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.

大多数HIV感染通过全球范围内通过粘膜（生殖器，口服或直肠）发生。总体目标 该建议是开发一种疫苗接种方法，该方法诱导强大的HIV特异性体液和细胞 生殖器，肠道和口服粘膜的免疫力。我们假设这种疫苗会引起强烈的抗HIV 在这些粘膜部位的免疫力将在很早的地方防止感染和迅速清除感染细胞 感染并增强保护。口腔富含含有抗原呈递细胞的淋巴组织，t 细胞和B细胞，为疫苗的粘膜输送提供了绝佳的机会。但是，这条路线 免疫已被用来输送疫苗，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，我们的目标是针对口头 使用无针器（Syrijet）作为口服疫苗输送系统进行免疫的粘膜以诱导 口服和肠粘膜部位的强烈免疫反应。 Syrijet可以将疫苗输送到口服 因此，粘膜将1）增强疫苗向局部淋巴组织的递送，这将促进DC的吸收 2）将通过防止口服蛋白酶降解来保持疫苗的完整性。测试我们的 假设，我们将使用由CD40L-Adjuvant的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路线传递的辅助DNA/MVA SIV疫苗可增强直肠的保护 抵抗中和的SIV挑战。添加与纳米颗粒的全身蛋白增强佐剂 将TLR7/8激动剂封装到DNA/MVA疫苗的鲁棒增强血清中的HIV信封特异性IgG 还增加了阴道和直肠分泌物中的抗体。在此提案中，在AIM 1中，我们将首先优化 口服疫苗输送的方法和位置，并比较蛋白质免疫原的不同辅助剂。我们将 比较有或没有Syrijet的舌下和颊免疫，以诱导强烈的Shiv- 口服和肠粘膜组织中的特定体液和细胞免疫。我们还将测试其他粘膜 用于蛋白质免疫的佐剂鞭毛蛋白和DMLT。在AIM 2中，使用最佳递送方法和佐剂 我们在AIM 1中确定的结合，我们将通过进化枝C进行直肠内挑战研究。这 研究还将集中于理解保护的免疫相关性。通过完成这些目标我们 希望能确定一种有效的粘膜疫苗接种方案，以增强对艾滋病毒的保护。