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

摘要 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(减毒活的和灭活的病原体、佐剂蛋白亚基)提供了一定的水平。 对各种危险疾病的保护。然而，有多种病原体没有 目前已有有效的疫苗可用。对许多病原体的保护性免疫可以通过长期的 活的和高亲和力的抗体反应，由T滤泡辅助细胞(TFH)驱动。TFH细胞是 生发中心(GC)的形成和维持所必需的，B细胞亲和力成熟的地方 发生了长寿命的血浆和记忆B细胞的开关和发育。因此，其规模或质量 疫苗诱导的抗体反应是由其诱导TFH细胞的能力决定的。身份的鉴定 疫苗平台或佐剂，可诱导强大的TFH细胞反应，并具有广泛的保护性和持久性 抗体反应是疫苗学中的一个重要需求。我们已经确定了一种有效的疫苗佐剂，脂类 纳米粒(LNPs)，可诱导强大的TFH细胞分化和持久的抗体反应 与蛋白质亚单位、灭活病毒或编码抗原的信使核糖核酸结合时的免疫。重要的是 我们的初步研究表明，LNP的佐剂活性优于FDA批准的疫苗 佐剂MF59，在比较研究中。这项提案旨在扩大我们的初步发现，审查 LNP在非人灵长类免疫研究中的佐剂作用并探讨其作用机制 LNPs。我们将在三个具体目标中：1.测定LNP在小鼠多个疫苗平台上的佐剂性。2.) 评估LNP佐剂寨卡病毒疫苗在非人类灵长类动物中的效力。3.)揭开由LNP引发的 调节TFH细胞生物学的免疫机制。 这项建议旨在证明LNPs可以用作各种常规(灭活)的佐剂 病原体和蛋白质亚基)和非常规(mRNA，DNA)疫苗类型诱导强大的TFH细胞和 持久的中和抗体反应。这一发现可能会对疫苗的开发产生重大影响 因为没有获得许可的疫苗或佐剂被证明能够有效地激活对耐久至关重要的TFH细胞 对多种病原体的保护性抗体反应。我们认为，这项提案中产生的数据 将能够将这种疫苗佐剂推向临床试验。

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.