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

流感病毒引起的呼吸道感染可导致人类严重的发病率和死亡率 和全世界的动物重要的是，在人类中， 流感感染见于老年人（> 65岁）。然而，清楚地了解衰老是如何 缺乏对免疫反应的影响，以及如何改进该年龄组的疫苗设计。 通过免疫抑制剂再刺激针对流感病毒保守表位的预先存在的记忆T细胞 疫苗可能会在这个年龄组提供保护性免疫力。老年人理想的疫苗应 因此参与激活抗原呈递细胞的模式识别受体（PRRs） 在一些实施方案中，抗原表位（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，用M2SR病毒的离体刺激导致稳健的再刺激 记忆性CD4和CD8 T细胞在老年人中没有引起病理性炎症， 参与非炎性体依赖性先天途径。我们在第1a阶段中展示了 临床研究表明，M2SR通常安全且耐受性良好，能够引发免疫反应， 血清阴性、血清阳性和血清保护受试者的应答。随后，我们展示了 M2SR接受者提供了对高度漂移的流感病毒的保护。在这 我们将探索M2SR在老年人中刺激抗病毒免疫应答的能力。 目标如下： 目标1。开展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.评价接种M2SR疫苗的老年人受试者的免疫应答 这些实验旨在改善老年人对流感介导的 疾病，通过了解有助于保护性免疫的免疫反应。的 实验的结果预计将对基本的 了解M2SR在易感老年人中引发免疫应答的能力 人群，并证明有效的疫苗给药方案的安全性。

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.