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，挽救数百万人的生命。各种类型的 许可的疫苗（减毒活的和灭活的病原体，佐剂化的蛋白质亚基）提供了一定水平的 对各种危险疾病的保护。然而，有多种病原体， 有效的疫苗是存在的。对许多病原体的保护性免疫可以通过长期- 活的和高亲和力的抗体反应，这是由T滤泡辅助（Tfh）细胞驱动。TFH细胞是 所需的形成和维持的生发中心（GC），其中B细胞亲和力成熟，类 转换，并发生长寿命血浆和记忆B细胞的发育。因此， 疫苗诱导的抗体应答由其诱导Tfh细胞的能力决定。的识别 诱导有效的Tfh细胞应答并具有广泛的保护性和持久性的疫苗平台或佐剂 抗体应答是疫苗学中的关键需求。我们已经发现了一种有效的疫苗佐剂，脂质 纳米颗粒（LNP），其在单次免疫后诱导强烈的Tfh细胞分化和持久的抗体应答。 当与蛋白质亚基、灭活病毒或编码抗原的mRNA组合时，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，MF 59，在比较研究中。这项建议旨在扩大我们的初步调查结果， LNP在非人灵长类动物免疫中的佐剂性研究，并研究LNP的作用机制。 LNP。在三个具体目标，我们将：1。在小鼠中测定LNP在多种疫苗平台中的佐剂性。2.） 评估LNP佐剂寨卡疫苗在非人灵长类动物中的效力。3.）第三章发现LNP诱导 调节Tfh细胞生物学的免疫机制。 该提议旨在证明LNP可用作各种常规（灭活）免疫接种中的佐剂。 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， 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 因为没有许可的疫苗或佐剂显示出有效激活Tfh细胞，Tfh细胞对于持久免疫至关重要。 针对许多病原体的保护性抗体反应。我们认为，该提案中产生的数据 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.