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: 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
• 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

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 疫苗可以预防数亿疾病，并每年挽救数百万生命。各种类型 许可的疫苗（活衰减和灭活病原体，辅助蛋白亚基）提供一定水平 保护各种危险疾病。但是，有多种病原体没有 有效的疫苗可用。可以通过长期来实现对许多病原体的保护性免疫力 寿命和高亲和力抗体反应，由T卵泡辅助器（TFH）细胞驱动。 TFH细胞是 生发中心（GC）的形成和维持所需的，B细胞亲和力成熟，类 切换以及长期血浆和记忆B细胞的发展。因此，大小或质量的 由疫苗诱导的抗体反应是由其诱导TFH细胞的能力来塑造的。识别 诱导有效的TFH细胞反应并广泛保护和耐用的疫苗平台或佐剂 抗体反应是疫苗学的关键需求。我们已经确定了有效的疫苗辅助脂质 纳米颗粒（LNP），诱导强大的TFH细胞分化和耐用的抗体反应。 与蛋白质亚基，灭活病毒或抗原编码mRNA结合时免疫接种。重要的是， 我们的初步研究表明，LNP的辅助活性优于FDA批准的疫苗 在比较研究中，MF59辅助。该建议将旨在扩大我们的初步发现，检查 LNP在非人类灵长类动物免疫研究中的辅助性，并研究了作用机理 LNP。在3个具体目标中，我们将：1。）确定小鼠多种疫苗平台中LNP的辅助性。 2.） 评估非人类灵长类动物中LNP辅助Zika疫苗的效力。 3.）发现LNP引起的 调节TFH细胞生物学的免疫机制。 该建议旨在证明LNP可以用作各种常规的佐剂（灭活 病原体和蛋白质亚基）和非常规的（mRNA，DNA）疫苗类型，以诱导强的TFH细胞和 耐用的中和抗体反应。这一发现可能会对疫苗开发产生重大影响 由于没有证明有执照的疫苗或佐剂可以有效激活对耐用的TFH细胞 针对许多病原体的保护性抗体反应。我们相信该提案中产生的数据 将能够将这种疫苗佐剂转移到临床试验中。