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NHP Core for Development of an Integrase Defective Lentiviral Vector HIV Vaccine

用于开发整合酶缺陷型慢病毒载体 HIV 疫苗的 NHP 核心

基本信息

批准号：
9039529
负责人：
SAMPA SANTRA
金额：
$ 61.26万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9039529
关键词：
Acute Affinity Animals Antibody Response Antigen Presentation Antigens Antiviral Agents B cell repertoire B-Lymphocytes Biological Assay Blood specimen CCR5 gene CD4 Positive T Lymphocytes CD8B1 gene Cell Lineage Cell Maturation Cells Clinical Clinical Trials Clinical assessments Cytomegalovirus Cytotoxic T-Lymphocytes Development Dose Engineering Enhancing Antibodies Evolution Exposure to Flow Cytometry Generations Genetic Recombination Goals HIV HIV vaccine HIV-1 HIV-1 vaccine HIV/SIV vaccine Immune response Immune system Immunity Immunization Individual Infection Integrase Interferon Type II Intramuscular Investigation Kinetics Lentivirus Vector Life Macaca mulatta Memory Monkeys Mus Mutate Program Research Project Grants Proteins Protocols documentation Recombinant Vaccines Regimen Risk SIV SIV Vaccines Safety Sampling Series Site Somatic Mutation Surface T cell response T-Lymphocyte Tissue Sample Vaccinated Vaccination Vaccines Variant Virion Virus Virus Diseases Work base immunogenic immunogenicity killings neutralizing antibody nonhuman primate novel strategies pre-clinical programs response safety study simian human immunodeficiency virus success transmission process vaccine trial vector

项目摘要

An effective HIV-1 vaccine is likely to require elicitation of broadly neutralizing antibodies to block virus infection at mucosal surfaces, as well as strong T cell responses to provide help to for the antibody responses and to kill virus-infected cells at the site of transmission. The most robust cellular immune responses induced to date have been generated employing live, recombinant vaccine vectors however they are limited by anti- vector immunity and raise significant safety issues. While the pivotal RV144 trial was encouraging with 31.2% protection, the humoral correlates of protection were not sustained. Integrase-defective lentiviral vectors (IDLV) engineered to enhance antigen expression with safe guards against integration, recombination, replication or vector mobilization are a novel approach to developing an effective HIV-1 vaccine which has the distinct advantage of providing long term antigen exposure with a single immunization. In preliminary studies, this vaccine approach has elicited persistent T cell responses as well as durable Envelope-specific antibody responses in both mice and nonhuman primates (NHP). Thus, we now aim to determine the ability of the persistent antigen expression provided by this vaccine regimen to elicit highly somatically-mutated antibody responses that are likely to result in broad neutralization capacity and develop functional CD4+ and CD8+ T cell responses in NHP that are desirable in an efficacious HIV-1 vaccine candidate. IDLV engineered to express the CH505 transmitted/founder envelope and a series of subsequent variants derived from an individual that was found to be associated with broadly neutralizing antibodies will be sequentially delivered to NHP with and without protein boost with the same immunogen. The NHP core of this program project grant, will perform the NHP immunization protocols and SHIV challenge and provide samples to Projects 1 and 2 of this program to assess the safety, immunogenicity and efficacy of the IDLV Env immunogen strategy. The core will also perform in-depth analyses of the vaccine-elicited, antigen specific functional CD4+ and CD8+ T . This work will determine whether the use of IDLV vector is a viable and effective strategy for HIV-1 vaccination that should be forwarded to clinical trials.

一种有效的HIV-1疫苗可能需要激发广泛中和的抗体来阻断病毒