DEVELOPMENT OF A NOVEL MULTIENVELOPE AIDS VACCINE

圣犹大儿童研究医院(SJCRH)五年前启动了一项HIV-1疫苗计划，坚信通过协调、多学科的方法将最有效地解决他的复杂问题；因此，该计划目前涉及SJCRH免疫学、病毒学、传染病和结构生物学系的研究人员。开发有效的HIV-1疫苗的中心问题在于病毒的抗原性多样性。SJCRH HIV-1疫苗计划通过将病原体的多样性与疫苗结构的多样性相匹配，在明确承认这种抗原复杂性方面是独一无二的。到目前为止，该计划内的工作已经启动了FDA批准的PolyEnv1的第一阶段临床试验，这是第一种包含一个或两个以上HIV包膜蛋白结构的HIV疫苗。正在进行的PolyEnv1临床试验使用了减毒活病毒载体来交付疫苗。初步数据表明，修改疫苗接种制度，以三种不同免疫原性形式(DNA、减毒病毒和天然蛋白)的顺序组合提供PolyEnv1中所代表的包膜蛋白结构的鸡尾酒，可能会导致中和抗体的产生滴度大大增加。项目1(P.Doherty)和项目2(R.Webster)的具体目标是使用小鼠模型来探索对免疫原形式组合的免疫反应的性质，优化疫苗接种方案，并确定免疫原复杂性和疫苗效率之间的关系。项目3(J.Hurwitz)在针对免疫缺陷病毒感染的灵长类(猕猴)疫苗接种模型中实施了项目1和2的发现，并开发了最佳疫苗制造方案。项目4(K.Slobod)建立在这些研究的基础上，启动了由免疫原膜组合组成的疫苗的安全性和有效性的临床试验。

St. Jude Children's Research Hospital (SJCRH) initiated an HIV-1 vaccine program five years ago with the conviction that his complex issue would be most effectively addressed through a coordinated, multi-disciplinary approach; the program thus currently involves investigators from SJCRH departments of Immunology , Virology, Infectious Diseases and Structural Biology. The central problem in developing an effective HIV-1 vaccine lies in the antigenic diversity of the virus. The SJCRH HIV-1 vaccine program is unique in explicitly acknowledging this antigenic complexity, by matching the diversity of the pathogen with a diversity of vaccine structures. Thus far, work within the program has resulted in the initiation of an FDA-approved, phase I clinical trial of PolyEnv1, the first HIV vaccine to encompass more than one or two HIV envelope protein structures. The ongoing clinical trial with PolyEnv1 has employed an attenuated live virus vehicle to deliver the vaccine. Preliminary data indicate that modification of the vaccination regime to deliver the cocktail of envelope protein structures represented in PolyEnv1 in a sequential combination of three different immunogenic forms (DNA, attenuated virus and native protein) may result in the generation of neutralizing antibodies at a much increased titer. Specific Aims in Projects 1 (P. Doherty) and 2 (R. Webster) use mouse models to explore the nature of the immune response to combinations of immunogenic forms, to optimize vaccination schemes and to determine the relationship between immunogen complexity and vaccine efficiency. Project 3 (J. Hurwitz) implements the findings of Projects 1 and 2 in a primate (macaques) model of vaccination against immunodeficiency virus infection, as well as developing optimal vaccine manufacturing schemes. Project 4 (K. Slobod) builds on these studies, initiating clinical trials of the safety and effectiveness of vaccines comprised of combinations of immunogenic envelopes.