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 相关的大脑功能和神经生物学变化的时间和解剖学特征，以及确定的变化是否与阿尔茨海默氏病 (AD) 中出现的大脑改变有关。被感染并随后表现出认知缺陷的人类的大脑结构和功能受到显着影响，虽然尚不清楚 COVID-19 是否可能是痴呆症的致病因素或加剧因素，但最近的一项研究报告称，与 AD 相关的外周生物标志物，例如在没有痴呆病史的住院 COVID+ 患者中，t-tau、p-tau181、GFAP 和 NfL 升高，这些标记物与 COVID-19 疾病的严重程度相关（Frontera 等人，2021）。在 COVID-19 患者中也表现出 AD 患者中的症状，目前尚不清楚是否有任何标记物在感染之前存在或因感染而改变。我们最近采用横断面实验设计，在非人类灵长类动物中应用脑磁图 (MEG) 来测试新型 COVID 疫苗的功效。记录感染 SARS-CoV-2 后流感动物和未接种疫苗的动物的静息态 (RS) 脑功能，发现各组之间的脑功能存在显着差异，我们将在黑长尾猴中扩展这些发现，以记录 RS 和感觉门控 (SG)。疫苗接种和感染之前的脑功能基线将确认我们在横断面研究中检测到的任何变化是否存在于疫苗接种和感染之前的基线。我们将在接种 Moderna mRNA 疫苗后测量 RS 和 SG 脑功能。或新型补骨脂素灭活病毒以及随后的活病毒攻击，这将使我们能够在感染过程的早期识别由新冠病毒感染引起的大脑活动变化的时间和解剖学特征。预我们将识别 RS 和 SG 大脑功能的变化，以将导致自我报告的认知缺陷（包括“大脑模糊”）的特定大脑区域的变化关联起来。我们将利用简单的双手行为协调任务来衡量与大脑功能变化和神经退行性变标志物相关的能力。 , 行为在感染和疫苗接种之前以及疾病过程早期的措施和生物标记物将为哪些大脑区域和神经退行性标记物可能受疾病过程影响最大提供有价值的见解。