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是通过性活动获得的，或者在较小程度上是通过注射吸毒者的静脉注射获得的，因此疫苗需要刺激循环和粘膜免疫反应，以提供最大限度的保护，防止艾滋病毒感染和传播。人类粘膜免疫的主要诱导位点是鼻呼吸道上皮。在我们实验室以及其他实验室的先前研究中，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。我们已经发现，用脊髓灰质炎病毒复制子进行RNA免疫，然后用重组蛋白进行鼻内接种，导致血清和分泌物中产生抗体。基于这些研究，我们提出，免疫与RNA载体在外周，然后加强鼻内免疫与重组蛋白可能是一种有效的方式来刺激全身和粘膜免疫。这项R21提案的目标是进一步开发这种新的初免-加强疫苗方法。建议的具体目标如下： 具体目标1：确定基于脊髓灰质炎病毒或SFV的复制子在重组抗原鼻内加强免疫后诱导循环和粘膜反应的启动是否更有效。我们将比较编码gag或包膜的脊髓灰质炎病毒或SFV复制子在通过肌内免疫给予时引发全身和粘膜免疫应答的能力的功效。 具体目标2：确定不同HIV-1进化枝的初免-加强是否会扩大免疫应答。编码进化枝C HIV-1 gag和包膜的RNA复制子（脊髓灰质炎或SFV）将用于肌内免疫。然后，我们将比较用重组进化枝B病毒gag和包膜鼻内免疫与用HIV-1进化枝C gag和包膜鼻内免疫诱导的免疫应答。 这些研究的结果应该提供有关RNA初免/重组抗原加强疫苗方案作为产生针对HIV-1的全身和粘膜免疫反应的手段的功效的重要临床前信息。

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.