| dc.description.abstract | Tissue-resident memory T cells (TRM) patrol non-lymphoid organs and provide superior protection against pathogens that commonly infect mucosal and barrier tissues, such as the lungs, intestine, liver, and skin. At these sites, TRM are ideally positioned to rapidly trigger an immune response upon pathogen encounter. Thus, there is a need for vaccine technologies that can induce TRM, in particular after mucosal immunization, which mimics routes of natural infection. Nanoparticle (NP) vaccines offer important advantages over conventional vaccines, including improved safety and ease of manufacturing; however, there has been minimal investigation into the design of mucosal NP-based vaccines for eliciting TRM responses. Here, we describe a pH-responsive polymeric nanoparticle vaccine for generating antigen-specific CD8+ TRM cells in the lungs. With a single intranasal dose, the NP vaccine elicited airway- and lung-resident CD8+ TRM cells and protected against respiratory virus challenge in both sublethal (vaccinia) and lethal (influenza) infection models for up to nine weeks after immunization. In elucidating the contribution of material properties to the resultant immune response, we found that the pH-responsive activity of the carrier was important, as a structurally analogous non-pH-responsive control carrier elicited significantly fewer lung-resident CD8+ T cells. We also demonstrated that dual-delivery of protein antigen and nucleic acid adjuvant on the same NP substantially enhanced the magnitude, functionality, and longevity of the antigen-specific CD8+ TRM response in the lungs. Compared to administration of soluble antigen and adjuvant, the NP mediated retention of vaccine cargo in pulmonary antigen-presenting cells (APCs), enhanced APC activation, and increased production of TRM-related cytokines. We were able to harness the modular nature of this NP platform to deliver multiple antigens and adjuvants with diverse physicochemical properties, including ovalbumin, a model antigen; nucleoprotein, an influenza A virus antigen; and innate immune agonists for distinct intracellular targets: CpG, poly(I:C), and nanoISD. We demonstrated that delivering these nucleic acid adjuvants on pH-responsive NP or its non-pH-responsive equivalent can alter patterns of APC activation in the lungs and lymph node and impact the magnitude of the CD8+ TRM response in distinct lung compartments. Overall, these data suggest a promising mucosal vaccine platform technology for rapid generation of CD8+ TRM cells that can protect
against respiratory viral pathogens. | |
