Vaccine Modalities to Prevent HIV-I Infection
预防 HIV-I 感染的疫苗方式
基本信息
- 批准号:6950125
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AIDS education /prevention AIDS therapy AIDS vaccines HIV infections Macaca Macaca mulatta Poxviridae active immunization attenuated microorganism biotechnology disease /disorder model genetic promoter element human immunodeficiency virus 1 immunogenetics nonhuman therapy evaluation recombinant proteins regulatory gene simian immunodeficiency virus structural genes vaccine development vaccine evaluation vector vaccine virus antigen virus genetics virus infection mechanism
项目摘要
Part 1. The first part of the research plan is to assess highly attenuated recombinant poxvirus vaccine candidates in the rhesus macaque model. This work is a collaborative effort with Aventis-Pasteur, which has a CRADA with the NCI, and involves intra-agency collaboration with the NIAID. Two vectors are being tested: a canarypox-based vector (ALVAC) and the genetically attenuated vaccinia strain (a derivative of the Copenhagen strain) NYVAC. Both vectors are able to complete their replication cycle and express heterologous genes under the control of early or early/late promoters. The working hypothesis is that, because both poxvirus vectors, even in the absence of a complete life cycle, still express a large number of their proteins, the response against the heterologous antigens may be limited. Thus we have investigated the hypothesis that conventional DNA plasmid (optimized for expression) may prime immune responses that may further amplify boosting with recombinant poxviruses carrying the same SIV genes. The results obtained indicate that, indeed, priming with DNA and boosting with NYVAC-SIV potentiate the virus-specific immune response at least tenfold. Accordingly, this immunization regimen afforded better containment of viremia following challenge exposure. We are also testing the importance of the addition of all the accessory/regulatory genes to the SIV/HIV structural genes. For this purpose we have constructed a novel recombinant protein encompassing the genetic information of rev, nef, and tat devoided of active site. This recombinant antigen will be used as a vaccine component. Once an optimal combination of modalities is achieved, other regimens of immunization may be further optimized by investigating the importance of the route of immunization and the help of immunomodulatory molecules. Part 2. In view of the encouraging results obtained with a preventive NYVAC-SIV-gag-pol-env vaccine candidate in rhesus macaques, we hypothesized that such a vaccine could also be effective in a regimen of immune intervention following SIV infection. Thus, we develop a model in macaques whereby to test the effect of vaccination in the presence or absence of antiretroviral therapy. A study was designed to assess whether vaccination of macaques treated with antiretroviral therapy could enhance SIV-specific CD4+ T-helper and CD8+ T-cell cytotoxic responses and whether vaccination increased the ability of the host to maintain viremia at low levels following antiretroviral therapy suspension. The highly attenuated poxvirus NYVAC-SIV-gag-pol-env live recombinant vaccine candidate was chosen as a vaccine approach to test these concepts because of its demonstrated effectiveness as a preventive vaccine candidate in macaques. The results demonstrate the feasibility to establish an animal model in which immunization and immune intervention could be assessed in a controlled fashion and that both CD4+ and CD8+ T-cell responses were elicited/boosted by a vaccine in infected animals treated with HAART. This point is very important in the context of the present concern that HAART may silence the immune response to the detriment of the host. The use of this attenuated live vector is safe in animals with active viral replication as well as in HAART-treated macaques, suggesting that the approach may be used in humans. A larger study on efficacy of vaccination in chronically SIV251 infected macaques has suggested that vaccination may confer some transient advantage (Tryniszewska et al., J Immunol, 2002). Because of the encouraging nature of these results, a safety and immunogenicity trial in HIV-1-infected individuals will be initiated in the year 2004 using a NYVAC-based HIV-1 vaccine. Lastly, the use of cytokines such as IL-7 and IL-15 as "systemic adjuvants" of vaccines is being investigated. References: Pal et al., J Virol, 2002. Stevceva et al., J Virol, 2002. Stevceva et al., J Virol, 2002. Hel et al., J Immunol, 2002. Tryniszewska et al., J Immunol, 2002. Hel et al., DNA Cell Biol, 2002. Fry et al., Blood, 2003. Franchini et al., Vaccine, 2002. Hel et al., Virology, 2002. Nacsa et al., Virology, 2003. Radaelli et al., Virology, 2003. Nacsa et al., Vaccine, in press. Moniuszko et al., J Virol, in press. Stevceva et al., Virology, in press. Franchini et al., Advances in Cancer Research, in press. Edghill-Smith et al., J Infect Dis, in press.
部分1.研究计划的第一部分是在恒河猴模型中评估高度减毒的重组痘病毒候选疫苗。这项工作是与Aventis-Pasteur的合作努力,Aventis-Pasteur与NCI有一个CRADA,并涉及与NIAID的机构内合作。正在测试两种载体:基于金丝雀痘的载体(ALVAC)和遗传减毒牛痘菌株(哥本哈根菌株的衍生物)NYVAC。两种载体都能够完成其复制周期,并在早期或早期/晚期启动子的控制下表达异源基因。工作假设是,因为这两种痘病毒载体,即使在没有完整的生命周期的情况下,仍然表达大量的蛋白质,对异源抗原的反应可能是有限的。因此,我们已经研究了这样的假设,即常规DNA质粒(针对表达进行了优化)可以引发免疫应答,所述免疫应答可以进一步放大携带相同SIV基因的重组痘病毒的加强。获得的结果表明,确实,用DNA引发并用NYVAC-SIV加强增强病毒特异性免疫应答至少十倍。因此,该免疫方案在攻击暴露后提供了更好的病毒血症遏制。我们还在测试将所有辅助/调节基因添加到SIV/HIV结构基因中的重要性。为此目的,我们构建了一种新的重组蛋白,包含rev,nef和达特的遗传信息,没有活性位点。该重组抗原将用作疫苗组分。一旦实现了最佳的模式组合,可以通过研究免疫途径的重要性和免疫调节分子的帮助来进一步优化其他免疫方案。部分2.鉴于在恒河猴中用预防性NYVAC-SIV-gag-pol-env候选疫苗获得的令人鼓舞的结果,我们假设这样的疫苗在SIV感染后的免疫干预方案中也是有效的。因此,我们在猕猴中开发了一种模型,以测试在存在或不存在抗逆转录病毒治疗的情况下疫苗接种的效果。一项研究旨在评估接种抗逆转录病毒治疗的猕猴是否可以增强SIV特异性CD 4 + T辅助细胞和CD 8 + T细胞的细胞毒性反应,以及接种疫苗是否增加宿主在抗逆转录病毒治疗暂停后维持低水平病毒血症的能力。选择高度减毒的痘病毒NYVAC-SIV-gag-pol-env活重组疫苗候选物作为疫苗方法来测试这些概念,因为其在猕猴中作为预防性疫苗候选物的有效性已得到证实。结果证明了建立动物模型的可行性,在该动物模型中,可以以受控的方式评估免疫和免疫干预,并且在用HAART治疗的感染动物中,疫苗引起/加强了CD 4+和CD 8 + T细胞应答。这一点是非常重要的背景下,目前的关注,HAART可能沉默免疫反应,损害主机。这种减毒活载体的使用在具有活跃病毒复制的动物中以及在HAART处理的猕猴中是安全的,这表明该方法可用于人类。在慢性SIV 251感染的猕猴中进行的关于疫苗接种功效的更大研究表明,疫苗接种可赋予一些暂时优势(Tryniszewska等人,J Immunol,2002)。由于这些结果令人鼓舞,将于2004年开始在HIV-1感染者中使用基于NYVAC的HIV-1疫苗进行安全性和免疫原性试验。最后,正在研究使用细胞因子如IL-7和IL-15作为疫苗的“全身佐剂”。参考文献:Wendy et al.,J Virol,2002. Stevceva等人,J Virol,2002. Stevceva等人,J Virol,2002. Hel等人,免疫学杂志,2002年。Tryniszewska等人,免疫学杂志,2002年。Hel等人,DNA Cell Biol,2002. Fry等人,血,2003年。Franchini等人,疫苗,2002年。Hel等人,病毒学,2002年。Nacsa等人,病毒学,2003年。Radaelli等人,病毒学,2003年。Nacsa等人,疫苗,正在印刷中。Moniuszko等人,J Virol,in press. Stevceva等人,病毒学,印刷中。Franchini等人,癌症研究进展,出版中。Edghill-Smith等人,J Infect Dis,in press.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Genoveffa Franchini其他文献
Genoveffa Franchini的其他文献
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6939813 - 财政年份:2003
- 资助金额:
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6939800 - 财政年份:2003
- 资助金额:
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DEVELOPMENT OF AN HIV-1 AND HTLV-1 VACCINE IN ANIMAL MODELS
在动物模型中开发 HIV-1 和 HTLV-1 疫苗
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2463673 - 财政年份:
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7038625 - 财政年份:
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预防 HIV-1 感染的疫苗方式组合
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6761611 - 财政年份:
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