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

Abstract

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.

Beyond antigens and adjuvants: formulating future vaccines

“…However, elastic particles (e.g., liposomes) that may deform during transport appear to have different size limits (25). Virus-like particles (VLPs), based on self-assembling proteins (26)(27)(28) and synthetic polymer or lipid nanoparticle formulations (21,(29)(30)(31)(32), have been demonstrated to enhance vaccine accumulation in LNs and to promote superior cellular and humoral immunity to a variety of antigens in mice relative to soluble forms of protein and peptide vaccines. In addition to size, particle surface chemistry plays a key role in lymphatic trafficking by regulating the tendency toward aggregation in physiological conditions and interactions with cells and/or ECM.…”

Nanoparticle conjugation of CpG enhances adjuvancy for cellular immunity and memory recall at low dose

“…Induction of long-lasting CTLs with subunit vaccines requires, first, delivery of antigen to cross-presenting dendritic cells (DCs) and, second, potent activation of these DCs by the vaccine adjuvant, which instructs DCs how to activate T cells. Nanocarriers can be used to modulate the immune response induced by antigens and adjuvants by modifying their characteristics, such as stability, tissue and cell targeting, and DC-activating capacity (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). We have previously described the targeting benefits of conjugating antigens to ultrasmall Pluronic-stabilized poly(propylene sulfide) (PPS) nanoparticles (NPs) in terms of CD8 + T-cell and Th1 responses (13,14).…”

Mucosal vaccines

“…163 This imprinting ability of lung DCs was confirmed in humans, as it was shown that CD1c lung DCs co-cultured with CD8 + T cells promote upregulation of CD103 and CD49a on these cells. 164 Other studies support the role of mucosal immunity in protecting against mucosal tumors.…”