A push-pull vaccine strategy using Toll-like receptor ligands, IL-15, and blockade of negative regulation to improve the quality and quantity of T cell immune responses

Abstract

We have developed a strategy to optimize the efficacy of vaccines to induce T-cell immunity against chronic viral infections and cancer based on a "push-pull" approach in which we first optimize the antigen structure by increasing the affinity of epitopes for major histocompatibility complex molecules ("epitope enhancement"), then push the response not only in magnitude but also in quality toward the desired response phenotype, using synergistic combinations of cytokines, Toll-like receptor ligands, and costimulatory molecules, and then pull the response by removing the brakes exerted by negative regulatory mechanisms, including regulatory cells, cell surface molecules, and cytokines. Components of this approach show promise in macaque models of AIDS virus infection and in murine models of cancer, and are being developed for human clinical trials.

Figure 1

Push-pull model to optimize immune responses to vaccines. The skeleton of a vaccine is an antigen used to induce an immune response. In this strategy, we 2) first improve the structure of the antigen by “epitope enhancement,” then 2) push the response toward not only higher but also higher quality immune responses, steering it in the right direction, using synergistic combinations of cytokines, Toll-like receptor (TLR) ligands and costimulatory molecules, and then 3) “pull” the response by removing the braking mechanisms to allow it to achieve its full potential. (Drawing courtesy of Dr. Masaki Terabe.) Modified from Sui and Berzofsky [56], with permission.