权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Nucleic acid-based formulation of cytomegalovirus-vectored HIV vaccines

基于核酸的巨细胞病毒载体 HIV 疫苗配方

基本信息

批准号：
10011665
负责人：
DENNIS J. HARTIGAN-O'CONNOR
金额：
$ 30万
依托单位：
TENDEL THERAPIES INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-07 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10011665
关键词：
Adjuvant Antigens Antiviral Agents Attenuated Vaccines Bacterial Artificial Chromosomes Blood CD8-Positive T-Lymphocytes Capital Cations Cells Characteristics Cold Chains Cytomegalovirus Cytomegalovirus Vaccines DNA DNA Vaccines Development Distant Endotoxins Epidemic Escherichia coli Evaluation Event Excision Formulation Gene Expression Generations Genome Goals Government Grant HIV HIV vaccine Hand Harvest Heterogeneity Histology Human Human Resources IL10 gene Immune Immune response Immunize Infant Infection Inflammatory Injections Interleukin-10 Lead Left Licensing Light Lipid Bilayers Macaca Macaca mulatta Mammalian Cell Methods Mutation Nucleic Acids Peripheral Blood Mononuclear Cell Persons Phase Phenotype Polymers Production Property Rhesus SIV SIV Vaccines Site T cell response Technology Testing Time Tissues Transfection Vaccinated Vaccination Vaccine Antigen Vaccines Viral Viral Genes Virion Virus Work adaptive immune response base clinical development design experimental study fighting global health immunoregulation improved in vivo innovation interest particle recombinase response restriction enzyme tissue/cell culture tool transcriptomics vaccine candidate vaccine delivery vaccine development vector vector vaccine

项目摘要

This grant is for translational development of a scalable, nucleic acid-based formulation of cytomegalovirus-vectored vaccines that can be distributed without a cold chain. HIV candidate vaccines that use cytomegalovirus (CMV) as delivery vector and immunomodulatory adjuvant have shown extraordinary promise. In our preliminary work, for example, a rhesus cytomegalovirus-vectored SIV vaccine lacking the viral IL-10 gene (RhCMVdIL10-SIVgag) protected 4/6 infants from SIV infection. Tendel Therapies Inc. is licensing a portfolio of technology centered on these second-generation, CMV-vectored vaccines. Manufacturing and distribution of CMV-based vaccines present daunting challenges: (i) replication of CMV in culture is markedly slower than that of other vaccine vectors; (ii) CMV undergoes rapid genetic change when amplified in culture; (iii) the virus is enveloped and thus difficult to separate from cell- and virus-derived lipid bilayers of a similar size; (iv) methods for extreme concentration of the heterogenous particles are unknown; and (v) a cold chain is required for distribution. To eliminate these problems, Tendel is also licensing technology for vaccine delivery using purified CMV genomes propagated in E. coli. The technology permits efficient “rescue” of the genomes after introduction to mammalian cells. Similarly efficient rescue in vivo should lead to immune responses that are equivalent to those provoked by conventional vaccination with virions. We hypothesize that viral IL-10-deficient, CMV-vectored vaccine genomes (DNA) provoke immune responses that are indistinguishable from the protective responses stimulated by encapsidated live vaccine. Aim 1. Assess antigen expression and vaccine vector replication after delivery of vaccine genomes to macaques. CMV-vectored vaccines given as virions first replicate locally, leading to inflammatory cell influx, and then systemically, leading to viral gene expression in distant tissues. Our hypothesis predicts that successful rescue of vaccine genomes should lead to the same events. Aim 2. Test if innate and adaptive immune responses to vaccination with nucleic acid are comparable to protective anti-SIV responses observed previously. Previous studies have shown that protection against SIV is associated with specific immune responses, particularly Mamu-E-restricted CD8+ T cell responses. These innovative Phase I experiments will be sufficient to establish both the technical merit and—in light of the proven commercial interest in CMV-vectored vaccines—the commercial potential of Tendel's approach. Phase II experiments will build on this work to (i) demonstrate that macaques vaccinated with nucleic acid are protected against SIV challenge (ii) continue development of replication-defective HCMV-HIV Gag and Env vaccines.

这笔拨款用于可扩展的，基于核酸的制剂的转化开发