Vaginal Immunity After Intranasal Listeria Vaccination

描述（由申请人提供）：上皮层是大多数HIV感染的攻击部位和第一道防线。不幸的是，这种防御是可以突破的。在4 200万艾滋病毒感染者中，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。这些粘膜表面的强化应该是HIV疫苗的优先事项。细胞免疫在控制疾病进展方面发挥着重要作用，但最终证明是不成功的，因为它发展得太慢。主动的局部免疫可以阻断最早的粘膜感染事件和病毒从这些部位的传播。虽然产生针对原代HIV分离株的中和抗体是有问题的，但几种试剂可以可靠地引起细胞免疫的诱导。由于鼻腔免疫经常被证明会产生阴道免疫反应，我们建议探索使用单核细胞增生李斯特菌（Lm），一种已知能诱导强细胞免疫的药物，作为HIV的鼻腔疫苗。一份报告已经表明，用Lm鼻内（IN）免疫可有效产生对高剂量鼻内或静脉内Lm攻击的抗性。我们自己的初步研究证实了这一点，并表明鼻粘膜甚至比肠道对Lm的感染和易位更敏感。我们建议检查IN Lm感染的早期细胞免疫应答，重要的是，测试这种方法的安全性和预测IN免疫与活的减毒Lm疫苗株的保护效力将延伸到女性生殖道。结合口服接种，Lm的重组菌株可能会导致保护阴道，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.