Vaginal Immunity After Intranasal Listeria Vaccination

描述（由申请人提供）：上皮层既是攻击部位，也是大多数HIV感染的第一道防线。不幸的是，这种防御是可以攻破的。在4200万艾滋病毒感染者中，有一半是经阴道感染的妇女，其余大多数是通过直肠上皮感染的男子。强化这些粘膜表面应该是HIV疫苗的优先事项。细胞免疫在控制疾病进展中起着深远的作用，但最终证明是不成功的，因为它发展得太慢。局部主动免疫可阻断粘膜最早的感染事件和病毒从这些部位的传播。虽然产生针对原代HIV分离物的中和抗体是有问题的，但有几种药物可以可靠地诱导细胞免疫。由于鼻腔免疫经常显示产生阴道免疫反应，我们建议探索使用单核细胞增生李斯特菌（Lm），一种已知可诱导强细胞免疫的药物，作为艾滋病毒的鼻腔疫苗。一份报告已经表明，鼻内接种Lm可有效产生对高剂量鼻内或静脉注射Lm的耐药性。我们自己的初步研究证实了这一点，并表明鼻黏膜比肠道对Lm的感染和易位更敏感。我们建议检查早期细胞免疫应答对IN Lm感染的反应，重要的是，测试这种方法的安全性，并预测用活的、减毒的Lm疫苗株免疫IN的保护效果将扩展到女性生殖道。与口服接种相结合，重组菌株Lm可能导致阴道、肠道和直肠表面免受HIV感染。

DESCRIPTION (provided by applicant): The epithelial layer is both the site of attack and the first line of defense for most HIV infections. Unfortunately, this defense is breachable. Half of the 42 million people living with HIV are women infected vaginally and most of the remainder are men infected through the rectal epithelium. Fortification of these mucosal surfaces should be a priority for HIV vaccines. Cellular immunity plays a profound role in controlling disease progression but ultimately proves unsuccessful since it develops too slowly. Active local immunity could block the earliest infection events at mucosae and the spread of virus from these sites. While the generation of neutralizing antibodies against primary HIV isolates is problematic, several agents can reliably elicit the induction of cellular immunity. Since nasal immunization has often been shown to generate vaginal immune responses, we are proposing to explore the use of Listeria monocytogenes (Lm), an agent known to induce strong cellular immunity, as a nasal vaccine for HIV. One report has already shown that intranasal (IN) immunization with Lm is effective for generating resistance to high dose intranasal or intravenous Lm challenge. Our own preliminary studies confirm this, and show that the nasal mucosa is even more sensitive than the gut to infection and translocation by Lm. We propose to examine the early cellular immune responses to IN Lm infection and importantly, test both the safety of this approach and the prediction that the protective efficacy of IN immunization with live, attenuated Lm vaccine strains will extend to the female genital tract. In combination with oral inoculation, recombinant strains of Lm may result in protection of vaginal, intestinal and rectal surfaces against HIV infection.