INFANT RHESUS MACAQUE MODEL FOR SIV VACCINES

用于 SIV 疫苗的婴儿恒河猴模型

• 批准号: 7348888
• 负责人: Deborah A. Lewinsohn
• 金额: $ 13.12万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7348888
• 关键词: INFANT; RHESUS; MACAQUE; MODEL; SIV

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. The World Health Organization estimates that 590,000 children acquire HIV infection each year. While highly active anti-retroviral therapy (HAART) has reduced the morbidity and mortality of HIV infection in the short term, it remains unavailable to much of the world and is not curative. Therefore, an HIV vaccine is urgently needed and breast-feeding infants born to HIV-infected women in the developing world are critical target cohorts for vaccine development. Insights gained from studies of the immunobiology of HIV suggest that an effective HIV vaccine will need to induce strong CD8+ T cell responses, CD4+ T cell responses, and neutralizing antibodies. However, the immune system of young infants is immature as evidenced by increased susceptibility to bacterial and viral infections, inability to respond to some vaccines, and deficiencies in T cell function. Therefore, an HIV vaccine designed for adults will need to be tested and potentially modified to be safe and effective in neonates. The immune system of infant rhesus monkeys resembles that of human infants. Infant monkeys have been utilized to study the use of vaccines that induce protective antibody responses in human infants. The well-developed SIV/rhesus macaque model has provided important insights into the immunobiology of HIV/SIV and a growing repertoire of reagents and methods have become available for detailed immunological analyses. The goal of this research is to develop, in conjunction with the Vaccine and Gene Therapy Institute at the Oregon National Primate Research Center, an immunologically sophisticated model to study T cell and B cell immunity in rhesus macaques and then use this as an animal model for HIV vaccine development for human infants. The specific aims are: 1) To determine if infant rhesus monkeys are deficient in their capacity to develop antigen-specific T and B cell immunity by comparison of the neonatal monkey to immunologically mature juvenile monkeys with regard to antigen-specific CD8+ and CD4+ T cell responses following vaccination with modified vaccinia virus Ankara (MVA) expressing SIV gag pol (MVA-SIV239 gag pol) and antigen-specific CD4+ T cell responses and antibody titers following vaccination with recombinant SIV Envelope protein (SIVmac239 gp130) in alum adjuvant; and 2) To determine if this MVA/recombinant gp130 vaccination is less protective in infant rhesus monkeys than in juvenile monkeys given a mucosal viral challenge with SIVmac251 by comparison of the degree of viral replication in challenged infants versus juvenile animals and the frequency and tempo of development of simian AIDS in challenged infants versus juvenile animals. To date, the study of the two juvenile groups of animals has been completed. In experimental animals, primed SIV Gag-specific CD8+ T cells were readily detected at frequencies 1/10,000 of total CD8+ T cells at the time of the second immunization (Week 6) in two animals and 3 weeks following the second immunization (Week 9) in all four animals. In control animals, SIV Gag-specific CD8+ T cells were not detected prior to SIV challenge. Following SIV challenge, T cell frequencies increased approximately 10-fold in experimental animals, as high as 1/200 of total CD8+ T cells, and became detectable in control animals (range, 1/10,000 to 1/1000). Interestingly, using soluble tetrameric Mamu-A*01/p11c, CM9 complexes to measure SIV Gag p11c, CM9-specific CD8+ T cells, we first detected responses over baseline in all four animals at Week 9. The study of neonatal animals is nearly completed. Immunogenicity of the vaccine, as measured by tetramer responses, was equivalent in neonates and juveniles. Antibody and additional T cell studies are in progress.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。世界卫生组织估计，每年有 590,000 名儿童感染艾滋病毒。虽然高效抗逆转录病毒疗法（HAART）在短期内降低了艾滋病毒感染的发病率和死亡率，但世界上许多地方仍然无法获得这种疗法，并且无法治愈。因此，迫切需要艾滋病毒疫苗，而发展中国家艾滋病毒感染妇女所生的母乳喂养婴儿是疫苗开发的关键目标人群。从 HIV 免疫生物学研究中获得的见解表明，有效的 HIV 疫苗需要诱导强烈的 CD8+ T 细胞反应、CD4+ T 细胞反应和中和抗体。然而，小婴儿的免疫系统还不成熟，对细菌和病毒感染的易感性增加、对某些疫苗无法产生反应以及 T 细胞功能缺陷。因此，为成人设计的艾滋病毒疫苗需要进行测试并可能进行修改，以确保对新生儿安全有效。恒河猴幼崽的免​​疫系统与人类婴儿的免疫系统相似。小猴已被用来研究在人类婴儿中诱导保护性抗体反应的疫苗的使用。完善的 SIV/恒河猴模型为 HIV/SIV 的免疫生物学提供了重要的见解，并且越来越多的试剂和方法已可用于详细的免疫学分析。这项研究的目标是与俄勒冈国家灵长类动物研究中心的疫苗和基因治疗研究所合作开发一种免疫学复杂的模型，用于研究恒河猴的 T 细胞和 B 细胞免疫，然后将其用作动物模型人类婴儿的艾滋病毒疫苗开发。具体目标是： 1) 通过将新生猴与免疫成熟的幼年猴的抗原特异性 CD8+ 和 CD4+ T 细胞进行比较，确定幼年恒河猴是否缺乏发展抗原特异性 T 和 B 细胞免疫的能力表达 SIV gag pol (MVA-SIV239 gag pol) 的改良痘苗病毒安卡拉 (MVA) 疫苗接种后的反应以及抗原特异性 CD4+ T 细胞反应和抗体滴度使用明矾佐剂中的重组 SIV 包膜蛋白 (SIVmac239 gp130) 进行疫苗接种后； 2) 通过比较受到攻击的婴儿与幼年动物的病毒复制程度以及病毒复制的频率和速度，确定这种 MVA/重组 gp130 疫苗接种对幼年恒河猴的保护作用是否低于接受 SIVmac251 粘膜病毒攻击的幼年猴。受挑战的婴儿与幼年动物中猿猴艾滋病的发展。迄今为止，对两组幼年动物的研究已经完成。在实验动物中，在两只动物的第二次免疫时（第 6 周）和第二次免疫后 3 周（第 9 周），很容易检测到已引发的 SIV Gag 特异性 CD8+ T 细胞，频率为总 CD8+ T 细胞的 1/10,000在所有四种动物中。在对照动物中，在 SIV 攻击之前未检测到 SIV Gag 特异性 CD8+ T 细胞。 SIV 攻击后，实验动物中的 T 细胞频率增加了约 10 倍，高达 CD8+ T 细胞总数的 1/200，并且在对照动物中可检测到（范围为 1/10,000 至 1/1000）。有趣的是，使用可溶性四聚体 Mamu-A*01/p11c、CM9 复合物来测量 SIV Gag p11c、CM9 特异性 CD8+ T 细胞，我们首次在第 9 周时检测到所有四只动物的反应超过基线。新生动物的研究已接近完成。通过四聚体反应测量，疫苗的免疫原性在新生儿和青少年中是相同的。抗体和其他 T 细胞研究正在进行中。