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

• 批准号: 10685476
• 负责人: Norbert Pardi
• 金额: $ 70.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10685476
• 关键词: Adjuvant; Adjuvanticity; Affinity; Animal Model; Animals; 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; DNA Vaccines; Dangerousness; Data; Dendritic Cells; Development; Dose; Effectiveness; Encapsulated; Endowment; 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; Licensing; Ligands; MF59; Macaca mulatta; Maintenance; Maps; Measures; Memory B-Lymphocyte; Messenger RNA; Modeling; Molecular; Mus; Nucleosides; Plasma; Plasma Cells; Protein Subunits; Proteins; Reaction; Route; Shapes; 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; candidate identification; comparative; experience; experimental study; genetic signature; influenza virus vaccine; 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

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.

抽象的 疫苗每年可预防数亿种疾病并挽救数百万人的生命。各种类型的 获得许可的疫苗（减毒活疫苗和灭活病原体、佐剂蛋白亚基）可提供一定水平的 预防各种危险疾病的保护。然而，有多种病原体无法应对。 已有有效的疫苗。针对许多病原体的保护性免疫力可以通过长期免疫来实现。 由滤泡辅助 T (Tfh) 细胞驱动的活性高亲和力抗体反应。 Tfh 细胞是 生发中心 (GC) 的形成和维持所需，其中 B 细胞亲和力成熟，类别 转换，并发生长寿命血浆和记忆 B 细胞的发育。因此，的大小或质量 疫苗诱导的抗体反应取决于其诱导 Tfh 细胞的能力。鉴定 诱导有效 Tfh 细胞反应并具有广泛保护性和持久性的疫苗平台或佐剂 抗体反应是疫苗学的一个关键需求。我们已经确定了一种有效的疫苗佐剂——脂质 纳米粒子（LNP），在单次注射后诱导强烈的 Tfh 细胞分化和持久的抗体反应 与蛋白质亚基、灭活病毒或抗原编码 mRNA 结合时产生免疫。重要的是， 我们的初步研究证明了 LNP 的佐剂活性优于 FDA 批准的疫苗 比较研究中的佐剂，MF59。该提案旨在扩展我们的初步发现，检查 LNP在非人灵长类免疫研究中的佐剂作用及作用机制探讨 LNP。我们将实现 3 个具体目标： 1.) 确定 LNP 在小鼠多个疫苗平台中的佐剂作用。 2.) 评估 LNP 佐剂的寨卡疫苗在非人类灵长类动物中的效力。 3.) 发现 LNP 诱导的 调节 Tfh 细胞生物学的免疫机制。 该提案旨在证明LNPs可以用作各种常规（灭活）佐剂 病原体和蛋白质亚基）和非常规（mRNA、DNA）疫苗类型，以诱导强 Tfh 细胞和 持久的中和抗体反应。这一发现可能对疫苗开发产生重大影响 因为尚无获得许可的疫苗或佐剂被证明能够有效激活 Tfh 细胞，而 Tfh 细胞对于持久性至关重要 针对许多病原体的保护性抗体反应。我们认为该提案中生成的数据 将能够将该疫苗佐剂推向临床试验。

项目成果

Enhancing prime editor activity by directed protein evolution in yeast.

通过酵母中的定向蛋白质进化增强主要编辑器活性。

• DOI: 10.1038/s41467-024-46107-z
• 发表时间: 2024
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Weber,Yanik;Böck,Desirée;Ivașcu,Anastasia;Mathis,Nicolas;Rothgangl,Tanja;Ioannidi,EleonoraI;Blaudt,AlexC;Tidecks,Lisa;Vadovics,Máté;Muramatsu,Hiromi;Reichmuth,Andreas;Marquart,KimF;Kissling,Lucas;Pardi,Norbert;Jinek,Martin

A Pvs25 mRNA vaccine induces complete and durable transmission-blocking immunity to Plasmodium vivax.

• DOI: 10.1038/s41541-023-00786-9
• 发表时间: 2023-12-14
• 期刊: NPJ vaccines
• 影响因子: 9.2