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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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COVID-19的临时和解剖学特征与脑功能和神经生物学的相关变化以及确定的变化是否与阿尔茨海默氏病（AD）中的脑改变有关。尽管Covid-19是一种新型的冠状病毒疾病，但研究报告说，大脑结构和功能在被感染并随后暴露的认知缺陷的人类中受到了显着影响。虽然尚不清楚Covid-19是否可能是痴呆症的严重或加剧因素，但最近的一项研究报告说，在没有痴呆症患者的COVID+患者中，诸如T-TAU，P-TAU181，GFAP和NFL等广告相关的外围生物标志物升高。这些标记与Covid-19疾病的严重程度相关（Frontera等，2021）。尽管在AD患者中也表现出COVID-19患者中看到的许多神经系统症状，但尚不清楚是否在感染之前存在任何标记或因感染而改变。在COVID-19疾病过程的早期，鉴定神经退行性变化的大脑功能和神经生物学标志物的变化的能力将有助于阐明特定的大脑区域是否比其他人更容易受到感染。使用横截面实验设计，我们最近在非人类灵长类动物中应用了磁脑电图（MEG）（MEG），以测试一种新型的covid疫苗记录静息状态（RS）脑功能在疫苗接种和未接种的动物中感染SARS-COV-2后的静息状态（RS），并发现小组之间的大脑功能之间存在显着差异。我们将在真空吸尘和感染之前将这些发现扩展在Vervet猴子中，以记录RS和感觉门控（SG）脑功能。基线大脑的活性将证实我们在疫苗和感染前基线发现我们在横断面研究中发现的任何变化是否存在。我们将使用Moderna mRNA疫苗或新型的杂种灭活病毒以及随后对活病毒的挑战来测量疫苗后的RS和SG脑功能。这将使我们能够确定感染过程早期Covid感染引起的大脑活动变化的暂时和解剖学特征。我们还将收集包括CSF和感染前和感染后血液的生物学样本，以跟踪由COVID感染导致的神经退行性疾病的外周生物标志物的水平。我们将确定RS和SG脑功能的变化，以将认知定义的自我报告为基础的特定大脑区域的变化，包括“雾脑大脑”和与“长covid”相关的Covid+患者在恢复期间报告的“长期兴趣”和混乱。我们将利用一个简单的双层协调任务作为一种行为度量，以将大脑功能变化和神经变性的标记相关联。在感染和疫苗接种之前捕获脑功能，行为测量和生物标志物，然后在疾病过程中的生物标志物的基线测量的能力将提供有价值的见解，以了解哪些脑部区域和神经退行性标记可能受到疾病过程的影响最大。