DEVELOPMENT OF A NOVEL MULTIENVELOPE AIDS VACCINE

五年前，圣裘德儿童研究医院（SJCRH）启动了一项HIV-1疫苗计划，坚信通过协调的多学科方法将最有效地解决他的复杂问题;该计划目前涉及免疫学，病毒学，传染病和结构生物学的SJCRH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，明确承认了这种抗原的复杂性，这是独一无二的。到目前为止，该项目的工作已经启动了FDA批准的PolyEnv 1的I期临床试验，这是第一个包含一种或两种以上HIV包膜蛋白结构的HIV疫苗。正在进行的PolyEnv 1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，疫苗接种方案的修改，以三种不同免疫原性形式（DNA、减毒病毒和天然蛋白质）的顺序组合递送PolyEnv 1中代表的包膜蛋白结构的混合物，可能导致产生滴度大大增加的中和抗体。项目1（P. Doherty）和项目2（R.韦伯斯特）使用小鼠模型来探索对免疫原性形式的组合的免疫应答的性质，以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）在免疫缺陷病毒感染的灵长类动物（猕猴）模型中实施项目1和2的研究结果，并制定最佳疫苗生产方案。项目4（K. Slobod）在这些研究的基础上，启动了由免疫原性包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.