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

• 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
• 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

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.

摘要 冠状病毒大流行目前正在进行中，为开发有效的疫苗以遏制 它目前正在制作中。以腺病毒(Ad)为基础的疫苗在临床试验中处于领先地位，而且将是 预计至少有一种疫苗配方将由Ad载体组成。这些载体是已知的诱导 粘膜部位的免疫反应被大量激活。胃肠道(GI)是主要的部位 艾滋病毒复制和CD4+T细胞耗尽。HIV引起粘膜部位的重大变化，从而影响它们的 屏障功能，允许微生物产品从肠腔转移到周围组织和 一般环流。微生物易位是慢性免疫激活和炎症的关键驱动因素 (IA/INFL)是导致艾滋病毒疾病进展的原因。IA/INFL对以下方面的结果产生了巨大影响 HIV感染，即使在接受抗逆转录病毒治疗(ART)的受试者中也是如此，阻碍了CD4+的正常恢复 T细胞，从而导致合并症和加速衰老。改善肠道健康和控制 因此，慢性IA/INFL是预防和治疗艾滋病毒相关合并症的主要目标之一 战略。可以想象，在艾滋病毒携带者中使用针对SARS-CoV-2的广告疫苗可能会 导致粘膜部位高水平的IA/INFL，这可能逆转ART提供的HIV控制。因此， 我们与匹兹堡大学的安德里亚·甘博托博士合作，他制作了一个重组的5型广告 编码SARS-CoV-2抗原S1亚单位(Ad5.SARS-CoV-2-S1)转基因载体。我们将使用这个 SIV感染、ART抑制的恒河猴(RMS)疫苗诱导有效的粘膜免疫反应 SARS-CoV2，我们将监测这些反应对艾滋病毒感染的主要致病特征的影响： (A)T细胞免疫激活，特别注意粘膜部位；(B)粘膜炎症和肠道 完整性；(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 年长的个人，包括年轻的和年老的RMS将被包括在内。我们的具体目标是测试SARS冠状病毒的影响- 2关于肠道功能障碍及其后果、全身免疫激活和炎症的疫苗 ART抑制的青年与老年RMS SIV感染对ART和病毒库的反应。 通过直接探测Ad5.SARS-CoV-2S1疫苗对艾滋病毒感染关键参数的影响，我们的 该方法将评估计划中的新冠肺炎疫苗是否有可能对艾滋病毒有害- 受感染的对象。我们还将评估健康的胃肠粘膜对 SARS-CoV-2疫苗，超越艾滋病毒感染领域，覆盖所有炎症性肠道疾病 病理学。