Vaccines containing novel adjuvant formulations are increasingly reaching advanced development and licensing stages, providing new tools to fill previously unmet clinical needs. However, many adjuvants fail during product development owing to factors such as manufacturability, stability, lack of effectiveness, unacceptable levels of tolerability or safety concerns. This Review outlines the potential benefits of adjuvants in current and future vaccines and describes the importance of formulation and mechanisms of action of adjuvants. Moreover, we emphasize safety considerations and other crucial aspects in the clinical development of effective adjuvants that will help facilitate effective next-generation vaccines against devastating infectious diseases.

Natural killer (NK) cells play a key role in the immune response to certain infections and malignancies by direct cytolysis of infected or transformed cells and by secretion of potent immune mediators. NK cells express an array of activating receptors that recognize self-molecules. If not restrained by inhibitory receptors recognizing major histocompatibility complex (MHC) class I proteins on the surface of self cells, NK cells are able to kill normal healthy cells. Not all NK cells express inhibitory receptors for self-MHC class I; thus, other tolerance mechanisms are necessary to prevent NK cell-mediated autoimmunity. Here we review the major mechanisms of NK cell education and tolerance.

Natural killer (NK) cells expressing inhibitory receptors that bind to self-MHC class I are “licensed” or rendered functionally more responsive to stimulation, whereas “unlicensed” NK cells lacking receptors for self-MHC class I are hyporesponsive. Here we show that, contrary to the licensing hypothesis, unlicensed NK cells were the primary mediators of NK cell-mediated control of mouse cytomegalovirus infection in vivo. Depletion of unlicensed, but not licensed, NK cells impaired control of viral titers. Transfer of unlicensed NK cells was more protective than licensed NK cells. SHP-1 signaling limited proliferation of licensed, but not unlicensed NK cells during infection. Thus, “unlicensed” NK cells are critical for protection against viral infection.