T Cell Vaccinology: Beyond the Reflection of Infectious Responses

Abstract

Inducing sustained, robust CD8(+) T cell responses is necessary for therapeutic intervention in chronic infectious diseases and cancer. Unfortunately, most adjuvant formulations fail to induce substantial cellular immunity in humans. Attenuated acute infectious agents induce strong CD8(+) T cell immunity, and are thought to therefore represent a good road map for guiding the development of subunit vaccines capable of inducing the same. However, recent evidence suggests that this assumption may need reconsideration. Here we provide an overview of subunit vaccine history as it pertains to instigating T cell responses. We argue that in light of evidence demonstrating that T cell responses to vaccination differ from those induced by infectious challenge, research in pursuit of cellular immunity-inducing vaccine adjuvants should no longer follow only the infection paradigm.

Figure 1

Schematic diagram comparing and contrasting the innate response to a model infectious organism (L. monocytogenes) with the response to a vaccine adjuvant. A. Major innate pathways induced and an estimate of the time frame over which they are active is shown in the blue arrows above. In general, most cytokines induced by these pathways extend over multiple days as bacterial growth expands and wanes. Various inflammatory cytokines are induced over time which facilitate stages of both innate and adaptive control of bacterial growth. Antigen load expands and contracts with bacterial load which is eventually eliminated 5–6 days after challenge. B. In contrast to the infectious process, the inflammation induced by the adjuvant spikes early and begins to wane a few days after injection, tracking with the level of antigen. The limited inflammation induced creates fewer and less inflammatory cytokines which are also produced within a highly compressed time frame as compared to the infectious process. By days 3–4 after injection, while the antigenic load and inflammatory factors are still increasing to the infection, factors important to the adjuvant-elicited response such as IL-27 and CD27 are likely already becoming highly limited in the inflammatory milieu of the adjuvant.