T Cell Vaccinology: Beyond the Reflection of Infectious Responses

Evidence is growing for divergent underlying mechanisms guiding the magnitude and duration of vaccine-elicited and infection-elicited CD8+ T cell responses. B cell responses can be successful after producing 10–20 000 'effectors' (antibody-secreting cells) whereas successful T cell responses require the mobilization of exponentially larger numbers of effectors. Most modern adjuvants and formulations are able to produce the required number of B cell effectors but generally cannot produce the required number of CD8 T cells. The few adjuvants which can induce potent cellular immunity in mice and primates rely heavily on TNF receptors (CD27/OX40) and IL-27 to promote sufficient T cell expansion and survival. These specific pathways are utilized very differently in response to infection, challenging whether the study of infectious responses can be expected to reveal a path forward for the development of T cell-inducing vaccine adjuvants. 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. 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.