Development of New Vaccine Adjuvants

新型疫苗佐剂的开发

• 批准号: 10636922
• 负责人: Zhongwu Guo
• 金额: $ 18.15万
• 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/10636922
• 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; Immunologic Stimulation; Immunologics; Immunotherapy; In Vitro; Infection; Innate Immune System; Investigation; 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; natural antibodies; 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.

摘要 传染病仍然是对人类生命的严重威胁。根据世界卫生组织的数据，约15% 在所有的人类死亡中，是由感染引起的。为了控制和预防传染病，接种疫苗一直是 事实证明，这是最经济有效的策略。一种疫苗要有效地发挥作用并引发持久的 对病原体的保护，需要用佐剂配制，佐剂是一种可以增强免疫力的物质 加强疫苗的反应和效力。然而，目前可供选择的佐剂有 有限的，少数已被批准用于人类的佐剂是复杂的混合物，基本上不知道 操作机制或受限的应用程序范围。更重要的是，它们没有表现出足够的疗效 许多疫苗正在研发中。以满足各种疫苗开发和疫苗接种日益增长的需求 计划，迫切和重要的是改善我们的佐剂工具箱的多样性。 本项目旨在通过设计和开发一个新的类来解决上述问题 具有共价偶联的2，4-硝基二苯基(DNP)表位的各种佐剂，称为“共轭佐剂” 单磷酰脂A(Mpla)。DNP和Mpla都是非常有效的免疫刺激剂，但它们促进了 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相同的免疫细胞上的共同定位和协同作用，以及招募的DNP抗体也可以 吸引更多的免疫细胞到接种部位，进一步增加疫苗与免疫细胞的相互作用。所有这些都是 活性有助于增强这些结合物的免疫刺激功能，以显示协同效应和 成为应用范围更广的更有效的佐剂。 因此，一系列与DNP在不同位置以不同方式连接到MPLA上的MPLADNP偶联物 链接器被设计并将在本项目中进行研究。将开发有效的合成方法来获得 这些结合物和合成的MPLA-DNP结合物将在体外和小鼠体内进行评估，以验证 这些新佐剂在增强疫苗免疫应答方面的协同作用和能力 更好地了解诱导的免疫反应及其作用机制。如果此项目达到其 目标，它将导致新的和更有效的佐剂的发现，这些佐剂不仅适用于疫苗 不仅是针对传染病的免疫疗法，也是针对其他疾病的免疫疗法。此外，创新的“共轭” 佐剂“的概念也将广泛适用于其他佐剂或免疫刺激剂。新型佐剂 具有明确的结构，这将使研究其结构-活性关系和行动成为可能 机制。这一结果将有助于指导未来新型佐剂的开发。因此，这个项目 将对整个疫苗研究领域产生巨大而广泛的影响。