Prophylactic oral vaccination for SIV and SHIV infections and AIDS prevention

针对 SIV 和 SHIV 感染以及艾滋病预防的预防性口服疫苗接种

基本信息

批准号：
9322435
负责人：
ANNA ALDOVINI
金额：
$ 80.33万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9322435
关键词：
AIDS prevention Acquired Immunodeficiency Syndrome Affinity Animals Antibodies Antibody Affinity Antibody Response Antigens Attenuated B-Lymphocytes Blood CD8-Positive T-Lymphocytes Cells Cellular Immunity Characteristics Control Animal DNA DNA Vaccines Development Disease Disease Progression Dose Engineering Enterotoxins Escherichia coli Evaluation Goals HIV Human Human poliovirus Humoral Immunities Immune response Immunity Immunization Immunoglobulin A Immunoglobulin G Infection Infection prevention Interleukin-15 Interleukin-2 Intestinal Mucosa Intestines Knowledge Macaca Macaca mulatta Mediating Memory Memory B-Lymphocyte Modeling Mutate Nose Oral Oral Poliovirus Vaccine Oral cavity Outcome Peripheral Blood Mononuclear Cell Process Property Protocols documentation Proviruses Recombinant DNA Recombinant modified vaccinia virus Ankara Recombinants Regimen Resistance to infection SIV Sampling Schedule Secretory Cell Secretory Immunoglobulin A Site Structure T cell response T-Lymphocyte Tissues Vaccinated Vaccination Vaccines Vagina Variant Viral Load result Viral reservoir Viremia Virus Replication base cell mediated immune response cytokine design env Gene Products experience experimental study follow-up immune activation immunogenicity improved mucosal site mutant novel vaccines particle pre-clinical preclinical trial prophylactic rectal response scaffold simian human immunodeficiency virus transmission process vaccine evaluation vaccine trial vector

项目摘要

SUMMARY This proposal is designed to extend our previous studies where we achieved significant systemic and mucosal cellular responses after oral cavity and intestinal immunizations with a SIV DNA-rMVA approach. These immunizations had two important impacts on SIV exposure and infection: 1. the intestinal immunization provided significant protection from infection but no protection from disease progression; 2. the oral cavity immunization provided significant protection from disease with no AIDS development observed during the post-challenge follow up and with more than 50% of the animals controlling virus replication to undetectable blood levels after experiencing a peak of viremia, and apparently clearing the infection, as no rebound was observed after CD8+ T-cell depletion. Here we propose to investigate in Cynomolgus macaques anti-SIV and SHIV oral immunization approaches aimed at stimulating cellular immune responses, previously achieved via oral immunization, and persistent anti-Env IgG and IgA titers, previously sporadic or missing, systemically and at mucosal sites where HIV exposure occurs in humans. The goal sof the proposal are the following: I. To evaluate how oral immunization regimens composed of 1. pSIVvaxE543 DNA, boosted with gp140(smE543) Env and rMVA, 2. pSIVvaxE543 DNA + SIVgag239 and SIVenvsmE543 recombinant OPVs (collectively called SIV-OPV), and 3. SIV-OPV alone compare in their stimulation of cell mediated and humoral immunity systemically and at mucosal sites where HIV transmission occurs in humans, and whether they provide protection from heterologous SIVmac251 infection and disease in Cynomolgus macaques (CM). II. To evaluate stimulation of systemic and mucosal cell-mediated immunity and humoral immunity by three regimes that include SHIVBG505 DNA + SIVgag239-OPV and HIV Env-OPV, where Env in this last component is linear HIVBG505 gp140 in Group 1, a SOSIP-gp140 BG505 in Group 2, and a V1-V2 BG505 scaffold in Group 3, and whether these responses provide protection from heterologous SHIVAD8 infection and disease in CM; III. To evaluate the extent of anti-HIV Env antibody affinity maturation observed with repeated SHIV-OPV immunization. During these experiments we will evaluate mechanistic characteristics of the anti-SIV or SHIV immune response and correlates of protection from infection and disease, with focus on the analysis of intestinal mucosa responses and viral loads, viral reservoirs, and possibly eradication post infection.

概括该提案旨在扩展我们之前的研究，在这些研究中我们取得了显着的系统和粘膜效果使用 SIV DNA-rMVA 方法进行口腔和肠道免疫后的细胞反应。这些免疫接种对 SIV 暴露和感染有两个重要影响： 1. 提供肠道免疫显着防止感染，但无法防止疾病进展； 2.口腔免疫提供了显着的预防疾病的保护作用，在挑战后的随访期间没有观察到艾滋病的发展超过 50% 的动物在经历病毒感染后将病毒复制控制在无法检测到的血液水平病毒血症的峰值，并且显然清除了感染，因为 CD8+ T 细胞耗尽后没有观察到反弹。在这里，我们建议研究食蟹猴抗 SIV 和 SHIV 口服免疫方法，旨在刺激细胞免疫反应（之前通过口服免疫实现）和持久性抗 Env IgG 和 IgA 滴度，以前是零星的或缺失的，在全身和在 HIV 暴露发生的粘膜部位人类。该提案的目标如下： I. 评估口服免疫方案的组成： 1. pSIVvaxE543 DNA，用 gp140(smE543) Env 和 rMVA 增强，2. pSIVvaxE543 DNA + SIVgag239 和 SIVenvsmE543 重组 OPV（统称为 SIV-OPV）与 3. 单独使用 SIV-OPV 的刺激效果进行比较细胞介导的免疫和体液免疫系统以及人类发生艾滋病毒传播的粘膜部位，以及它们是否能保护食蟹猴免受异源 SIVmac251 感染和疾病（厘米）。二.评估三种药物对全身和粘膜细胞介导的免疫和体液免疫的刺激包括 SHIVBG505 DNA + SIVgag239-OPV 和 HIV Env-OPV 的方案，其中最后一个组件中的 Env 是线性的第 1 组中的 HIVBG505 gp140、第 2 组中的 SOSIP-gp140 BG505 和第 3 组中的 V1-V2 BG505 支架，以及是否这些反应提供了针对异源 SHIVAD8 感染和 CM 疾病的保护；三．评估重复 SHIV-OPV 免疫观察到的抗 HIV Env 抗体亲和力成熟程度。在这些期间实验中我们将评估抗 SIV 或 SHIV 免疫反应的机制特征以及相关性防止感染和疾病，重点分析肠粘膜反应和病毒载量、病毒储存库，并可能在感染后根除。