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实验的目的是选择一种疫苗形式，该疫苗形式有望解决目前正在开发的候选DEN疫苗中的重大缺陷。减毒活疫苗很可能不能在单型免疫母亲所生的婴儿中诱导对所有四种DEN血清型的内源性应答，并且在母体抗体衰减之前进行免疫。如果通过推迟接种直到母体抗体衰减到足以允许使用减毒活疫苗来避免这个问题，那么这些婴儿在此期间将不会受到严重DEN疾病的保护。登革病毒DNA疫苗很可能避免母源抗体问题，但DNA疫苗在人体试验中通常令人失望，特别是在诱导体液反应方面，这是保护登革病毒最重要的反应。我们已经提出了一系列的实验，将首先确定的E蛋白的配置最有效地诱导小鼠和猕猴的反应，测试一个有前途的新的配置E在可溶性形式，显示出显着改善的中和反应。第二，我们将在小鼠和幼年猕猴中确定VRP疫苗混合物是否诱导对所有四种血清型的平衡应答，并且在被动转移的中和抗体存在下安全地诱导，如我们先前在小鼠中使用DEN 2-VRP的实验所预测的。第三，我们将测试一种新开发的DNA启动形式的VEE载体的效用a）在小鼠和猕猴中，B）在面对抗DEN中和抗体时，和c）在存在VEE中和抗体时。最后，我们将测试混合模式初免-加强方案，其可以很好地代表基于VEE的疫苗载体的最佳疫苗接种策略。我们认为，在这些研究的结论，我们将建立一个坚实的理由，推进基于VEE的候选疫苗登进入第一阶段人体试验。

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.