Antibody-Based Enhancement of CMV Vaccine Vectors for HIV

基于抗体的 HIV CMV 疫苗载体增强

• 批准号: 10002326
• 负责人: Justin Greene
• 金额: $ 34.7万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-11-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002326
• 关键词: Acquired Immunodeficiency Syndrome; Alleles; Animals; Anti-Retroviral Agents; Antibodies; Antibody Response; Antigens; Antiviral Agents; Binding; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cellular Immunity; Cessation of life; Clinical Trials; Complex; Controlled Study; Correlation Studies; Cytomegalovirus; Cytomegalovirus Vaccines; DNA; Dose; Epidemic; Epitopes; Exhibits; Frequencies; Genetic; Genetic Variation; HIV; HIV Infections; HIV vaccine; Haplotypes; Human; Immune response; Immunization; Incidence; Individual; Infection; Infection Control; Lead; Macaca; Macaca fascicularis; Macaca mulatta; Matched Group; Measurement; Mediating; Monitor; Mutation; Plasma; Population; Prevention; Proteins; Regimen; Reproducibility; Rhesus; SIV; T cell response; T memory cell; Vaccinated; Vaccination; Vaccines; Viral; Viral Load result; Viral Physiology; Viremia; Virus; Virus Diseases; Virus Replication; Work; base; cohort; design; neutralizing antibody; nonhuman primate; novel; novel strategies; prevent; protective efficacy; response; retanef; simian human immunodeficiency virus; stem; vaccine efficacy; vaccine trial; vector; vector vaccine; vector-induced; virtual

PROJECT SUMMARY Over 36 million people are living with human immunodeficiency virus (HIV) and it infects over 1 million new people every year. Several advancements in treatment and prevention have helped reduce HIV incidence and AIDS-related deaths, but are insufficient to stem the spread of the epidemic. An effective HIV vaccine is needed to help reduce new HIV infections. As demonstrated by the RV144 Thai Vaccine Trail, a successful HIV vaccine will need to induce both antibodies to prevent acquisition and a cellular immune response to control breakthrough virus. Rhesus cytomegalovirus, strain 68-1, expressing SIV antigens (RhCMV/SIV) enables stringent control of SIV replication in 50% of vaccinated rhesus macaques. This vaccine protects animals by inducing effector memory T cells that reside at the portals of entry. While the CD8+ T cell response in vaccinated rhesus macaques is well-characterized and highly unconventional, it does not directly correlate with protection. In contrast, little is known about the RhCMV/SIV-induced CD4+ T cell response. Because the rhesus macaque is outbred and diverse, their MHC II alleles are complex and prevent controlled studies of the CD4+ T cell response. In contrast, Mauritian cynomolgus macaques have limited genetic diversity and we can identify MHC-II-matched MCM. Therefore, we will vaccinate MHC-II-matched MCM with CyCMV expressing SHIV antigens to study the CD4+ T cell response. We predict that the frequency and function of the SHIV-specific CD4+ T cell response will correlate with post-infection SHIV control. In addition, CMV vaccine vectors for HIV do not protect against acquisition and do not elicit neutralizing antibodies. Therefore, we intend to induce antibodies in conjunction with CyCMV vaccination by combining CyCMV with sequential HIV-Env DNA/protein immunizations. We hypothesize that CMV vaccine regimens can be enhanced to protect against acquisition by the induction of HIV-Env specific antibodies and can protect against a novel SHIV challenge virus. In conclusion, we propose to enhance our understanding of CMV vaccine vectors and to increase the protective efficacy of this vaccine regimen. These findings will be directly applicable to impending clinical trials of CMV vaccine vectors in humans for HIV.

项目摘要 超过3600万人患有人类免疫缺陷病毒（HIV），并感染了超过100万的新型 每年的人。治疗和预防方面的几个进步有助于降低艾滋病毒的发病率和 与艾滋病有关的死亡，但不足以阻止流行病的传播。需要有效的HIV疫苗 帮助减少新的艾滋病毒感染。正如RV144泰国疫苗径所证明的那样，成功的HIV疫苗 将需要诱导两种抗体，以防止获取和细胞免疫反应以控制突破 病毒。恒河猴颗粒病毒，菌株68-1，表达SIV抗原（RHCMV/SIV）可以严格控制 在50％的接种恒河猕猴中，SIV复制。该疫苗通过诱导效应器来保护动物 位于入口门户的内存T单元。而接种恒河猕猴中的CD8+ T细胞反应 是特征良好的且高度非常规的，它与保护不直接相关。相反，几乎没有 有关RHCMV/SIV诱导的CD4+ T细胞反应的已知。因为恒河猕猴杂种 不同的MHC II等位基因是复杂的，并防止对CD4+ T细胞反应的对照研究。相比之下， 毛里求斯cynomolgus猕猴的遗传多样性有限，我们可以识别MHC-II匹配的MCM。 因此，我们将使用表达SHIV抗原的CYCMV接种MHC-II匹配的MCM来研究CD4+ T 细胞反应。我们预测SHIV特异性CD4+ T细胞响应的频率和功能将相关 通过感染后SHIV控制。此外，艾滋病毒的CMV疫苗向量不能防止收购和 不要引起中和抗体。因此，我们打算与CYCMV诱导抗体 通过将CYCMV与顺序的HIV-ENV DNA/蛋白质免疫结合在一起，疫苗接种。我们假设这一点 可以增强CMV疫苗方案，以防止通过诱导HIV-ENV特异性 抗体并可以防止新型的SHIV挑战病毒。总之，我们建议增强我们的 了解CMV疫苗向量并提高该疫苗方案的保护效果。这些 调查结果将直接适用于HIV人类中CMV疫苗向量的临床试验。