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

• 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
• 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

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.

流感病毒的呼吸道感染在人类中造成严重的发病率和死亡率 以及世界各地的动物。重要的是，在人类中，大多数发病率和死亡率 流感感染见于年龄较大的人(65岁)。然而，清楚地了解衰老是如何 缺乏对免疫反应的影响，以及如何改进这一年龄段的疫苗设计。 用A型流感病毒的保守表位重新刺激先前存在的记忆T细胞 在这个年龄段，疫苗可能会产生保护性免疫。一种理想的老年人疫苗应该是 因此，激活抗原提呈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病毒的体外刺激会导致强大的再刺激 对老年人记忆中的CD4和CD8 T细胞的影响，而不会引起病理性炎症 参与非炎症体依赖的先天通路。我们已经在阶段1a中展示了 临床研究表明，M2SR一般安全，耐受性好，具有诱导免疫的能力 血清阴性、血清阳性和血清保护性受试者的反应。随后，我们展示了 M2SR受体提供了对高度漂移的流感病毒的保护。在这 建议，我们将探索M2SR刺激老年人抗病毒免疫反应的能力 以下目标的主题： 目的1.进行1b阶段研究，测试M2SR在老年人中的安全性和免疫原性 研究对象。 目的2.评估接种M2SR疫苗的老年人的免疫反应 这些实验的目的是加强对老年人免受流感影响的保护。 疾病，通过了解有助于保护性免疫的免疫反应。这个 预计实验的结果将对基础研究产生重大影响 了解M2SR在易感老年人中诱导免疫反应的能力 并证明了有效的疫苗剂量方案的安全性。