A NASAL DNA/PROTEIN VACCINE FOR ANTI-HIV ANTIBODY AND CTL

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 简介：艾滋病毒疫苗开发的一个优先事项是在生殖道和直肠产生抗病毒免疫反应，艾滋病毒传播最经常发生在生殖道和直肠。最近的数据表明，口服或直肠免疫接种将需要在疫苗接种者中诱导最佳肠道免疫。然而，口服疫苗必须保护免受胃酸以及肠腔中的降解酶的影响。确定脂质体和肠溶胶囊双重包封疫苗口服后是否能诱导免疫应答。 研究方法：将含有SIV包膜蛋白和编码非感染性SHIV89.6P颗粒的DNA的阳离子脂质体冷冻干燥并置于肠溶包衣胶囊内，所述肠溶包衣胶囊设计成抵抗十二指肠的酸性pH但不抵抗中性pH。在第0周和第6周，用含有脂质体DNA/蛋白的胶囊口服免疫先前通过鼻途径用SHIV DNA/SIV Env蛋白免疫的12只恒河猴。结果/讨论：在第一次口服免疫后1个月，在所有动物的血液中观察到对SIV Env和Gag蛋白的强烈淋巴增殖反应。 在第一次免疫后的大多数动物中，以及在第二次免疫后的所有动物中，产生IFN-g和TNF-a的SIV Env特异性T细胞和Gag特异性T细胞的频率增加。SIV特异性粘膜或全身抗体没有增加。利用阳离子脂质体和肠溶胶囊的双重包封策略可成功地用于在小肠中递送DNA/蛋白质以诱导疫苗特异性T细胞。 然而，产生肠道伊加反应将需要更大剂量的蛋白质或口服佐剂。 应进行旨在优化口服HIV疫苗的进一步研究，因为与肌肉注射和鼻腔途径相比，同时使用鼻腔和口服给药途径的方案更有可能在生殖道和直肠中诱导保护性免疫。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction: A priority in HIV vaccine development is to generate antiviral immune responses in the genital tract and rectum, where HIV transmission most frequently occurs. Recent data suggests that oral or rectal immunization will be required to induce optimal intestinal immunity in vaccine recipients. However, oral vaccines must be protected from stomach acid as well as degradative enzymes in the intestinal lumen. To determine if dual encapsulation of vaccine in liposomes and enteric-coated capsules can induce immune responses after oral delivery. Methods: Cationic liposomes containing SIV envelope protein and DNA encoding noninfectious SHIV89.6P particles were freeze-dried and placed inside enteric-coated capsules designed to resist acidic pH but not the neutral pH of the duodenum. Twelve rhesus macaques that had been previously immunized by the nasal route with SHIV DNA/SIV Env protein were orally-immunized on weeks 0 and 6 with a capsule containing liposomal DNA/protein. Results/Discussion: Strong lymphoproliferative responses to the SIV Env and Gag proteins were observed in blood of all animals 1 month after the 1st oral immunization. The frequencies of SIV Env- and Gag-specific T cells producing IFN-g and TNF-a were increased in the majority of animals after the 1st immunization, and in all animals after the 2nd immunization. There were no increases in SIV-specific mucosal or systemic antibodies. A dual encapsulation strategy utilizing cationic liposomes and enteric-coated capsules can be used successfully to deliver DNA/protein in the small intestine for induction of vaccine-specific T cells. However, generating intestinal IgA responses will require larger doses of protein or an oral adjuvant. Further studies aimed at optimizing oral HIV vaccines should be performed since regimens that utilize both the nasal and oral delivery routes are more likely to induce protective immunity in the genital tract and rectum than those that utilize the intramuscular and nasal routes.