Safety and Immunogenicity of H3N2 M2SR monovalent influenza vaccine in older subjects

H3N2 M2SR 单价流感疫苗在老年受试者中的安全性和免疫原性

基本信息

批准号：
10436972
负责人：
Pamuk Bilsel
金额：
$ 130.42万
依托单位：
FLUGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-25 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436972
关键词：
Accounting Affect Age Age-Years Aging Animals Antibody Response Antibody titer measurement Antigen-Presenting Cells B-Lymphocytes CD8-Positive T-Lymphocytes Cells Cessation of life Chronic Disease Clinical Clinical Research Data Defect Dendritic Cells Disease Dose Double-Blind Method Elderly Enrollment Epitopes Exhibits FluMist Genes Hospitalization Human Immune Immune response Immune system Immunity Impairment Inactivated Vaccines Individual Inflammasome Inflammation Inflammatory Response Influenza Influenza A Virus, H3N2 Subtype Influenza A virus Influenza prevention Interferon Type I Interferons Intramuscular Investigation Mediating Memory Methods Morbidity - disease rate Mucosal Immune System Natural Immunity Outcome Pathologic Pathway interactions Pattern recognition receptor Peripheral Blood Mononuclear Cell Phase Placebos Population Predisposition Process Receptor Signaling Regimen Research Respiratory Disease Respiratory Tract Infections Retinoic Acid Receptor Safety Sampling Signal Transduction T cell response T memory cell T-Lymphocyte Testing Time Tretinoin Vaccinated Vaccination Vaccine Design Vaccinee Vaccines Viral Load result Virus Vulnerable Populations Work adaptive immune response adaptive immunity age group aged cytokine design disability risk experimental study first-in-human flu human old age (65+)human study human subject immune function immunogenicity immunosenescence improved influenza infection influenza virus vaccine influenzavirus insight monocyte mortality novel randomized placebo controlled study response safety testing seropositive standard of care transcriptome vaccine candidate vaccine response

项目摘要

Respiratory infections with influenza viruses cause severe morbidity and mortality in humans and animals worldwide. Importantly, in humans, the majority of morbidity and mortality following flu infection is seen in older individuals (> 65 years old). Yet, clear understanding of how aging impacts on immune responses, and how to improve vaccine design in this age group is lacking. Restimulating preexisting memory T cells against conserved epitopes in influenza virus by a vaccine might confer protective immunity in this age group. An ideal vaccine for elderly should therefore engage pattern recognition receptors (PRRs) that activate antigen-presenting cells (APCs), generate conserved antigenic epitopes, while avoiding overt inflammatory responses. We have demonstrated that ex-vivo stimulation with M2SR virus results in robust restimulation of memory CD4 and CD8 T cells in older humans without causing pathological inflammation by engaging non-inflammasome dependent innate pathways. We have shown in a Phase 1a clinical study that M2SR is generally safe and well-tolerated with the ability to elicit immune responses in seronegative, seropositive and seroprotected subjects. Subsequently, we showed that M2SR recipients provided protection against a highly drifted influenza virus. In this proposal, we will explore the ability of M2SR to stimulate antiviral immune responses in older subjects in the following aims: Aim 1. Conduct Phase 1b study testing safety and immunogenicity of M2SR in older subjects. Aim 2. Evaluate immune responses from older human subjects vaccinated with M2SR These experiments are aimed at improving protection of older humans from influenza-mediated disease, by understanding the immune responses that contribute to protective immunity. The outcome of the experiments is expected to have high impact with respect to the fundamental understanding of the ability of M2SR to elicit immune responses in the susceptible elderly population, and in demonstrating safety of an effective vaccine dosing regimen.

流感病毒呼吸道感染导致人类严重发病和死亡和世界各地的动物。重要的是，在人类中，大多数发病率和死亡率如下流感感染常见于老年人（> 65 岁）。然而，清楚地了解衰老是如何发生的目前还缺乏对免疫反应的影响，以及如何改进该年龄段的疫苗设计。通过一种方法重新刺激先前存在的针对流感病毒保守表位的记忆 T 细胞疫苗可能会赋予这个年龄段的保护性免疫力。适合老年人的理想疫苗应该因此，激活抗原呈递细胞的模式识别受体（PRR）（APC），产生保守的抗原表位，同时避免明显的炎症反应。我们已经证明，M2SR 病毒的离体刺激会导致强烈的再刺激老年人中的记忆 CD4 和 CD8 T 细胞不会引起病理性炎症参与非炎症小体依赖性先天通路。我们已经在 Phase 1a 中展示了临床研究表明 M2SR 通常是安全的且耐受性良好，并且能够引发免疫血清阴性、血清阳性和血清保护受试者的反应。随后，我们展示了 M2SR 接受者可以针对高度漂移的流感病毒提供保护。在这个提案中，我们将探索 M2SR 刺激老年人抗病毒免疫反应的能力科目目标如下：目标 1. 进行 1b 期研究，测试 M2SR 在老年人中的安全性和免疫原性科目。目标 2. 评估接种 M2SR 疫苗的老年受试者的免疫反应这些实验旨在加强对老年人的保护，使其免受流感介导的侵害通过了解有助于保护性免疫的免疫反应来预防疾病。这预计实验结果将对基本原理产生重大影响了解 M2SR 在易感老年人中引发免疫反应的能力人群，并证明有效疫苗给药方案的安全性。