Development of New Vaccine Adjuvants

总结 传染病仍然是对人类生命的严重威胁。根据世界卫生组织，CA。百分之十五 所有人类死亡的原因都是感染。为了控制和预防传染病， 被证明是最经济有效的策略。为了让疫苗有效地发挥作用， 为了防止病原体，它需要与解毒剂一起配制-这种物质可以增强免疫力 提高疫苗的有效性。然而，目前，佐剂的可用选择是 有限的，已经被批准用于人类使用的少数佐剂是复杂的混合物， 行动机制或有限的应用范围。更重要的是，它们没有表现出足够的功效， 许多疫苗正在开发中。为了满足各种疫苗开发和疫苗接种日益增长的需求， 因此，改善我们佐剂工具箱的功能是迫切而重要的。 本项目旨在通过设计和开发一种新颖的类来解决上述问题 佐剂，称为“缀合物佐剂”，其具有共价偶联的2，4-硝基二苯基（DNP）表位 与单磷酰脂质A（MPLA）。DNP和MPLA都是非常有效的免疫刺激剂，但它们可以增强免疫系统的功能。 免疫系统通过不同的机制和途径-DNP通过招募增强免疫应答 内源性DNP抗体天然存在于人血清中，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的共价缀合将确保它们的结合。 在相同的免疫细胞上和免疫细胞中的共定位和协同作用，并且募集的DNP抗体也可以 将更多的免疫细胞吸引到疫苗接种部位，以进一步增加疫苗-免疫细胞相互作用。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协同效应， 成为更有效的助剂，应用范围更广。 因此，一系列DNP在不同位置和通过不同方式与MPLA连接的MPLA-DNP缀合物被制备。 连接器的设计，并将在这个项目中进行研究。将开发有效的合成方法， 这些缀合物和合成的MPLA-DNP缀合物将在体外和小鼠中进行评估，以验证 这些新佐剂在增强对疫苗的免疫应答和获得免疫应答方面的协同效应和能力， 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，它将导致发现新的和更有效的佐剂，这不仅适用于疫苗， 抗传染病的免疫疗法，以及其他疾病的免疫疗法。此外，创新的“共轭 “佐剂”概念也将广泛应用于其它佐剂或免疫刺激剂。新的佐剂 具有明确的结构，这将使研究其结构-活性关系和作用成为可能 机制等研究结果对今后开发新的佐剂有一定的指导意义。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。

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.