An NLRP3-stimulatory adjuvant improves the immunogenicity of influenza virus vaccines in mice and non-human primates

Dendritic cells (DCs) are the primary inducers of immunity induced by infection or vaccination. To stimulate durable T cell-mediated immunity, multiple DC activities are required. DCs must present antigen, express costimulatory molecules, and secrete inflammatory cytokines to direct T cell activation. These activities must be coordinated with DC migration to the lymph node and production of memory T cell-inducing cytokines, such as IL-1β. Common vaccination approaches use adjuvants that stimulate a subset of these activities, leading to diminished T cell activities and poor immune durability. We describe herein a lipid-based adjuvant, called a hyperactivator, which elicits all five of the aforementioned DC activities. Other adjuvants examined, including those used clinically, were defective for one or more of the key activities needed for robust T cell activation. Vaccines in mice and nonhuman primates targeting influenza virus antigens, including the quadrivalent commercial product Afluria, displayed enhanced adaptive immune responses when administered using hyperactivators as adjuvants. These data highlight the impact of hyperactivator adjuvants as a means to enhance antigen-specific immunity, with potential applications towards a universal influenza vaccine. IMPORTANCE The generation of vaccines that stimulate T cell activities is an unmet need for the scientific community, as T cells are the primary mediators of immune memory. In this study, we report a new vaccine adjuvant called a hyperactivator. This hyperactivator adjuvant diversifies the T cell and antibody responses to virus antigens, such that in nonhuman primates, all influenza strains in the clinical vaccine Afluria are targeted. Hyperactivator adjuvants may represent a means to achieve the long-sought-after goal of a universal influenza vaccine.