DEVELOPMENT OF A NOVEL MULTIENVELOPE AIDS VACCINE

圣犹达儿童研究医院（SJCRH）五年前启动了一项艾滋病毒-1疫苗方案，深信这一复杂问题将通过协调的多学科方法得到最有效的解决；因此，该项目目前涉及SJCRH免疫学、病毒学、传染病和结构生物学部门的研究人员。开发有效的HIV-1疫苗的核心问题在于病毒的抗原多样性。SJCRH HIV-1疫苗项目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，该项目已经启动了fda批准的PolyEnv1 I期临床试验，这是第一种包含超过一种或两种HIV包膜蛋白结构的HIV疫苗。正在进行的PolyEnv1临床试验采用了减毒活病毒载体来递送疫苗。初步数据表明，修改疫苗接种制度，以三种不同的免疫原性形式（DNA、减毒病毒和天然蛋白）的顺序组合递送PolyEnv1中所代表的包膜蛋白结构鸡尾酒，可能导致产生效价大大提高的中和抗体。项目1 （P. Doherty）和2 （R. Webster）的具体目标使用小鼠模型来探索免疫原形式组合的免疫反应性质，优化疫苗接种方案，并确定免疫原复杂性与疫苗效率之间的关系。项目3 （J. Hurwitz）在灵长类动物（猕猴）的免疫缺陷病毒感染疫苗模型中实施了项目1和项目2的发现，并制定了最佳的疫苗制造方案。项目4 （K. Slobod）以这些研究为基础，开始对由免疫原包膜组合组成的疫苗的安全性和有效性进行临床试验。

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.