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

描述（由申请方提供）：使用由痘病毒ALVAC gag/pol/gp 120初免联合重组gp 120加强免疫组成的全身性异源初免-加强免疫方案的RV 144 HIV-1疫苗试验的结果表明，全身性初免/加强免疫方案有可能诱导适度但显著的HIV-1感染保护，推测其为抗体介导的。由于HIV-1感染主要是一种粘膜获得性感染，因此使用有效的粘膜免疫可能提供比RV 144试验中观察到的保护更上级的保护。该提案的目的是在非人灵长类动物中利用先前开发的全身性初免-加强免疫方案，并开发新的异源粘膜初免-加强免疫接种策略，以测试优化的粘膜接种提供对抗粘膜SHIV攻击的保护的假设，其上级于全身免疫诱导的保护。为了实现这一目标，我们将利用三种新的疫苗组分优化粘膜免疫：1）新型病毒载体，2）新型gp 120融合蛋白和3）新型粘膜疫苗佐剂。表达HIV-1 gp 140的新病毒载体是一种重组改良的安卡拉牛痘，经工程改造可产生A型包涵体（MVA/ATI-gp 140）。ATI含有成熟病毒（MV）颗粒，并且使用MVA ATI作为疫苗载体预期会增加MVA疫苗载体的粘膜感染，并允许重组MVA抵抗MVA特异性抗体的中和。新的gp 120融合蛋白将含有与gp 120基因融合的腺病毒2型尾丝（Ad 2F）。以往的研究表明，Ad 2F作为粘膜靶向配体，可增强重组蛋白抗原的粘膜免疫原性，诱导中和抗体应答。此外，Ad 2F可以支持gp 120的三聚化，产生更天然的构象，这可以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，其已用于在非人灵长类动物中鼻免疫后安全地诱导保护性免疫。 公共卫生相关性：HIV-1感染仍然是一个重大的全球公共卫生危机。这些研究的目标是开发一种HIV-1疫苗系统，该系统可以在不使用针头的情况下接种，从而在血液和粘膜分泌物中诱导抗HIV-1抗体反应，以防止HIV感染。

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.