Mucosal vaccination to protect against HIV-1 infection at mucosal sites

描述（由申请人提供）：RV144 HIV-1疫苗试验的结果表明，采用由痘病毒ALVAC gag/pol/gp120引物结合重组gp120增强剂组成的系统性异种引物-增强免疫方案，系统性引物/增强疫苗方案有可能诱导对HIV-1感染的中度但显著的保护，这种保护被认为是抗体介导的。由于HIV-1感染主要是粘膜获得性感染，使用有效的粘膜免疫可能提供优于RV144试验中观察到的保护。本提案的目标是利用先前开发的非人类灵长类动物的系统初始-增强免疫方案，并开发一种新的异源粘膜初始-增强疫苗接种策略，以验证优化的粘膜疫苗接种对粘膜SHIV攻击的保护优于系统免疫诱导的保护的假设。为了实现这一目标，我们将利用三种新的疫苗成分来优化粘膜免疫：1)一种新的病毒载体，2)一种新的gp120融合蛋白和3)一种新的粘膜疫苗佐剂。表达HIV-1 gp140的新病毒载体是一种重组修饰的安卡拉牛痘，它被设计成产生a型内含物（MVA/ATI- gp140）。ATI含有成熟病毒（MV）颗粒，使用MVA ATIs作为疫苗载体有望增加MVA疫苗载体的粘膜感染，并使重组MVA抵抗MVA特异性抗体的中和。新的gp120融合蛋白将包含与gp120基因融合的腺病毒2型纤维（Ad2F）。既往研究表明，Ad2F作为粘膜靶向配体，可增强重组蛋白抗原的粘膜免疫原性，诱导中和抗体反应。此外，Ad2F可能支持gp120的三聚化，产生更天然的确认，从而增强其诱导保护性抗体的能力。新型疫苗佐剂由阳离子宿主防御肽组成，已用于非人灵长类动物鼻腔免疫后安全诱导保护性免疫。

DESCRIPTION (provided by applicant): Results from the RV144 HIV-1 vaccine trial that utilized a systemic heterologous prime-boost immunization regimen consisting of a poxvirus ALVAC gag/pol/gp120 prime combined with a recombinant gp120 boost demonstrated that systemic prime/boost vaccination regimens have the potential to induce modest but significant protection against HIV-1 infection that is presumed to be antibody-mediated. Since HIV-1 infection is predominantly a mucosally-acquired infection, the use of effective mucosal immunization may provide protection superior to that observed in the RV144 trial. The goal of this proposal is to utilize a previously developed systemic prime- boost immunization regimen in non-human primates and develop a new heterologous mucosal prime-boost vaccination strategy to test the hypothesis that optimized mucosal vaccination provides protection against a mucosal SHIV challenge that is superior to protection induced by systemic immunization. To achieve this goal, we will optimize mucosal immunization utilizing three new vaccine components: 1) a novel viral vector, 2) a novel gp120 fusion protein and 3) novel mucosal vaccine adjuvants. The new viral vector that expresses HIV-1 gp140 is a recombinant modified vaccinia Ankara engineered to produce A-type inclusions (MVA/ATI- gp140). The ATI contain mature virus (MV) particles and the use of the MVA ATIs as vaccine vectors is expected to increase mucosal infection with the MVA vaccine vector and allow the recombinant MVA to resist neutralization by MVA-specific antibodies. The novel gp120 fusion protein will contain the adenovirus type 2 fiber (Ad2F) genetically fused to gp120. Previous studies have demonstrated that Ad2F serves as a mucosal targeting ligand to enhance the mucosal immunogenicity of recombinant protein antigens for the induction of neutralizing antibody responses. Additionally, Ad2F may support trimerization of gp120 producing a more native confirmation that may enhance its ability to induce protective antibodies. The novel vaccine adjuvant consist of cationic host defense peptides that have been used to safely induce protective immunity after nasal immunization in non-human primates. PUBLIC HEALTH RELEVANCE: HIV-1 infection continues to be a significant world-wide public health crisis. The goal of the studies proposed is to develop an HIV-1 vaccine system that can be administered without the use of needles that induces anti-HIV-1 antibody responses in the blood and mucosal secretions to protect against HIV infection.