Impact of a SARS-CoV-2 vaccine on gut integrity, immune activation and efficacy of ART

SARS-CoV-2 疫苗对肠道完整性、免疫激活和 ART 疗效的影响

基本信息

批准号：
10175857
负责人：
CRISTIAN APETREI
金额：
$ 70.53万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-04 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10175857
关键词：
2019-nCoV AIDS prevention Acquired Immunodeficiency Syndrome Address Adenovirus Vector Adenoviruses African American Age Aging Animals Antigens Attention Blood Circulation CD4 Positive T Lymphocytes COVID-19 California Cardiovascular Diseases Cessation of life Characteristics Chronic Clinical Clinical Trials Coagulation Process Communities Control Groups Coronavirus Disease Disease Progression Elderly Epidemic Excess Mortality Exposure to Fibrin fragment D Functional disorder Gastrointestinal tract structure Goals HIV HIV Infections Health Herd Immunity Human Immune response Immune system Immunity Immunologics Impairment Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Intestines Lead Lesion Macaca mulatta Mainstreaming Michigan Monitor Mucosal Immune Responses Mucosal Immunity Mucositis Mucous Membrane National Institute of Diabetes and Digestive and Kidney Diseases New York Outcome Pathogenesis Pathogenicity Pathology Patients Persons Population Population Group Procedures Process Race Recombinants Recovery Research Risk Route SIV Severities Site T-Cell Activation T-Cell Depletion T-Lymphocyte Testing Thrombophilia Time Tissues Transgenes Treatment Efficacy Tropism United States Universities Vaccination Vaccines Viral Viral reservoir Virus age group aged aging population antiretroviral therapy base comorbidity cytokine cytokine release syndrome design dosage drug metabolism gastrointestinal immune activation improved microbial microbiome mucosal site novel coronavirus outcome forecast pandemic disease prevent response side effect vaccine development vector virtual

项目摘要

Abstract A coronavirus pandemic is currently in progress and a tremendous effort for developing effective vaccines to curb it is currently being made. Adenovirus (Ad)-based vaccines are in the lead in the clinical trials, and it is to be expected that at least one vaccine formulation will comprise of an Ad vector. These vectors are known for inducing massive activation of the immune responses at the mucosal sites. The gastrointestinal (GI) tract is the primary site of HIV replication and CD4+ T cell depletion. HIV induces major alterations at the mucosal sites, which impact their barrier function, permitting transfer of microbial products from the intestinal lumen into the surrounding tissues and general circulation. Microbial translocation is a key driver of the chronic immune activation and inflammation (IA/INFL) that are responsible for HIV disease progression. IA/INFL have a tremendous impact on the outcome of HIV infection and persist even in subjects on antiretroviral therapy (ART), preventing a proper recovery of the CD4+ T cells and thus being responsible for comorbidities and accelerated aging. Improving gut health and controlling chronic IA/INFL is thus one of the major goals both for prevention of HIV-associated comorbidities and for cure strategies. It is conceivable that the use of Ad-based vaccines for the SARS-CoV-2 in people living with HIV may result in high levels of IA/INFL at the mucosal sites, which may reverse HIV control provided by ART. Therefore, we teamedwith Dr. Andrea Gambotto from the University of Pittsburgh, who produced a recombinant type 5 Ad vector encoding the transgene for the antigen SARS-CoV-2 S1 subunit (Ad5.SARS-CoV-2-S1). We will use this vaccine in SIV-infected, ART-suppressed rhesus macaques (RMs) to induce effective mucosal immune responses to SARS-CoV2, and we will monitor the impact of these responses on the key pathogenic features of HIV infection: (a) T-cell immune activation, with particular attention given to the mucosal sites; (b) mucosal inflammation and gut integrity; (c) microbial translocation; (d) microbiome; (e) hypercoagulability; (f) impact on the drug metabolism and viral suppression; (g) impact on the viral reservoirs. Since severe SARS-CoV-2 infection disproportionately target older individuals, both young and old RMs will be included. Our specific aim is to test the impact of a SARS-CoV- 2 vaccine on the gut dysfunction and its consequences, systemic immune activation and inflammation and on the response to ART and viral reservoirs in ART-suppressed SIV infection of young versus old RMs. By directly probing the impact of an Ad5.SARS-CoV-2 S1 vaccine on key parameters of HIV infection, our approach will assess whether the planned COVID-19 vaccination has the potential of being deleterious to HIV- infected subjects. We will also assess the importance of a healthy gastrointestinal mucosa to the efficacy of the SARS-CoV-2 vaccine, which goes beyond the HIV infection field, covering all the inflammatory bowel disease pathology.

抽象的目前，冠状病毒大流行正在发生，人们正在付出巨大努力来开发有效的疫苗来遏制目前正在制作中。腺病毒（Ad）疫苗在临床试验中处于领先地位，有待开发预计至少一种疫苗制剂将包含Ad载体。已知这些载体可诱导粘膜部位免疫反应的大量激活。胃肠道 (GI) 是主要部位 HIV 复制和 CD4+ T 细胞耗竭。 HIV 会引起粘膜部位发生重大改变，从而影响其功能屏障功能，允许微生物产物从肠腔转移到周围组织，一般流通。微生物易位是慢性免疫激活和炎症的关键驱动因素 (IA/INFL) 是导致 HIV 疾病进展的因素。 IA/INFL 对结果有巨大影响 HIV 感染甚至在接受抗逆转录病毒治疗 (ART) 的受试者中也持续存在，从而阻碍 CD4+ 的正常恢复 T 细胞因此导致合并症和加速衰老。改善肠道健康并控制因此，慢性 IA/INFL 是预防 HIV 相关合并症和治愈的主要目标之一策略。可以想象，在 HIV 感染者中使用基于 Ad 的 SARS-CoV-2 疫苗可能会导致粘膜部位 IA/INFL 水平升高，这可能会逆转 ART 提供的 HIV 控制。所以，我们与匹兹堡大学的 Andrea Gambotto 博士合作，生产了重组 5 型广告编码抗原 SARS-CoV-2 S1 亚基转基因 (Ad5.SARS-CoV-2-S1) 的载体。我们将使用这个在感染 SIV 且 ART 抑制的恒河猴 (RM) 中使用疫苗可诱导有效的粘膜免疫反应针对 SARS-CoV2，我们将监测这些反应对 HIV 感染的关键致病特征的影响： (a) T 细胞免疫激活，特别注意粘膜部位； (b) 粘膜炎症和肠道正直; (c) 微生物易位； (d) 微生物组； (e) 高凝状态； (f) 对药物代谢的影响病毒抑制； (g) 对病毒库的影响。由于严重的 SARS-CoV-2 感染不成比例地针对老年人，包括年轻和年长的 RM 都将包括在内。我们的具体目标是测试 SARS-CoV 的影响 2 疫苗对肠道功能障碍及其后果、全身免疫激活和炎症的影响比较年轻 RM 与老年 RM 中 ART 抑制的 SIV 感染对 ART 和病毒库的反应。通过直接探讨 Ad5.SARS-CoV-2 S1 疫苗对 HIV 感染关键参数的影响，我们方法将评估计划中的 COVID-19 疫苗接种是否有可能对 HIV 有害受感染的受试者。我们还将评估健康的胃肠粘膜对疗效的重要性 SARS-CoV-2疫苗，超越HIV感染领域，覆盖所有炎症性肠病病理。