New Approaches To Active Immunoprophylaxis

主动免疫预防的新方法

• 批准号: 7592233
• 负责人: Robert H. Purcell
• 金额: $ 208.07万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592233
• 关键词: Adjuvant; Adverse effects; Annual Reports; Antibodies; Antibody Formation; Attenuated; Belgium; Biological Models; Clinical Trials; Collaborations; Cooperative Research and Development Agreement; DNA Vaccines; Dose; Future; Genes; Glycoproteins; Goals; Hepatitis; Hepatitis A; Hepatitis A Vaccines; Hepatitis B; Hepatitis B Vaccines; Hepatitis C; Hepatitis C virus; Hepatitis E; Hepatitis Viruses; Immune response; Immunologic Adjuvants; In Vitro; Infection prevention; Licensing; Life; Macaca mulatta; Mus; Pan Genus; Pan troglodytes; Plasmids; Proteins; Recombinant Vaccines; Recombinants; Technology; Testing; Treatment Protocols; Vaccine Clinical Trial; Vaccines; Vaccinia; Viral hepatitis; Virulent; Virus; aluminum sulfate; base; env Gene Products; experience; expression vector; hepatitis C virus envelope 2 protein; immunogenic; immunoprophylaxis; improved; man; novel strategies; preclinical study; prevent

Hepatitis A and E vaccines. The HVS in collaboration with GlaxoSmithKline (GSK), Rixensart, Belgium, has developed several candidate live attenuated HAV vaccines. One such candidate was modified to become the currently licensed GSK inactivated HAV vaccine. In addition, the HVS has developed a candidate recombinant hepatitis E vaccine that is highly promising and that has recently completed clinical trials. In studies to further characterize this candidate hepatitis E vaccine, we have performed extensive pre-clinical trials to determine the potency of the vaccine, the duration of protection, the optimum regimen for administration, its protective efficacy against homologous versus heterologous virus strains, its ability to prevent infection as well as hepatitis and the minimum antibody titer that was effective in preventing infection and hepatitis, respectively. In the clinical trial, the vaccine was 96% efficacious in preventing hepatitis E following three doses of vaccine and 87% efficacious following two doses. The vaccine had no detectable side effects. These results are outstanding for a vaccine. GSK is currently determining its plans for future manufacture and distribution of the vaccine. Hepatitis B and C vaccines. The HVS has studied the technology of DNA vaccines with a model system based upon hepatitis B virus (HBV) vaccine, a vaccine with which the HVS has had extensive experience. We have tested the efficacy of an immunostimulant (CpG) as an adjuvant for DNA vaccines, as well as for protein vaccines. Protein vaccines were found to be superior to DNA vaccines when compared in chimpanzees, a surrogate of man. CpG provided a greater but short-lived antibody response when compared to alum adjuvant. In addition, the utility of DNA vaccines for the control of hepatitis C virus (HCV) has been explored. A DNA vaccine based on the E2 envelope protein of HCV proved to be highly immunogenic in mice and rhesus monkeys and moderately immunogenic in chimpanzees, but the chimpanzees were not fully protected when they were challenged with live HCV. A similar approach has been utilized in the study of a DNA vaccine based on the E1 envelope protein of HCV: various constructs of the E1 gene were prepared as DNA vaccines (expression vector plasmids) and as vectored vaccines (recombinant vaccinia) and tested in mice. The mice had excellent immune responses to the DNA vaccine as well as to the vaccinia boost. In other studies, recombinant HCV E1 envelope glycoprotein has been tested in chimpanzees as an immunoprophylactic vaccine. This vaccine, developed by Innogenetics and tested by HVS as part of a CRADA with the company, was administered to 9 chimpanzees, which were then challenged with virulent HCV provided by the HVS. As described in another annual report, we have identified in vitro correlates of protection that will be instrumental in identifying ineffective vaccines before testing in chimpanzees.

甲型和戊型肝炎疫苗。HVS与GlaxoSmithKline（GSK）（里克森萨尔，比利时）合作开发了几种候选的减毒活HAV疫苗。其中一种候选疫苗经过改良，成为目前获得许可的GSK灭活HAV疫苗。此外，HVS还开发了一种非常有前途的候选重组戊型肝炎疫苗，最近已完成临床试验。在进一步表征该候选戊型肝炎疫苗的研究中，我们进行了广泛的临床前试验，以确定疫苗的效力、保护持续时间、最佳给药方案、其对同源与异源病毒株的保护效力、其预防感染和肝炎的能力以及分别有效预防感染和肝炎的最低抗体滴度。在临床试验中，三剂疫苗预防戊型肝炎的有效性为96%，两剂疫苗的有效性为87%。 这种疫苗没有明显的副作用。 这些结果对于疫苗来说是杰出的。 葛兰素史克目前正在确定其未来生产和分销疫苗的计划。 B和C型肝炎疫苗。HVS已经研究了DNA疫苗技术，其模型系统基于HVS具有丰富经验的疫苗B型肝炎病毒（HBV）疫苗。我们已经测试了免疫刺激剂（CpG）作为DNA疫苗以及蛋白质疫苗的佐剂的功效。在黑猩猩（人类的替代品）中进行比较时，发现蛋白质疫苗上级DNA疫苗。与明矾佐剂相比，CpG提供了更大但短暂的抗体应答。此外，DNA疫苗用于控制丙型肝炎病毒（HCV）的效用已被探索。基于HCV E2包膜蛋白的DNA疫苗在小鼠和恒河猴中被证明具有高度免疫原性，在黑猩猩中具有中等免疫原性，但当黑猩猩被活HCV攻击时，它们没有得到完全保护。类似的方法已被用于基于HCV的E1包膜蛋白的DNA疫苗的研究中：将E1基因的各种构建体制备为DNA疫苗（表达载体质粒）和载体疫苗（重组牛痘），并在小鼠中进行测试。小鼠对DNA疫苗和牛痘疫苗都有很好的免疫反应。在其他研究中，重组HCV E1包膜糖蛋白已在黑猩猩中作为免疫预防疫苗进行了测试。这种疫苗由Innogenetics开发，由HVS测试，作为与该公司合作的CRADA的一部分，给9只黑猩猩接种，然后用HVS提供的强毒HCV进行攻击。 正如在另一份年度报告中所描述的，我们已经确定了体外保护的相关性，这将有助于在黑猩猩试验之前确定无效的疫苗。