Robust IgG responses to nanograms of antigen using a biomimetic lipid-coated particle vaccine

Abstract

New subunit vaccine formulations with increased potency are of interest to improve immune responses against poorly immunogenic antigens, avoid vaccine shortages in pandemic situations, and to promote dose-sparing of potent adjuvant molecules that can cause unacceptable side effects in prophylactic vaccination. Here we report strong class-switched, high avidity humoral immune responses elicited by a vaccine system based on poly(lactide-co-glycolide) micro- or nano-particles enveloped by PEGylated phospholipid bilayers, with protein antigens covalently anchored to the lipid surface and lipophilic adjuvants inserted in the bilayer coating. Strikingly, these particles elicited high endpoint antigen-specific IgG titers (>106) sustained for over 100 days after two immunizations with as little as 2.5 ng of antigen. At such low doses, the conventional adjuvant alum or the molecular adjuvants monophosphoryl lipid A (MPLA) or α-galactosylceramide (αGC) failed to elicit responses. Co-delivery of antigen with MPLA or αGC incorporated into the particle bilayers in a pathogen-mimetic fashion further enhanced antibody titers by ~12-fold. MPLA provided the highest sustained IgG titers at these ultra-low antigen doses, while αGC promoted a rapid rise in serum IgG after one immunization, which may be valuable in emergencies such as disease pandemics. The dose of αGC required to boost the antibody response was also spared by particulate delivery. Lipid-enveloped biodegradable micro- and nano-particles thus provide a potent dose-sparing platform for vaccine delivery.

Influence of cationic lipid concentration on properties of lipid–polymer hybrid nanospheres for gene delivery

“…The LP HNSs were fabricated by modifying the double-emulsion solvent-evaporation process by allowing lipids and protamine to self-assemble on the surface of a polymer core. 14,20 Protamine was used as the condensing agent. 31 In this study, four different concentrations of lipids with constant protamine were used to construct LPHNSs, and their properties and transfection efficiencies were compared.…”

“…20 Briefly, protamine sulfate (10 µg/mL) was dissolved in aqueous solution. The cationic lipid (1,2-di-(9Z-octadecenoyl)-3-trimethylammoniumpropane (chloride salt) [DOTAP]) and PLGA (3% w/v) were dissolved in dichloromethane.…”

“…DLS analysis revealed that there was a significant size reduction (Figures 2A, S1) compared to bare PLGA NSs (247±12.8 nm), which could be explained by the fact that the processing of those particles in a single step was stabilized by the function of the lipids with PVA. 15,20 It was also found that there was a decrease in particle size Notes: LPHNSs that consisted of DOTAP-protamine-PLGA for efficient gene delivery were fabricated by emulsion-solvent evaporation with a self-assembly process.…”

“…15 Although successful outcomes have been achieved using the single-step method, a better understanding of the parameters involved in the fabrication process is required in order to significantly improve the design and fabrication of LPHNSs. 19,20 Specifically, cationic lipids forming outer shells could allow for superior gene-delivery capabilities. However, it is still not clear how lipid concentration affects the formation of LPHNSs.…”

Nonlinear Response Amplification Mechanisms for Low Doses of Natural Product Nanomedicines: Dynamical Interactions with the Recipient Complex Adaptive System

“…Therefore, NPs intended for therapeutic applications often have unique capabilities for targeting specific cells, crossing membranes to enter cells more effectively than bulk form materials, and exerting effects for longer periods of time per dose. NP-based vaccines also provide indications of markedly enhanced adjuvant capacity for immune activation, thereby reducing the antigen doses required to evoke a vigorous response in the overall organism [48,76]. NPs from silica can mobilize inflammasome proteins inside a cell [35,77,78].…”