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Design and optimization of DL-NLTs and molecular adjuvants to increase potency and promote NAb formation in vivo

DL-NLT 和分子佐剂的设计和优化，以提高效力并促进体内 NAb 形成

基本信息

批准号：
10589587
负责人：
DAVID B. WEINER
金额：
$ 142.76万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-08 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589587
关键词：
Adjuvant Antibodies Antibody Response Antigens Apical Automobile Driving B-Lymphocytes Benchmarking Binding Sites CCL27 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Lineage Cells Cellular Immunity Clinic Clinical Clinical Trials Complex Conceptions DNA DNA Vaccines Development Dose Epitopes Evaluation Formulation Frequencies Genetic Goals HIV HIV Vaccine Trials Network HIV vaccine HIV-1 HIV-1 vaccine Human Humoral Immunities Immune response Immunity Immunization Interleukin-12 Knock-in Mouse Laboratories Mediating Molecular Mucous Membrane Mus Plasmids Population Property Regimen Reporting Selection Criteria Surface T cell response T-Lymphocyte Tissues Vaccinated Vaccines design effector T cell immune function immunogenicity in vivo interleukin-21 nanoparticle neutralizing antibody novel programs response self assembly synthetic construct vaccine candidate vaccine-induced immunity

项目摘要

Project 1 Summary Extensive efforts have been carried out over the years to design a HIV-1 vaccine candidate which elicits robust immune responses supporting broad neutralization and effector T cell responses. Recently the Weiner and Kulp laboratories reported the development of novel DNA-launched, in vivo, self-assembling immunogens, including both DNA launched native like trimers (DL-NLTs) and DNA-launched nanoparticle immunogens (DLNPs). Both DNA launched NLTs and NPs assemble and display appropriate epitopes for neutralizing antibodies while occluding epitopes for non-neutralizing antibodies in vivo. Additionally, they drive robust T cell immunity. These vaccine candidates are being moved to the clinic under studies HVTN-304 and HVTN-305. synDNA facilitates rapid immunogen design, co-delivery of molecular adjuvants, supports expression and assembly of complex structural antigens in vivo, has a safe clinical track record, and maintains boost-ability. Building on progress from our previous IPCAVD, combining these designs, we will be working with Dr. Kulp under Project 2 to formulate DLNPs bearing NLTs displaying Apex and CD4 binding-site B cell lineage targeting Epitopes (DLNP-ACEs). Furthermore, we have designed and characterized several synDNA-encoded molecular adjuvants to support enhanced humoral immunity, cell-mediated immunity, and direct antigen-specific responses to mucosal surfaces. The overarching goal of Project 1 is to combine these novel immunogens with DNA-delivered genetic adjuvant combinations and/or heterologous adjuvant regimens, in dual expressing plasmids developed with Project 3 to support vaccine-induced immunity and represents a great leap forward in the design of HIV-1 vaccines.

项目1概述