ATTENUATED RECOMBINANT LISTERIA AS ORAL AIDS VACCINE

减毒重组李斯特菌作为口腔艾滋病疫苗

• 批准号: 8172340
• 负责人: Ruth Margrit Ruprecht
• 金额: $ 4.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172340
• 关键词: Adenoviruses; Animals; Antibodies; Antibody Formation; Attenuated; Cellular Immunity; Colony-forming units; Computer Retrieval of Information on Scientific Projects Database; Control Groups; Dose; Equilibrium; Exposure to; Funding; Gagging; Generations; Grant; HIV; HIV-1; Humoral Immunities; Immune response; Immunization; Institution; Life; Listeria; Listeria monocytogenes; Macaca mulatta; Modality; Monkeys; Oral; Prevention; Proteins; Recombinants; Research; Research Personnel; Resources; SIV; Schedule; Source; Systemic infection; Testing; United States National Institutes of Health; Vaccinated; Vaccines; Virus; gp160; neutralizing antibody; simian human immunodeficiency virus; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. After determining the optimal dose of the third-generation live attenuated Listeria monocytogenes vector encoding SIV gag, termed Lmdd-BdopSIVgag, we examined a different dose-schedule, administering the vaccine (3 x1012 colony-forming units (CFU)) intragastrically every other day for 4 doses at weeks 0 and 12 to five rhesus monkeys. Controls received the "empty" vector, Lmdd-Bdop. However, the analysis showed that this every-other-day schedule was not as good as administering the vaccine daily for three consecutive days. To test whether the vaccinated animals had been tolerized by the repeated exposure to the Listeria vaccine, we re-immunized them with the same Lmdd-BdopSIVgag according to the prior daily x 3 schedule; this group of monkeys was designated Group 1B. A new group of 5 na¿ve monkeys received the vaccine in parallel (Group 1A). New na¿ve controls (Group 2; 5 monkeys) received only empty vector. Good cellular immunity was seen in Groups 1A as well as 1B, effectively ruling out tolerization. Both Groups then received two mucosal boosts with live attuenated adenovirus encoding SIV Gag (Ad5hrSIVGag), which resulted in strong increases in Gag-specific cellular immunity. Next, Groups 1a and 1B received protein immunizations consisting of trimeric HIV-1 gp160 and Tat with the aim to induce neutralizing antibody responses. At the conclusion of the protein boosts, the monkeys were challenged with 5 low, weekly intrarectal doses of a neutralization-sensitive R5 SHIV encoding a heterologous HIV clade C envelope. Substantial protection was seen, including prevention of systemic infection. We conclude that inducing balanced immune responses consisting of cellular as well as humoral immunity can be successful. Strong cellular immunity was induced with oral Lmdd-BdopSIVgag priming, followed by mucosal boosting with Ad5hrSIVGag, whereas cross-neutralzing antibodies were generated with HIV-1 gp160 and Tat. Our multi-modality vaccine approach that targeted several SHIV gene products is promising, even against heterologus virus challenge.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 After determining the optimal dose of the third-generation live attenuated Listeria monocytogenes vector encoding SIV gag, termed Lmdd-BdopSIVgag, we examined a different dose-schedule, administering the vaccine (3 x1012 colony-forming units (CFU)) intragastrically every other day for 4 doses at weeks 0 and 12 to five rhesus monkeys.控件收到了“空”向量LMDD-BDOP。但是，分析表明，每天的时间表不如连续三天每天服用疫苗那么好。为了测试疫苗是否通过反复接触李斯特菌疫苗来耐受疫苗，我们根据先前的每日X 3时间表将其与相同的LMDD-BDOPSIVGAG重新免疫；这群猴子被指定为1B组。一组新的5na¿猴子并行接种了该疫苗（第1A组）。新的na¿ve控制（第2组； 5只猴子）仅收到空载体。在第1A组和1B中可以看到良好的细胞免疫力，从而有效排除了耐受性。然后，两组都获得了两个粘膜促进，并带有现场衰减的编码SIV GAG（AD5HRSIVGAG）的粘膜升高，这导致了 GAG特异性细胞免疫的强烈增加。 接下来，1A和1B组接受了由三聚体HIV-1 GP160和TAT组成的蛋白免疫抑制，目的是诱导中和抗体反应。在蛋白质促进的结论结束时，猴子受到5个低的，每周的内和敏感的R5 SHIV的挑战，编码了异源HIV Crade C Invelope。 看到了实质性的保护，包括预防全身感染。我们包括，由细胞和体液免疫组切成症组成的诱导均衡免疫调查会成功。用口服LMDD-BDOPSIVGAG启动诱导了强细胞免疫组织切，然后用AD5HRSIVGAG促进粘膜，而跨性和中和抗体则用HIV-1 GP160和TAT产生。即使针对异源性病毒挑战，我们也有承诺针对几种SHIV基因产物的多模式疫苗方法。