Development of New Vaccine Adjuvants

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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.