Synthesis of a Small Library of Compounds Inspired by Bacteroides fragilis Lipid A as Potential Vaccine Adjuvants

Adjuvants are substances that improve the overall efficacy of vaccines, enhancing the response towards antigens and allowing for the use of lower doses of active ingredients1. Moreover, adjuvants provide functionally appropriate immune response by modulating the generation of specific immune system cell types1,2. Until now, only a few vaccine adjuvants have been approved and their complete mechanism of action must be fully elucidated yet. Therefore, new research efforts are needed with the aim to identify novel chemical entities to be developed as adjuvants. Some low-toxicity Lipid A molecules can positively modulate the human’s immune system through their interaction with key components of the innate immune system, such as the Toll-like receptors (TLRs). An illustrative example is “Monophosphoryl Lipid A”, a modified Lipid A from Salmonella minnesota R595, the first TLR-agonist authorized as vaccine adjuvant3. Recently, new Lipid A moieties of Bacteroides fragilis, a Gram-negative bacterium belonging to the gastrointestinal microbiota, have been isolated. Their promising immunomodulatory activities4 and their probable low toxicity make them interesting candidates for the development of new vaccine adjuvants. The glycolipid mixture isolated from B. fragilis has been only partially characterized and their exact structures is still not completely established. In this context, our project is focused on the chemical synthesis of a small library of Lipid A structures (Figure 1), based on the available information, with the aim to define their chemical structures and their immunological properties, as well as to investigate their potential application as vaccine adjuvants.