Adjuvant options for subunit vaccine design are extremely limited. Apart from alum, just two adjuvants are approved for use in the US: squalene and the combination adjuvant system AS04, which combines traditional alum with a partial agonist of TLR4, monophosphoryl lipid A (MPL). MPL adjuvant is notable because it is the first and only purified TLR agonist in a licensed vaccine in the US, was tested extensively for safety and efficacy in large clinical trials, and shows promise as an adjuvant in ambitious vaccine projects such as the RTS,S/AS01 vaccine to prevent malaria. Alum+MPLA is currently the best example we have of a clinically successful adjuvant but the factors that make it successful are poorly understood. Moreover, MPL is a heterogeneous mixture of lipid A structures in which a hexa-acylated structure is thought to be the ?active? component, but the functions of other components have never been tested in human immune cells. Preliminary studies support the hypothesis that MPL adjuvant contains an immunomodulatory inhibitor of human TLR4 that constrains endotoxic responses with less impact on adaptive priming. This project will identify the inhibitor, determine if and how it has differential effects on MyD88- vs TRIF-signaling, and evaluate synthetic analogues of MPL with amplified properties as adjuvants.
Prophylactic immunization has been exceptionally successful at improving public health. However, there are still no vaccines available for many infectious diseases and it is thought that more powerful ways to stimulate the immune system will be needed in order for them to be successful. Adjuvants are additives for vaccines designed to stimulate the immune response better than before without causing harm to the persons being vaccinated; the goal of this project is to build on the success of an existing combination adjuvant by learning how it works and applying those lessons for development of new vaccine adjuvants.
|Mitchell, Thomas C; Casella, Carolyn R (2017) No pain no gain? Adjuvant effects of alum and monophosphoryl lipid A in pertussis and HPV vaccines. Curr Opin Immunol 47:17-25|