Attenuated listeria vectors as an AIDS vaccine in macaques

减毒李斯特菌载体作为猕猴的艾滋病疫苗

• 批准号: 7952751
• 负责人: Ruth Margrit Ruprecht
• 金额: $ 34.44万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-11 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7952751
• 关键词: AIDS Vaccines; African; Alanine; Anabolism; Animal Model; Antibody Formation; Attenuated; Bacterial Chromosomes; Bacterial Genes; Biological Models; CD8B1 gene; Cell Wall; Cells; Chromosomes; Clinical Trials; Cytotoxic T-Lymphocytes; Dose; Drug Kinetics; E-Cadherin; Engineering; Enterocytes; Food; Gagging; Generations; Genes; Goals; Growth; HIV; Human; Immune response; Immunocompromised Host; Individual; Infant; Infection; Intramuscular; Life; Listeria; Listeria monocytogenes; Lymphoid Tissue; Macaca; Macaca mulatta; Measures; Monitor; Monkeys; Mus; Newborn Animals; Newborn Infant; Oral; Oral Administration; Pathogenesis; Pilot Projects; Plasma; Pregnant Women; Primate Lentiviruses; Primates; Recombinants; Route; Safety; Sepsis; T-Lymphocyte; Testing; Treatment Protocols; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccines; Vaccinia virus; Viral Genes; Virus; Work; immunogenic; immunogenicity; neonate; novel vaccines; offspring; pathogen; pregnant; research study; response; safety study; safety testing; simian human immunodeficiency virus; stillbirth; vaccine candidate; vector

We seek to develop recombinant Lmdd, a vector generated from Listeria monocytogenes (Lm) by deleting two genes essential for the biosynthesis of the unnatural D-alanine (D-ala), as an oral AIDS vaccine. Without exogenous D-ala, the resulting vector, termed Lmdd, is unable to form cell walls or replicate. The first vaccine candidate, Lmdd-gag, was generated by stably inserting HIV gag into the Lmdd chromosome. In mice, Lmdd-gag, co-administered with D-ala, elicited long-lived CD8+ T-cell responses. In rhesus monkeys, wild-type Lm closely mimics infection and pathogenesis in humans (stillbirths, sepsis), who get infected mostly via contaminated food. Because of this natural oral route of Lm infection, Lmdd vectors hold promise as oral AIDS vaccines, in a pilot study, we administered Lmdd-gag orally to two monkeys with short D-ala courses; one monkey was boosted orally and developed cytotoxic T-lymphocyte (CTL) responses against HIV Gag, indicating that this candidate vaccine is immunogenic after oral administration. The other monkey developed strong antibody responses after i.m. boosting. The Specific Aims are to: 1. Test the hypothesis that oral vaccination will generate T helper type 1 (Thl) responses, whereas oral priming/i.m, boosting will result in Th2 responses. 2. Test safety, immunogenicity, and efficacy of Lmdd encoding SHIV89.6P gag, tat, env or nef. Groups of monkeys will be vaccinated with Lmdd encoding individual viral genes or with a combination all four vectors and challenged mucosally with pathogenic SHIV89.6P. 3. Test safety, immunogenicity, and efficacy of Lmdd encoding genes of SHIV-1157ip, which contains env of a HIV clade C isolated from a maternally infected African infant. SHIV-1157ip has been adapted to rhesus monkeys and replicates to high levels. Vaccinees will be challenged mucosally or intravenously with SHIV-1157ip. 4. Test long-term safety, immunogenicity, and efficacy of Lmdcl vaccines against SHIV-1157ip in pregnant macaques and monitor long-term safety in Lmdd vaccine-exposed offspring. 5. Test safety, immunogenicity and efficacy of the best anti-SHIV1157ip Lmdd vaccine in newborn monkeys. These primate studies represent crucial steps towards developing recombinant Lmdd vectors for clinical trials as oral AIDS vaccine candidates that could be administered easily, even in the developing world.

我们寻求开发重组 Lmdd，这是一种通过删除单核细胞增生李斯特菌 (Lm) 产生的载体 两种对于生物合成非天然 D-丙氨酸（D-ala）（作为口服艾滋病疫苗）至关重要的基因。 如果没有外源 D-ala，所得载体（称为 Lmdd）无法形成细胞壁或复制。这 第一个候选疫苗 Lmdd-gag 是通过将 HIV gag 稳定插入 Lmdd 染色体而产生的。在 小鼠中，Lmdd-gag 与 D-ala 共同给药，引发了长寿命的 CD8+ T 细胞反应。在恒河猴中， 野生型 Lm 与人类感染和发病机制非常相似（死产、败血症），人类会被感染 主要是通过受污染的食物。由于 Lm 感染的这种自然口服途径，Lmdd 载体有望实现 作为口服艾滋病疫苗，在一项试点研究中，我们给两只短 D-ala 猴子口服 Lmdd-gag 课程；一只猴子口服加强剂量后，产生了细胞毒性 T 淋巴细胞 (CTL) 反应 HIV Gag，表明该候选疫苗口服后具有免疫原性。另一只猴子 肌内注射后产生强烈的抗体反应。助推。具体目标是： 1. 检验以下假设：口服疫苗会产生 1 型辅助性 T (Thl) 反应，而口服疫苗 启动/强化将导致 Th2 反应。 2.测试编码SHIV89.6P gag、tat、env或nef的Lmdd的安全性、免疫原性和功效。团体 猴子将接种编码单个病毒基因的 Lmdd 疫苗或所有四种病毒基因的组合疫苗 载体并用致病性 SHIV89.6P 进行粘膜攻击。 3. 测试含有env的SHIV-1157ip的Lmdd编码基因的安全性、免疫原性和有效性 从母体感染的非洲婴儿中分离出的 HIV C 分支。 SHIV-1157ip 已适应 恒河猴并复制到高水平。疫苗将通过粘膜或静脉注射受到攻击 与 SHIV-1157ip。 4. 测试孕妇针对 SHIV-1157ip 的 Lmdcl 疫苗的长期安全性、免疫原性和有效性 猕猴并监测 LMDD 疫苗暴露后代的长期安全性。 5. 测试最佳抗SHIV1157ip Lmdd疫苗在新生儿中的安全性、免疫原性和功效 猴子。 这些灵长类动物研究代表了开发用于临床的重组 Lmdd 载体的关键步骤 作为口服艾滋病候选疫苗的试验即使在发展中国家也可以轻松使用。