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.

The mechanisms by which squalene, which in oil-and-water emulsions has been shown to be an excellent formulation for TLR agonists, enhances the magnitude and quality of adaptive immune responses are not thoroughly defined. In this issue of the European Journal of Immunology [Eur. J. Immunol. 2015. 45: XXXX-XXXX], Desbien et al. show that a squalene/TLR4-based adjuvant augments antigen-specific Th1 responses in vaccinated mice through a caspase/IL-18-dependent mechanism. This commentary will discuss the authors’ findings in the context of elucidating the mechanism of action of squalene as an adjuvant, and the new questions that the work generates.