Generation of Effector Memory T Cell–Based Mucosal and Systemic Immunity with Pulmonary Nanoparticle Vaccination

A lipid nanocapsule vaccine promotes cross-presentation of antigen with enhanced draining lymph node delivery to elicit an effector memory CD8+ T cell response. Nanoparticle Vaccine Delivered to Lungs Delivering vaccines to the lungs has been shown to protect against not only respiratory infections but also pathogens that enter in other organs, including the gastrointestinal and reproductive tracts. To capitalize on this phenomenon, Li and colleagues designed a pulmonary vaccination strategy that uses nanoparticle carriers to deliver antigen and adjuvant to the mucosal surface lining the lungs. Nanosized particles called interbilayer-crosslinked multilamellar vesicles (ICMVs) were engineered to contain antigen along with two Toll-like receptor agonists, which served as adjuvants to stimulate airway epithelial cells and promote dendritic cell uptake and cross-presentation. Mice that received ICMVs containing the model antigen ovalbumin (OVA) showed a greater T cell response than did those that received soluble OVA vaccine, with more OVA-specific T cells in the lungs after 11 weeks. ICMV-based vaccines were next put to the test in therapeutic tumor and prophylactic viral challenge models. As a therapeutic vaccine, all mice that received OVA-ICMVs after an injection of OVA-expressing melanoma cells resisted tumor formation and had prolonged survival. In the challenge model, animals were first given ICMV vaccines loaded with the peptide antigen AL11 [from simian immunodeficiency virus (SIV) gag], then exposed to vaccinia virus expressing SIV gag. Only animals that received pulmonary vaccination—not subcutaneous or soluble vaccine—were protected from viral challenge, showing a reduction of viral titers in the lungs and other organs. The nanoparticle vaccine demonstrated systemic protection when delivered locally to the lung mucosa. The authors suggest that ICMV vaccines stimulated the generation of a large population of effector memory T cells in the lungs and circulation, thus conferring such high protection in mice. Although the ICMVs were determined to be safe and well tolerated in small animals, additional safety and efficacy studies will be needed in larger animals before translation. Many pathogens infiltrate the body and initiate infection via mucosal surfaces. Hence, eliciting cellular immune responses at mucosal portals of entry is of great interest for vaccine development against mucosal pathogens. We describe a pulmonary vaccination strategy combining Toll-like receptor (TLR) agonists with antigen-carrying lipid nanocapsules [interbilayer-crosslinked multilamellar vesicles (ICMVs)], which elicit high-frequency, long-lived, antigen-specific effector memory T cell responses at multiple mucosal sites. Pulmonary immunization using protein- or peptide-loaded ICMVs combined with two TLR agonists, polyinosinic-polycytidylic acid (polyI:C) and monophosphoryl lipid A, was safe and well tolerated in mice, and led to increased antigen transport to draining lymph nodes compared to equivalent subcutaneous vaccination. This response was mediated by the vast number of antigen-presenting cells (APCs) in the lungs. Nanocapsules primed 13-fold more T cells than did equivalent soluble vaccines, elicited increased expression of mucosal homing integrin α4β7+, and generated long-lived T cells in both the lungs and distal (for example, vaginal) mucosa strongly biased toward an effector memory (TEM) phenotype. These TEM responses were highly protective in both therapeutic tumor and prophylactic viral vaccine settings. Together, these data suggest that targeting cross-presentation–promoting particulate vaccines to the APC-rich pulmonary mucosa can promote robust T cell responses for protection of mucosal surfaces.