CMV-vectored Vaccine Approaches to Induce Protective Antibodies to HIV-1 Env

CMV 载体疫苗诱导 HIV-1 包膜保护性抗体的方法

• 批准号: 9415296
• 负责人: Peter A Barry
• 金额: $ 23.27万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-26 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9415296
• 关键词: Acute; Animals; Antibodies; Antibody Response; Antigens; Avidity; B-Lymphocytes; Binding; Blood; CD8-Positive T-Lymphocytes; Cytomegalovirus; Cytomegalovirus Vaccines; Data; Detection; Development; Ebola Vaccines; Ebola virus; Enzyme-Linked Immunosorbent Assay; Foundations; Future; Generations; Glycoproteins; HIV; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Immune response; Immunity; Immunization; Immunize; Immunologic Memory; Infection; Investigation; Macaca; Macaca mulatta; Mediating; Modality; Pathogenicity; Protein Subunits; Protocols documentation; Publishing; Recombinant Proteins; Recombinants; Reporting; SHIV vaccine; SIV; Secondary Immunization; T cell response; T-Lymphocyte; Testing; Time; Transcriptional Regulation; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Viral Antigens; Viral Proteins; Virus Diseases; base; design; env Gene Products; env Genes; gag Gene Products; improved; in vitro Assay; lymph nodes; mucosal site; neutralizing antibody; novel strategies; promoter; protective efficacy; prototype; response; retanef; stability testing; vaccine trial; vector; vector vaccine; vector-based vaccine

Project Summary Immunization of rhesus cytomegalovirus (RhCMV)-positive rhesus macaques (RM) with the prototype RhCMV68-1-vectored simian immunodeficiency virus (SIV) vaccine expressing Gag, Retanef, Pol and Env is effective in approximately 50% of animals, with protected animals demonstrating almost complete control of systemic SIV infection following mucosal challenge with pathogenic SIV. However, efficacy occurs in the absence of vaccine-induced antibody (Ab) responses, and is instead associated with unconventional anti-SIV MHC-II and MHC-E-restricted CD8 T cell responses. Although this level of SIV control is remarkable, further development of the CMV vaccine platform will clearly be necessary to induce a humoral response to the SIV Env protein: a response considered by many to be essential for an efficacious vaccine. The conditions necessary for induction of such desired Ab responses are currently unclear. Our preliminary data indicate that RhCMV expressing SIV Gag is capable of inducing Gag-specific Ab, but only in RhCMV-negative RM. The same RhCMV-Gag vaccine does not induce comparable Ab responses in RhCMV-positive RM. This finding is consistent with previous published reports showing either negligible or no induction of SIV Env-specific Ab in RhCMV-positive RM vaccinated with RhCMV-Env. These findings suggest that pre-existing RhCMV immunity may be one critical factor that restricts Ab induction to vaccine antigens delivered by RhCMV vectors using protocols based on RhCMV SIV vaccines alone. Magnitude of vaccine antigen expression from prototype RhCMV vaccines may be another factor, particularly for the RhCMV-Env vaccine that was intentionally designed for low expression of the “toxic” Env gene. We propose that robust antigen expression will also be critical for Ab induction in RhCMV-positive RM immunized with RhCMV-SIV vaccines. The current proposal is an exploratory investigation into i) approaches to promote humoral responses to RhCMV-vectored SIV vaccines in the face of pre-existing RhCMV immunity, and ii) strategies to stably increase SIV antigen expression. This investigation is based on our overall hypothesis that pre-existing RhCMV immunity and magnitude of SIV antigen expression are critical modifiable factors contributing to restricted humoral responses observed in RhCMV-positive macaques. Aim 1 will investigate induction of SIV-specific Ab in RhCMV-positive macaques by two distinct prime-boost protocols that utilize recombinant subunit proteins (Env and Gag) and RhCMV-SIV vaccines. Immunized animals will be examined for circulating and mucosal Ab responses, B cell and T cell responses in blood and lymph nodes. Aim 2 focuses on the generation of candidate RhCMV human immunodeficiency virus (HIV)-1 Env vaccines designed to enhance Env expression using a novel strategy recently described for a modified RhCMV-vectored Ebola virus vaccine. Proposed studies will provide a timely foundation for future investigation into combination RhCMV-SHIV vaccine protocols that include recombinant Env proteins together with RhCMV-Env vaccines designed for improved CMV-HIV vaccine protective efficacy.

项目摘要 恒河猴的免疫（RhCMV） - 阳性恒河猕猴（RM）与原型 RHCMV68-1矢量示威的免疫缺陷病毒（SIV）疫苗表达GAG，RETANEF，POL和ENV是 在大约50％的动物中有效，受保护的动物几乎完全控制了 致病SIV粘膜挑战后的全身性SIV感染。但是，有效发生在 缺乏疫苗诱导的抗体（AB）反应，而是与非常规抗SIV相关的 MHC-II和MHC-E限制的CD8 T细胞反应。尽管这种SIV控制水平是显着的，但进一步 显然，CMV疫苗平台的开发显然是必要的，以引起对SIV的体液反应 env蛋白：许多人认为对有效疫苗必不可少的反应。条件 目前尚不清楚诱导这种所需的AB反应所需的必要条件。我们的初步数据表明 表达SIV GAG的RHCMV能够诱导特异性AB，但仅在RHCMV阴性RM中。这 相同的RHCMV-GAG疫苗不会在RHCMV阳性RM中诱导可比的AB反应。这个发现是 与以前已发表的报告一致，表明在 RHCMV阳性RM接种RHCMV-ENV。这些发现表明先前存在的RHCMV免疫力 可能是将AB诱导限制在RHCMV载体使用的疫苗抗原中的关键因素 仅基于RHCMV SIV疫苗的方案。原型疫苗抗原表达的大小 RHCMV疫苗可能是另一个因素，特别是对于有意的RHCMV-ENV疫苗 设计用于低表达“有毒” Env基因。我们建议强大的抗原表达也将是 对用RHCMV-SIV疫苗免疫的RHCMV阳性RM的AB诱导至关重要。当前的建议是 对i）促进对RHCMV矢量SIV的体液反应的方法的探索性研究 面对先前存在的RHCMV免疫的疫苗，以及II）稳定增加SIV抗原的策略 表达。这项投资基于我们的总体假设，即先前存在的RHCMV免疫和 SIV抗原表达的大小是关键的可修改因素，导致受限制的体液反应 在RHCMV阳性猕猴中观察到。 AIM 1将研究RHCMV阳性中SIV特异性AB的诱导 使用重组亚基蛋白（ENV和GAG）和 RHCMV-SIV疫苗。将检查免疫动物的循环和粘膜AB反应，B细胞 血液和淋巴结中的T细胞反应。 AIM 2专注于候选人RHCMV人类的产生 免疫缺陷病毒（HIV）-1 ENV疫苗旨在使用新型策略增强ENV表达 最近描述了用于修饰的RHCMV载体的埃博拉病毒疫苗。拟议的研究将及时提供 将未来投资于联合RHCMV-SHIV疫苗协议的基础，包括重组 ENV蛋白与旨在提高CMV-HIV疫苗保护效率的RHCMV-ENV疫苗一起。