Optimizing Adjuvants and Needle Free Delivery Methods for Oral HIV Vaccination

优化口服 HIV 疫苗的佐剂和无针注射方法

• 批准号: 9187197
• 负责人: Rama Rao Amara
• 金额: $ 85.84万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187197
• 关键词: AIDS/HIV problem; Adjuvant; Agonist; Antibodies; Antibody Formation; Antibody Response; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Blood; CD8B1 gene; Cells; Cellular Immunity; Clinical; DNA; DNA Vaccines; Data; Dendritic Cells; Development; Devices; Encapsulated; Flagellin; Genital system; Goals; HIV; HIV Infections; HIV vaccine; Homing; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; In Vitro; Infection; Infection prevention; Intestinal Mucosa; Intestines; Life; Location; Lymphoid Tissue; Macaca; Macaca mulatta; Methods; Modified Vaccinia Virus Ankara; Mucosal Immune Responses; Mucous Membrane; Needles; Oral; Oral cavity; Oral mucous membrane structure; Palatine Tonsil; Peptide Hydrolases; Phase; Property; Proteins; Regimen; Resistance; Route; SIV; SIV Vaccines; Saliva; Serum; Site; Surface; System; T cell response; T-Lymphocyte; TLR7 gene; TNFSF5 gene; Testing; Tissues; Toxic effect; Vaccination; Vaccines; Vagina; Virus Replication; base; cost; imprint; in vivo; mucosal site; mucosal vaccination; nanoparticle; novel; oral HIV; oral vaccine; pre-clinical; prevent; programs; receptor expression; rectal; response; simian human immunodeficiency virus; uptake; vaccine delivery

The majority of HIV infections occur via mucosal routes (genital, oral or rectal) world-wide. The overall goal of this proposal is to develop a vaccination approach that induces strong HIV-specific humoral and cellular immunity in genital, intestinal and oral mucosae. We hypothesize that vaccines, which elicit strong anti-HIV immunity at these mucosal sites, will prevent infection and rapidly clear infected cells very early at the site of infection and enhance protection. Oral cavity is rich in lymphoid tissue containing antigen presenting cells, T cells and B cells, and provides an excellent opportunity for mucosal delivery of vaccines. However, this route of immunization has been under utilized to deliver vaccines in part due to the presence of proteases in saliva that can degrade vaccines. This is particularly true for protein-based vaccines. Here, we aim to target the oral mucosa for immunization using a needle free device (Syrijet) as an oral vaccine delivery system to induce strong immune responses at oral and intestinal mucosal sites. The syrijet can deliver vaccines into the oral mucosa thus will 1) enhance the delivery of vaccine to local lymphoid tissue that will facilitate uptake by DC and 2) will maintain integrity of the vaccine by preventing degradation by oral proteases. To test our hypothesis, we will use a heterologous prime/boost regimen consisting of CD40L-adjuvanted DNA, MVA and protein vaccines expressing SHIV immunogens. In our preclinical macaque studies we showed that CD40L- adjuvanted DNA/MVA SIV vaccines delivered via IM route provide enhanced protection against intrarectal neutralization resistant SIV challenges. The addition of systemic protein boost adjuvanted with nanoparticle encapsulated TLR7/8 agonist to the DNA/MVA vaccine robustly boosted HIV envelope-specific IgG in serum and also increased antibody in vaginal and rectal secretions. In this proposal, in Aim 1, we will first optimize the method and location of oral vaccine delivery and compare different adjuvants for protein immunogen. We will compare sublingual and buccal immunizations delivered with and without syrijet for induction of strong SHIV- specific humoral and cellular immunity in the oral and gut mucosal tissue. We will also test other mucosal adjuvants flagellin and dmLT for protein immunizations. In Aim 2, using the best delivery method and adjuvant combination that we identify in Aim 1, we will conduct an intrarectal challenge study with clade C SHIV. This study will also focus on understanding the immune correlates for protection. By completion of these Aims we hope to have identified an efficient mucosal vaccination regimen for enhancing protection against HIV.

全世界大多数艾滋病毒感染都是通过粘膜途径（生殖器、口腔或直肠）发生的。总体目标为 该提案旨在开发一种疫苗接种方法，可诱导强烈的 HIV 特异性体液和细胞免疫反应 生殖器、肠道和口腔粘膜的免疫力。我们假设疫苗能够产生强烈的抗艾滋病毒 这些粘膜部位的免疫力，将预防感染并在感染部位很早就迅速清除受感染的细胞 感染，加强防护。口腔内含有丰富的淋巴组织，含有抗原呈递细胞、T 细胞和 B 细胞，并为粘膜递送疫苗提供了绝佳的机会。然而，这条路线 免疫接种未能充分利用来提供疫苗，部分原因是唾液中存在蛋白酶， 可以降解疫苗。对于基于蛋白质的疫苗尤其如此。在这里，我们的目标是口语 使用无针装置（Syrijet）作为口服疫苗输送系统对粘膜进行免疫接种，以诱导 口腔和肠粘膜部位有强烈的免疫反应。 Syrijet 可以将疫苗输送到口腔中 因此，粘膜将 1) 增强疫苗向局部淋巴组织的输送，从而促进 DC 的摄取 2) 通过防止口腔蛋白酶降解来保持疫苗的完整性。来测试我们的 假设，我们将使用由 CD40L 佐剂 DNA、MVA 和 表达 SHIV 免疫原的蛋白质疫苗。在我们的临床前猕猴研究中，我们表明 CD40L- 通过 IM 途径递送的佐剂 DNA/MVA SIV 疫苗可增强对直肠内感染的保护 抵抗中和的 SIV 挑战。添加纳米颗粒佐剂的全身蛋白增强剂 DNA/MVA 疫苗的封装 TLR7/8 激动剂可显着增强血清中的 HIV 包膜特异性 IgG 阴道和直肠分泌物中的抗体也增加。在本提案中，在目标 1 中，我们将首先优化 口服疫苗递送的方法和位置，并比较蛋白质免疫原的不同佐剂。我们将 比较使用和不使用 Syrijet 进行舌下和口腔免疫接种以诱导强 SHIV- 口腔和肠道粘膜组织中的特异性体液和细胞免疫。我们还将测试其他粘膜 用于蛋白质免疫的鞭毛蛋白和 dmLT 佐剂。在目标2中，使用最佳的递送方法和佐剂 结合我们在目标 1 中确定的组合，我们将对 C 型 SHIV 进行直肠内攻击研究。这 研究还将重点了解保护的免疫相关性。通过完成这些目标，我们 希望找到一种有效的粘膜疫苗接种方案来增强对艾滋病毒的保护。