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

• 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
• 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

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.

摘要 这项建议旨在扩展我们之前的研究，在这些研究中，我们实现了重要的系统性和粘膜 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 显著预防感染，但不能预防疾病进展；2.口腔免疫 提供了有效的疾病保护，在挑战后的后续行动中没有观察到艾滋病的发展 超过50%的动物在经历了一次 病毒血症高峰期，感染明显清除，CD8+T细胞耗尽后未见反弹。 在这里，我们建议研究食蟹猴抗SIV和SIV口服免疫方法，目的是 在刺激细胞免疫反应方面，以前通过口服免疫和持久的抗Env IgG实现 和IgA滴度，以前零星或缺失，系统性和在发生艾滋病毒暴露的粘膜部位 人类。该提案的目标如下：1.评价口服免疫方案是如何由1。 PSIVvaxE543 DNA，用gp140(SmE543)env和rMVA增强，2.pSIVvaxE543 DNA+SIVgag239和 SIVenvsmE543重组OPV(统称SIV-OPV)和3.SIV-OPV单独刺激 在人类中发生艾滋病毒传播的粘膜部位和系统地进行细胞介导和体液免疫， 以及它们是否对食蟹猴的异源SIVmac251感染和疾病提供了保护 (厘米)。二、评价三种免疫制剂对系统和粘膜细胞免疫和体液免疫的刺激作用 包括SHIVBG505 DNA+SIVgag239-OPV和HIV Env-OPV的制度，其中最后一个成分中的Env是线性的 组1的HIVBG505 gp140，组2的SOSIP-gp140 BG505，组3的V1-V2 BG505支架，以及 这些反应提供了对CM中异源SHIVAD8感染和疾病的保护；III.评估 重复接种SIV-OPV观察抗HIV Env抗体亲和力成熟的程度。在此期间 我们将评估抗SIV或SIV免疫反应的机制特征及其与 预防感染和疾病，重点是分析肠道粘膜反应和病毒载量、病毒 水库，并可能在感染后根除。