DNA IMMUNIZATION AGAINST SIVMNE USING MULTIPLE VIRAL ANTIGENS

使用多种病毒抗原进行针对 SIVMNE 的 DNA 免疫

• 批准号: 6116356
• 负责人: Nancy L Haigwood
• 金额: $ 8.67万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6116356
• 关键词: AIDS; Mammalia; Primates; animal tissue; biomaterials; biotechnology; disease /disorder prevention /control; immunology; infection; inflammation; lymphatic system; vaccines; virus

We used SIV infection of macaques as an animal model to assess DNA immunization as a strategy for protecting against HIV infection in humans. We compared the efficacy of DNA immunization alone and in combination with subunit protein boosts. The DNA vaccine consisted of all structural and regulatory genes of SIVmne cloned into mammalian expression vectors. Eight cynomolgus macaques were immunized twice, at weeks 0 and 8, with plasmid DNA and four control animals received vector DNA alone. Four primed macaques also received DNA boosters at weeks 16 and 36, while the second group of four were boosted with recombinant Env plus recombinant Gag-Pol particles in oil emulsion adjuvant. Two controls received vector-only DNA and two received adjuvant alone. As expected, humoral immune responses were stronger in the macaques that received subunit boosts, but responses were sustained in both groups, as measured by ELISA antibody titers to SIV Env. We measured neutralizing antibody titers, cytotoxic T lymphocyte responses, and T cell proliferative responses in all vaccinees over the course of immunization. All animals were challenged at week 38 with SIVmne by the intrarectal route. Post-challenge virus load was measured in all animals and there were major differences between the groups in the challenge outcome. Surprisingly, sustained low virus loads were observed only in the DNA group (2/4 macaques), suggesting that 4 immunizations with DNA alone elicited more effective immune responses than 2 DNA primes combined with 2 protein boosts. This study represents the first case of DNA immunization eliciting protective immunity against a pathogenic SIV challenge. Multigenic DNA vaccines such as these, bearing all structural and regulatory genes, show significant promise and may be a safe alternative to live-attenuated vaccines.

我们使用猕猴的SIV感染作为动物模型来评估DNA免疫，以此作为预防人类中HIV感染的策略。 我们比较了单独的DNA免疫的功效，并与亚基蛋白促进的功效进行了比较。 DNA疫苗由克隆到哺乳动物表达载体的所有结构和调节基因组成。 在第0和第8周，将八个Cynomolgus猕猴免疫两次，质粒DNA和四只对照动物仅接受载体DNA。 在第16周和第36周，有四个尖锐猕猴还接受了DNA助推器，而第二组则用重组ENV加上重组加人的GAG-POL颗粒在油乳液佐剂中提高。 两个对照仅接受载体的DNA，两个对照单独接受辅助。 正如预期的那样，在获得亚基增强的猕猴中的体液免疫反应更强，但两组的反应均维持，如ELISA抗体滴度对SIV Env的衡量。在免疫过程中，我们测量了所有疫苗中中和抗体滴度，细胞毒性T淋巴细胞反应和T细胞增殖反应。 所有动物在第38周通过直肠途径挑战了Sivmne。 在所有动物中都测量了挑战后病毒负荷，并且两组之间的挑战结果之间存在主要差异。 令人惊讶的是，仅在DNA组（2/4猕猴）中观察到持续的低病毒载荷，这表明4种单独使用DNA的免疫引起的免疫反应比2种蛋白质增强的2个DNA质量更有效。 这项研究代表了DNA免疫的第一个病例，从而引发了针对致病SIV挑战的保护性免疫。 具有所有结构性和调节基因的多基因DNA疫苗（例如这些疫苗）都表现出巨大的希望，并且可能是实时侵入疫苗的安全替代品。