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.

概括 传染病仍然对人类生命构成严重威胁。据世界卫生组织称，大约。 15% 的人类死亡是由感染引起的。为了控制和预防传染病，已进行了疫苗接种 事实证明这是最经济有效的策略。为了使疫苗有效发挥作用并激发持久的效果 为了对抗病原体，它需要与佐剂一起配制——佐剂可以增强免疫 反应并增强疫苗的有效性。然而，目前，可用的佐剂选择有 有限，并且已批准用于人类使用的少数佐剂是复杂的混合物，其中大部分未知 作用机制或应用范围受限。更重要的是，它们没有表现出足够的功效 许多疫苗正在研发中。满足各种疫苗研发和接种日益增长的需求 计划中，改善我们佐剂工具箱的多样性是紧迫且重要的。 该项目旨在通过设计和开发一个新颖的类来解决上述问题 佐剂，称为“缀合佐剂”，具有共价偶联的 2,4-硝基二苯基 (DNP) 表位 与单磷酰脂质 A (MPLA) 一起使用。 DNP 和 MPLA 都是非常有效的免疫刺激剂，但它们可以增强 通过不同机制和途径的免疫系统——DNP 通过募集增强免疫反应 内源性 DNP 抗体天然存在于人体血清中，而 MPLA 则可刺激免疫系统 通过与 Toll 样受体 4 的相互作用。此外，DNP 与 MPLA 的共价缀合将确保其 同一免疫细胞上和细胞内的共定位和协同作用，并且所招募的 DNP 抗体还可以 吸引更多的免疫细胞到疫苗接种部位，进一步增加疫苗与免疫细胞的相互作用。所有这些 活性可以帮助增强这些缀合物的免疫刺激功能，以显示出协同效应， 成为更有效、应用范围更广的助剂。 因此，一系列 MPLA-DNP 缀合物，其中 DNP 在不同位置并通过不同方式与 MPLA 连接。 连接器的设计和研究将在该项目中进行。将开发有效的合成方法来获取 这些缀合物以及合成的 MPLA-DNP 缀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反应和获得​​免疫应答方面的协同效应和能力 更好地了解诱导的免疫反应和作用机制。如果这个项目达到了 目标，它将导致发现新的、更有效的佐剂，这些佐剂不仅适用于疫苗 对抗传染病以及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增强剂。新佐剂 具有明确的结构，这将有助于研究其结构-活动关系和作用 机制。该结果应该有助于指导新佐剂的未来开发。因此，本项目 将对整个疫苗研究领域产生重大而广泛的影响。