Neuroprotective Potential of Vaccination Against SARS-CoV-2 in Nonhuman Primates

SARS-CoV-2 疫苗对非人灵长类动物的神经保护潜力

• 批准号: 10646617
• 负责人: JAMES B DAUNAIS
• 金额: $ 42.63万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646617
• 关键词: 2019-nCoV; Acceleration; Address; Adverse event; Ageusia; Alzheimer' s Disease; Alzheimer' s disease patient; Amygdaloid structure; Anatomy; Animals; Anterior; Anxiety; Area; Auditory; Behavioral; Biological; Biological Markers; Blood; Brain; Brain region; COVID diagnosis; COVID-19; COVID-19 detection; COVID-19 impact; COVID-19 patient; COVID-19 severity; COVID-19 vaccination; COVID-19 vaccine; Cercopithecus tantalus; Cognitive deficits; Confusion; Cross-Sectional Studies; Data; Dementia; Development; Disease; Dizziness; Dose; Exhibits; Experimental Designs; Glial Fibrillary Acidic Protein; Headache; Hippocampus; Hospitalization; Human; Inactivated Vaccines; Infection; Long COVID; Macaca; Macaca fascicularis; Magnetic Resonance Imaging; Magnetoencephalography; Manuals; Measurement; Measures; Mental Depression; Monkeys; Nature; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurologic; Neurologic Symptoms; Pathology; Patient Self-Report; Patients; Peripheral; Process; RNA vaccine; Recording of previous events; Recovery; Regimen; Reporting; Rest; Retrospective Studies; Risk; SARS-CoV-2 B.1.617.2; SARS-CoV-2 exposure; SARS-CoV-2 infection; Sampling; Serum Markers; Signal Transduction; Smell Perception; Structure; Symptoms; Thalamic structure; Thick; Vaccinated; Vaccination; Vaccines; Viral Load result; Virus; behavior measurement; brain based; brain fog; brain size; coronavirus disease; efficacy testing; executive function; gray matter; improved; information processing; insight; interest; neuroprotection; nonhuman primate; novel; novel coronavirus; sensory gating; tau Proteins; three-arm study; unvaccinated; vaccine adverse event

This project will determine the temporal and anatomic profile of COVID-19 related changes in brain function and neurobiology and whether identified changes relate to brain alterations seen in Alzheimer’s Disease (AD). Although COVID-19 is a novel coronavirus disease, studies have reported that brain structure and function is significantly impacted in humans who become infected and subsequently exhibit cognitive deficits. While it is unclear whether COVID-19 may be a causative or exacerbating factor for dementia, a recent study reported that AD-associated peripheral biomarkers such as t-tau, p-tau181, GFAP, and NfL were elevated in hospitalized COVID+ patients without a history of dementia. These markers correlated with severity of COVID-19 illness (Frontera et al., 2021). While many of the neurological symptoms seen in COVID-19 patients are also exhibited in AD patients, it remains unclear whether any of the markers were present prior to infection or changed because of infection. The ability to identify changes in brain function and neurobiological markers of neurodegeneration early in the COVID-19 disease process would help illuminate whether specific brain regions are more vulnerable than others to infection. Using a cross-sectional experimental design, we recently applied magnetoencephalography (MEG) in nonhuman primates to test the efficacy of a novel COVID vaccine to record resting state (RS) brain function in vaccinated and unvaccinated animals after infection with SARS-CoV-2 and found significant differences in brain function between the groups. We will extend these findings in vervet monkeys to record RS and sensory gating (SG) brain function PRIOR to vaccination and infection. Baseline brain activity will confirm whether any of the changes we detected in the cross-sectional study exist at baseline prior to vaccination and infection. We will measure RS and SG brain function AFTER vaccination with the Moderna mRNA vaccine or a novel psoralen inactivated virus and subsequent challenge with live virus. This will allow us to identify the temporal and anatomical profile of changes in brain activity that result from COVID infection early in the infection process. We will also collect biological samples including CSF and blood pre- and post-infection to track levels of peripheral biomarkers of neurodegenerative diseases that result from COVID infection. We will identify changes in RS and SG brain function to correlate changes in specific brain regions that underlie self-reports of cognitive deficits including ‘foggy brain’ and confusion related to “long COVID” that COVID+ patients report during the recovery period. We will utilize a simple bimanual coordination task as a behavioral measure with which to correlate changes in brain function and markers of neurodegeneration. The ability to capture baseline measures of brain function, behavioral measures and biomarkers prior to infection and vaccination and then early in the disease process will provide valuable insight into which brain regions and neurodegenerative markers may be most impacted by the disease process.

该项目将确定与COVID-19相关的脑功能和神经生物学变化的时间和解剖特征，以及已确定的变化是否与阿尔茨海默病（AD）的脑改变有关。尽管COVID-19是一种新型冠状病毒疾病，但研究报告称，被感染并随后表现出认知缺陷的人的大脑结构和功能受到严重影响。虽然尚不清楚COVID-19是否可能是痴呆的病因或加重因素，但最近的一项研究报告称，ad相关的外周生物标志物，如t-tau、p-tau181、GFAP和NfL在住院的无痴呆史的COVID+患者中升高。这些标志物与COVID-19疾病的严重程度相关（Frontera et al., 2021）。虽然在COVID-19患者中发现的许多神经系统症状也出现在AD患者中，但尚不清楚是否有任何标志物在感染前存在或因感染而改变。在COVID-19疾病过程早期识别脑功能变化和神经退行性变的神经生物学标志物的能力将有助于阐明特定大脑区域是否比其他区域更容易受到感染。采用横断面实验设计，我们最近在非人灵长类动物中应用脑磁图（MEG）来测试新型COVID疫苗在接种和未接种SARS-CoV-2后记录静息状态（RS）脑功能的有效性，并发现两组之间的脑功能存在显著差异。我们将在长尾猴身上扩展这些发现，以记录接种疫苗和感染前的RS和感觉门控（SG）脑功能。基线脑活动将证实我们在横断面研究中发现的任何变化是否存在于接种疫苗和感染之前的基线。我们将在接种Moderna mRNA疫苗或一种新型补骨脂素灭活病毒和随后用活病毒攻毒后测量RS和SG脑功能。这将使我们能够在感染过程的早期确定由COVID感染引起的大脑活动变化的时间和解剖学特征。我们还将收集感染前和感染后的生物样本，包括脑脊液和血液，以跟踪由COVID感染引起的神经退行性疾病的周围生物标志物水平。我们将确定RS和SG脑功能的变化，以关联特定大脑区域的变化，这些变化是认知缺陷自我报告的基础，包括“脑雾”和与COVID+患者在康复期间报告的“长COVID”相关的困惑。我们将利用一个简单的双手协调任务作为一种行为测量，与脑功能和神经变性标志物的变化相关联。在感染和接种疫苗之前以及在疾病过程早期捕获脑功能基线测量、行为测量和生物标志物的能力，将为了解哪些大脑区域和神经退行性标志物可能受疾病过程的影响最大提供有价值的见解。