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Lipid nanoparticles as novel adjuvants inducing effective T follicular helper cell and humoral immune responses

脂质纳米颗粒作为新型佐剂诱导有效的滤泡辅助性 T 细胞和体液免疫反应

基本信息

批准号：
10461926
负责人：
Norbert Pardi
金额：
$ 62.64万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10461926
关键词：
Adjuvant Adjuvanticity Affinity Animal Model Animals Antibodies Antibody Affinity Antibody Response Antigens Atlases Attenuated Automobile Driving B cell repertoire B-Lymphocytes Binding Biological Assay Biology Cell Differentiation process Cells Cellular biology Clinical Trials Communicable Diseases Comparative Study DNA Vaccines Dangerousness Data Dendritic Cells Development Dose Effectiveness Encapsulated Enzyme-Linked Immunosorbent Assay FDA approved Flow Cytometry Helper-Inducer T-Lymphocyte Hemagglutination Human Immune Immune response Immunity Immunization Immunoglobulin Class Switching In Vitro Inactivated Vaccines Interferon Type I Kinetics Knowledge Ligands Light MF59 Macaca mulatta Maintenance Maps Measures Memory B-Lymphocyte Messenger RNA Modeling Molecular Mus Nucleosides Plasma Plasma Cells Protein Subunits Proteins Reaction Route Signal Transduction Structure of germinal center of lymph node Subunit Vaccines Testing Vaccine Adjuvant Vaccines Virus Virus Diseases Zika virus vaccine adaptive immune response aluminum sulfate base comparative experience experimental study genetic signature influenza virus vaccine influenzavirus lipid nanoparticle neutralizing antibody nonhuman primate novel novel vaccines pathogen plasmid DNA prevent rational design receptor response transcriptomics vaccine access vaccine development vaccine evaluation vaccine platform vaccine trial vaccinology

项目摘要

ABSTRACT Vaccines prevent hundreds of millions of illnesses and save millions of lives every year. Various types of licensed vaccines (live attenuated and inactivated pathogens, adjuvanted protein subunits) provide some level of protection against a variety of dangerous illnesses. However, there are multiple pathogens for which no effective vaccines are available. Protective immunity against many pathogens can be achieved through long- lived and high-affinity antibody responses, which are driven by T follicular helper (Tfh) cells. Tfh cells are required for the formation and maintenance of germinal centers (GC), where B cell affinity maturation, class switch, and development of long-lived plasma and memory B cells occur. Thus, the magnitude or quality of antibody responses induced by a vaccine is shaped by its ability to induce Tfh cells. The identification of vaccine platforms or adjuvants that induce potent Tfh cell responses and broadly protective and durable antibody responses is a critical need in vaccinology. We have identified a potent vaccine adjuvant, lipid nanoparticles (LNPs), which induce strong Tfh cell differentiation and durable antibody responses after a single immunization when combined with protein subunits, inactivated virus or antigen-encoding mRNA. Importantly, our preliminary studies demonstrated the superiority of LNP's adjuvant activity over the FDA-approved vaccine adjuvant, MF59, in comparative studies. This proposal will aim to extend our preliminary findings, examine LNP's adjuvanticity in non-human primate immunization studies and investigate the mechanisms of action of LNPs. In 3 specific aims we will: 1.) Determine LNP's adjuvanticity in multiple vaccine platforms in mice. 2.) Assess the potency of LNP-adjuvanted Zika vaccines in non-human primates. 3.) Uncover LNP-induced immune mechanisms that regulate the biology of Tfh cells. This proposal aims to demonstrate that LNPs can be used as adjuvants in various conventional (inactivated pathogen and protein subunits) and unconventional (mRNA, DNA) vaccine types to induce strong Tfh cell and durable neutralizing antibody responses. This finding could have a significant impact on vaccine development as no licensed vaccines or adjuvants have been shown to potently activate Tfh cells that are critical for durable protective antibody responses against many pathogens. We believe that the data generated in this proposal will be capable of moving this vaccine adjuvant towards clinical trials.

摘要