Chimeric Pathogen-Associated Molecular Patterns (PAMPs) as Vaccine Adjuvants

The development of pathogen-associated molecular patterns (PAMPs) that signal via pathogen recognition receptors (PRRs) on innate immune cells is a strategy that is widely adopted in adjuvant research. Less well studied is how covalently linking different PAMPs affects the immune response. Herein, we summarise the research on the effect of PAMP linkage on innate and adaptive immune responses. These covalently linked or "chimeric" PAMPs often lead to immune cell synergies that are greater than those exhibited by the admixed (unconjugated) PAMPs, with several PAMP conjugates exhibiting remarkable adjuvant activity in a variety of disease contexts that include infectious disease, allergy, and cancer immunotherapy. This improvement in immune cell activation is thought to be due to more effective crosstalk between the different PRR signalling pathways, as conjugation ensures that each cell receives each class of PAMP. In addition, PAMP conjugates can form particulates, which has been postulated to lead to improved adjuvanticity, or they may facilitate the targeting of endosomal PRRs via the PRR-mediated endocytosis of the alternative PAMP in the conjugate. PAMP conjugates can also reduce the toxicity of individual PAMPs. However, not all PAMP conjugates are effective, and there are still many aspects of this research platform that are poorly understood, including how linker chemistry affects the immune response and how PRR signalling pathways or PAMP combinations combine to skew the immune response. We will address these and other outstanding questions that relate to the use of PAMP conjugates as vaccine adjuvants.