RNA Replicons to Enhance Nasal Vaccines

描述(由申请人提供)：开发有效和安全的疫苗是预防和控制艾滋病的重要组成部分。由于大多数新的艾滋病毒感染要么是通过性行为获得的，要么是在注射吸毒者中感染的，程度较小的是静脉注射，因此疫苗需要刺激循环和粘膜免疫反应，以最大限度地预防艾滋病毒感染和传播。鼻腔呼吸道上皮是人类黏膜免疫的一个主要诱导部位。在我们实验室和其他实验室以前的研究中，基于脊髓灰质炎病毒或塞姆利基森林病毒(SFV)的RNA载体(复制子)的使用已经确立了RNA免疫的潜力。我们发现，用脊髓灰质炎病毒复制体进行RNA免疫，然后经鼻接种重组蛋白，可以在血清和分泌物中产生抗体。在这些研究的基础上，我们提出了用RNA载体进行外周免疫，然后用重组蛋白加强鼻腔免疫是一种刺激全身和粘膜免疫的有效方法。因此，这项R21提案的目标是进一步开发这种新的优质增强疫苗方法。提出了以下具体目标： 具体目的1：确定脊髓灰质炎病毒或基于SFV的复制体在重组抗原鼻腔注射后诱导循环和粘膜反应中哪一个更有效。我们将比较编码Gag或包膜的脊髓灰质炎病毒或SFV复制体在通过肌肉免疫时启动系统和粘膜免疫反应的能力的有效性。 具体目标2：确定不同HIV-1分支的Prime-Boost是否会扩大免疫反应。编码C分支HIV-1 Gag和包膜的RNA复制子(脊髓灰质炎或SFV)将用于肌肉免疫。然后，我们将比较重组B分支病毒Gag和包膜与HIV-1 C分支Gag和包膜鼻腔免疫诱导的免疫应答。 这些研究的结果应该提供重要的临床前信息，即RNA初级/重组抗原增强疫苗方案作为产生对HIV-1的系统和粘膜免疫反应的一种手段的有效性。

DESCRIPTION (provided by applicant): The development of an effective and safe vaccine is an essential component in the prevention and control of AIDS. Since most of the new HIV infections are acquired either through sexual activity, or to a lesser extent intravenously among injecting drug abusers, a vaccine will need to stimulate both the circulatory and mucosal immune responses to provide maximal protection against HIV infection and transmission. A major inductive site for mucosal immunity in humans is the nasal respiratory epithelium. In previous studies from our laboratory as well as others, the use of RNA vectors (replicons) based on poliovirus or Semliki Forest Virus (SFV) have established the potential of RNA immunization. We have found that RNA immunization with poliovirus replicons followed by intranasal inoculation with recombinant protein resulted in the production of antibodies in both the serum and secretions. Based on these studies, we propose that immunization with RNA vectors in the periphery, followed by booster intranasal immunization with recombinant proteins could be an effective way to stimulate both systemic and mucosal immunity. The goal of this R21 proposal then is to further develop this novel prime-boost vaccine approach. The following Specific Aims are proposed: Specific Aim 1: To determine if poliovirus or SFV based replicons are more effective in priming for induction of circulatory and mucosal response following nasal boost with recombinant antigen. We will compare the efficacy of poliovirus or SFV replicons that encode gag or envelope for the capacity to prime both the systemic and mucosal immune response when given via intramuscular immunization. Specific Aim 2: To determine if prime-boost with different HIV-1 clades will broaden the immune response. RNA replicons (polio or SFV) encoding clade C HIV-1 gag and envelope will be used for intramuscular immunization. We will then compare the immune response by intranasal immunization with recombinant clade B virus gag and envelope with that induced by intranasal immunization with HIV-1 clade C gag and envelope. The results of these studies should provide essential pre-clinical information as to the efficacy of the RNA prime/recombinant antigen boost vaccine protocol as a means to generate both systemic and mucosal immune responses to HIV-1.