Development of New Vaccine Adjuvants

新型疫苗佐剂的开发

• 批准号: 10480226
• 负责人: Zhongwu Guo
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-06 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480226
• 关键词: 2,4-Dinitrophenol; Adaptive Immune System; Address; Adjuvant; Antibodies; Attention; Binding; Biological; Cause of Death; Cell Communication; Cells; Communicable Diseases; Complex Mixtures; Coupled; Coupling; Development; Disease; Drug resistance; Ensure; Epitopes; Exhibits; Fc Receptor; Future; Glycoconjugates; Goals; Health; Human; Immune; Immune response; Immune system; Immunity; Immunization Programs; Immunologic Adjuvants; Immunologics; Immunotherapy; In Vitro; Infection; Investigation; Lead; Link; Lipid A; Liposomes; Methods; Mus; Pathway interactions; Positioning Attribute; Prevention; Preventive vaccine; Series; Serum; Site; Structure; Structure-Activity Relationship; TLR4 gene; Vaccination; Vaccine Adjuvant; Vaccine Research; Vaccines; Variant; Work; World Health Organization; aluminum sulfate; amphiphilicity; design; emerging pathogen; improved; in vivo evaluation; innovation; novel; novel vaccines; pathogen; prevent; recruit; therapeutic vaccine; vaccine development; vaccine effectiveness; welfare

Summary Infectious diseases remain a serious threat to human lives. According to World Health Organization, ca. 15% of all human deaths are caused by infections. To control and prevent infectious diseases, vaccination has been proved to be the most economical and effective strategy. For a vaccine to work effectively and provoke a lasting protection against a pathogen, it needs to be formulated with an adjuvant—the substance that can boost immune responses and enhance the effectiveness of vaccines. However, currently, the available choices of adjuvant are limited, and the few adjuvants that have been approved for human use are complex mixtures with largely unknow action mechanisms or restricted application scopes. More significantly, they do not exhibit sufficient efficacy for many vaccines in development. To meet the growing demands from various vaccine development and vaccination programs, it is urgent and important to improve the diversities of our toolbox of adjuvants. This project intends to address the above-mentioned issue through design and development of a novel class of adjuvants, known as “conjugate adjuvants”, which have the 2,4-nitrodiphenyl (DNP) epitope covalently coupled with monophosphoryl lipid A (MPLA). Both DNP and MPLA are very potent immunostimulants, but they boost the immune system via different mechanisms and pathways—DNP enhances immune responses through recruiting endogenous DNP antibodies naturally existing in the human serum, whilst MPLA stimulates the immune system through interactions with toll-like receptor 4. In addition, covalent conjugation of DNP with MPLA will ensure their co-localization and concerted action on and in the same immune cells, and the recruited DNP antibodies can also attract more immune cells to the vaccination site to further increase the vaccine—immune cell interaction. All these activities can help enhance the immunostimulating functions of these conjugates to show a synergistic effect and become more effective adjuvants with a broader application scope. Accordingly, a series of MPLA-DNP conjugates with DNP linked to MPLA at different positions and by different linkers are designed and will be studied in this project. Efficient synthetic methods will be developed to access these conjugates, and the synthesized MPLA-DNP conjugates will be evaluated in vitro and in mice to validate the synergistic effect and the capacities of these new adjuvants in boosting immune responses to vaccines and to gain a better understanding of the induced immune responses and the action mechanisms. If this project reaches its goal, it will result in the discovery of new and more effective adjuvants, which are applicable to not only vaccines against infectious diseases but also immunotherapies for other diseases. In addition, the innovative “conjugate adjuvant” concept will be widely applicable to other adjuvants or immunostimulants as well. The new adjuvants have well-defined structures, which will enable the investigation of their structure-activity relationships and action mechanisms. The results should be useful to guide future development of new adjuvants. Therefore, this project will have a big and broad impact on the whole field of vaccine research.

概括 传染病仍然对人类生命构成严重威胁。根据世界卫生组织的说法。 15％ 所有人类死亡都是由感染引起的。为了控制和预防感染，疫苗已经是 被证明是最经济和有效的战略。让疫苗有效工作并引起持久 防止病原体的保护，需要通过调节来配制它 - 可以增强免疫力的物质 反应并增强疫苗的有效性。但是，目前，可用的调整选择是 有限的，少数已批准用于人类使用的调节器是复杂的混合物，在很大程度上未知 动作机制或限制应用程序范围。更重要的是，它们没有足够的效力 许多疫苗正在开发中。满足各种疫苗开发和疫苗的需求不断增长 程序，提高我们的调节器工具箱的多样性是迫切且重要的。 该项目旨在通过设计和开发新颖的班级来解决上述问题 调节器，称为“结合调节器”，它们具有2,4-硝基苯基（DNP）表位的共价耦合 与单磷酸脂质A（MPLA）。 DNP和MPLA都是非常潜在的免疫刺激剂，但它们可以提高 免疫系统通过不同的机制和途径 - DNP通过招募增强免疫反应 内源性DNP抗体自然存在于人血清中，而MPLA刺激免疫系统 通过与Toll样受体4的相互作用。此外，DNP与MPLA的共价结合将确保其 在相同的免疫细胞上和在同一免疫细胞中的共定位和协同作用，招募的DNP抗体也可以 吸引更多的免疫细胞到疫苗部位，以进一步增加疫苗 - 免疫细胞相互作用。所有这些 活动可以帮助增强这些偶联者的免疫刺激功能，以表现出协同作用和 具有更广泛的应用范围，成为更有效的调节器。 彼此之间，一系列与DNP的MPLA-DNP共轭物在不同位置和不同位置链接到MPLA 链接器的设计并将在此项目中进行研究。将开发有效的合成方法来访问 这些结合物以及合成的MPLA-DNP共轭物将在体外和小鼠中进行评估，以验证 这些新调节器的协同作用和这些新调节器的能力在增强对疫苗的免疫反应并获得 更好地理解诱导的免疫反应和作用机制。如果这个项目达到了 目标，这将导致发现新的，更有效的调节器，这不仅适用于疫苗 针对传染病，但也针对其他疾病进行免疫疗法。此外，创新的“共轭 佐剂概念也将广泛适用于其他调节器或免疫刺激剂。新调节器 具有明确定义的结构，这将使他们的结构活动关系和行动能够投资 机制。结果对于指导新佐剂的未来发展应该很有用。因此，这个项目 将对疫苗研究的整个领域产生巨大的影响。