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.

项目概要 使用原型对恒河猴巨细胞病毒（RhCMV）阳性恒河猴（RM）进行免疫 表达 Gag、Retanef、Pol 和 Env 的 RhCMV68-1 载体猿免疫缺陷病毒 (SIV) 疫苗 对大约 50% 的动物有效，受保护的动物几乎完全控制了 然而，在受到致病性全身性 SIV 的粘膜攻击后，SIV 感染才有效。 缺乏疫苗诱导的抗体 (Ab) 反应，而是与非常规抗 SIV 相关 MHC-II 和 MHC-E 限制 CD8 T 细胞反应，尽管这种 SIV 控制水平非常显着，但进一步。 CMV 疫苗平台的开发显然对于诱导针对 SIV 的体液反应是必要的 包膜蛋白：许多人认为这种反应对于有效疫苗至关重要。 目前尚不清楚诱导这种所需的抗体反应所必需的。 表达 SIV Gag 的 RhCMV 能够诱导 Gag 特异性抗体，但仅限于 RhCMV 阴性 RM。 相同的 RhCMV-Gag 疫苗不会在 RhCMV 阳性 RM 中诱导类似的抗体反应。 与之前发表的报告一致，显示 SIV Env 特异性抗体的诱导可以忽略不计或没有 RhCMV 阳性 RM 肺炎伴 RhCMV-Env。这些发现表明，预先存在的 RhCMV 免疫。 可能是限制 Ab 诱导到由 RhCMV 载体递送的疫苗抗原的关键因素 仅基于 RhCMV SIV 疫苗的方案 原型中疫苗抗原表达的幅度。 RhCMV 疫苗可能是另一个因素，特别是对于有意研发的 RhCMV-Env 疫苗 设计用于“有毒”Env 基因的低表达，我们建议稳健的抗原表达也将是这样的。 对于用 RhCMV-SIV 疫苗免疫的 RhCMV 阳性 RM 的抗体诱导至关重要。 对 i) 促进对 RhCMV 载体的 SIV 体液反应的方法的探索性调查 面对预先存在的 RhCMV 免疫的疫苗，以及 ii) 稳定增加 SIV 抗原的策略 这项研究基于我们的总体假设，即预先存在的 RhCMV 免疫和 SIV 抗原表达的强度是导致体液反应受限的关键可改变因素 在 RhCMV 阳性猕猴中观察到的结果 目标 1 将研究在 RhCMV 阳性中诱导 SIV 特异性抗体。 猕猴通过两种不同的初免-加强方案利用重组亚基蛋白（Env 和 Gag）和 RhCMV-SIV 疫苗将检查免疫动物的循环和粘膜抗体反应、B 细胞。 目标 2 重点关注候选 RhCMV 人类的产生。 免疫缺陷病毒 (HIV)-1 Env 疫苗旨在使用新策略增强 Env 表达 最近描述的针对改进的 RhCMV 载体的埃博拉病毒疫苗的研究将为我们提供及时的建议。 为未来研究包括重组的 RhCMV-SHIV 联合疫苗方案奠定基础 Env 蛋白与 RhCMV-Env 疫苗一起设计，旨在提高 CMV-HIV 疫苗的保护功效。