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.