功应用于流感和其他病毒和细菌病原体，并且与佐治亚大学的 Ted Ross 博士合作，在流感 VLP 生产和疫苗测试方面拥有丰富的经验，将提供两种不同的工程 VLP 策略。进行测试：(i) 添加效应表位和 (ii) 去除 Treg 表位在此处描述的概念验证计划中使用这些原型效应 T 细胞表位增强的 VLP 疫苗，我们将评估疫苗的免疫原性和功效。并推进第二阶段计划，以进一步优化疗效并在临床试验前完成安全性/毒性研究。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Novel H7N9 influenza immunogen design enhances mobilization of seasonal influenza T cell memory in H3N2 pre-immune mice.

新型 H7N9 流感免疫原设计增强了 H3N2 免疫前小鼠季节性流感 T 细胞记忆的动员。

DOI：
发表时间：
2022-11-30
期刊：
影响因子：
4.8
作者：
Moise, Leonard;Meyers, Lauren M;Jang, Hyesun;Grizotte;Boyle, Christine M;McGonnigal, Bethany;Ge, Pan;Ross, Ted M;De Groot, Anne S
通讯作者：
De Groot, Anne S