New vaccine modalities need to be developed that can activate more potently the immune system, in this regard, adjuvants augment adaptive immune responses and can improve vaccine performance. Aluminum salt (alum) is the most commonly used adjuvant for human vaccination. However, it drives primarily TH2-effector responses and is not effective for vaccines that target mucosal surfaces. Thus, safe and potent adjuvants need to be developed that can increase and direct vaccines specific immunity. Recent advances in our understanding of innate immune responses are providing opportunities to design better adjuvants. In this regard, within this project, we have design novel chimeric compounds to synergistically activate several pattern recognition receptors (PRRs). These compounds will activate TLR2 and NOD1/NOD2, two major classes of PRRs stimulated in response to bacterial infection.
This project is important for the society because there is an unmet need for the development of vaccine modalities able to activate more potently the immune system. Thus, the design of new adjuvants able to boost the immune response and provide better protection against bacterial infection is important to reduce mortality and morbidity. This is especially important in high-risk groups, as babies and elderly people which in particular suffer from immune-senescence and they respond less potently to vaccination than young people and adults.
In view of the above-mentioned need for the development of new vaccine modalities, the goal of this project has been to generate safe and potent adjuvants that in conjunction with a specific antigen will elicit protective immunity. The project had the following main objectives:
(a) Synthesize a panel of chimeric agonists (fusion PAMPs) for TLR2-NOD2 and TLR2-NOD1 innate immune receptors.
(b) Determine the adjuvant function and pattern recognition receptor requirements of the synthetic compounds by examining cytokine production and T-cell activation by DCs.
(c) Examine the immune activating and protective properties of the chimeric compounds in a mouse model.
The results obtained during the development of this project validate the hypothesis of the project, the covalent attachment of NOD and TLR2 agonist results in efficient cross talk of signal transduction pathways and in synergistic immune activation. We found that the chimeric compounds induce higher production of IL-6 and TFNα than the NOD or TLR2 agonists alone. These studies are very promising and can be used for the design of new adjuvant modalities that will improve vaccines performance.
