A Tetravalent Dengue Vaccine Based on Alphavirus Replicons

描述(由申请人提供)： 本申请中提出的临床前试验的目标是选择一种疫苗模式，希望能够解决目前正在开发的候选DEN疫苗的重大缺陷。减毒活疫苗很可能无法在母体抗体衰退之前免疫的单型免疫母亲所生婴儿中诱导对所有四种DEN血清型的内源性反应。如果通过推迟接种疫苗来避免这个问题，直到母体抗体充分腐烂，从而允许使用减毒活疫苗，那么在此期间，这些婴儿将失去对严重登革热的保护。针对登革热的DNA疫苗可能会绕过母体抗体问题，但DNA疫苗在人体试验中普遍令人失望，特别是在诱导体液反应方面，体液反应是预防登革热的最重要反应。我们已经提出了一系列实验，首先将确定在小鼠和猕猴中最有效地诱导反应的E蛋白的配置，测试一种有希望的可溶形式的E的新配置，该配置显示出显著改善的中和反应。其次，我们将在小鼠和婴儿猕猴身上确定VRP疫苗鸡尾酒是否能诱导对所有四种血清型的平衡反应，并且像我们之前在小鼠上进行的DEN2-VRP实验中预测的那样，在被动转移的中和抗体存在的情况下安全地做到这一点。第三，我们将测试一种新开发的DNA启动形式的VEE载体在小鼠和猕猴中的有效性，b)面对抗DEN中和抗体，以及c)VEE中和抗体的存在。最后，我们将测试混合模式PRIME-BOOST方案，它们可能很好地代表基于VEE的疫苗载体的最佳接种策略。我们认为，在这些研究结束时，我们将为将基于VEE的DEN候选疫苗推进到I期人体试验奠定坚实的基础。

DESCRIPTION (provided by applicant): The objective of the pre-clinical experiments proposed in this application is to select a vaccine modality that hopefully will address significant deficiencies in the slate of candidate DEN vaccines currently in development. Live attenuated vaccines likely will fail to induce endogenous responses to all four DEN serotypes in infants born to monotypically immune mothers and immunized prior to the decay of maternal antibody. If this problem is avoided by delaying vaccination until maternal antibody decays sufficiently to allow use of live attenuated vaccines, then these infants will be left unprotected from severe DEN disease during this period. DNA vaccines for DEN are likely to circumvent the maternal antibody problem, but DNA vaccines generally have been disappointing in human trials, especially in terms of inducing humoral responses which are the most important responses for protection against DEN. We have proposed a sequence of experiments that will first determine the configuration of the E protein most effective in inducing responses in mice and macaques, testing a promising new configuration of E in soluble form that showed a significantly improved neutralizing response. Second, we will determine in mice and infant macaques whether a VRP vaccine cocktail induces a balanced response to all four serotypes and does so safely and in the presence of passively transferred neutralizing antibodies, as would be predicted from our previous experiments with DEN2-VRP in mice. Third, we will test a newly developed DNA launched form of the VEE vectors for their utility a) in mice and macaques, b) in the face of anti-DEN neutralizing antibodies, and c) in the presence of neutralizing antibodies to VEE. Finally, we will test mixed modality prime-boost regimens that may well represent the optimal vaccination strategy for VEE based vaccine vectors. We feel that at the conclusion of these studies, we will have established a solid justification for advancement of a VEE based vaccine candidate for DEN into phase I human trials.