Toward a Single‐Dose Vaccination Strategy with Self‐Encapsulating PLGA Microspheres

Abstract

Poly(lactic-co-glycolic acid) (PLGA) microspheres have been widely examined for vaccine applications due to their attractive features of biocompatibility, biodegradability, ability to be internalized by antigen-presenting cells, and long-term antigen release. However, one of the major challenges for PLGA particle vaccines is the potential for antigen instability and loss of antigenicity and immunogenicity. To address this challenge, we have developed a new method of “self-healing” encapsulation in PLGA microspheres, where pre-made PLGA microspheres are loaded with protein antigens under aqueous conditions with minimal impact on their antigenicity and immunogenicity. In this report, we show that mice immunized with self-encapsulating PLGA microspheres in a prime-boost regimen generated significantly enhanced antigen-specific CD8α+ T cell and antibody responses, compared with mice immunized with free, soluble protein admixed with calcium phosphate gel, a widely used adjuvant. Furthermore, a single-dose of microspheres designed for >40 day sustained antigen release elicited robust cellular and humoral immune responses as efficiently as the prime-boost vaccinations with calcium phosphate gel. Overall, these results suggest excellent potential of our self-encapsulating PLGA microspheres as a vaccine platform for multiple-dose as well as single-dose vaccinations.

Materials for Immunotherapy

“…The following year, Blanco‐Prieto and co‐workers developed PEG‐coated PLGA microparticles to deliver cytokines for heart regeneration in a rat myocardial infarction model . Soon after, Moon and co‐workers developed a PLGA microsphere capable of self‐healing for the enhanced protection and sustained delivery of OVA . Due to the self‐healing nature of their microparticles, antigens were released for up to 40 days while preserving antigenicity, improving immunity with a single administration compared to two separate administrations of OVA with CaHPO 4 adjuvant, toward a single dose vaccine.…”

“…Given its success as a nanoscale delivery material, PLGA was a natural choice for an aAPC that is biodegradable and thus potentially translatable for in vivo T cell induction. Further, PLGA microspheres have been shown to improve the protection of antigens, toward a single dose vaccine . In 2008, Fahmy and Steenblock were among the first to employ PLGA microparticles as aAPCs, whereby particles encapsulated IL‐2 for slow release and were decorated with MHCs presenting OVA antigens and anti‐CD28 costimulatory molecules .…”

“…In 2017, Green and co‐workers studied the combination of PLGA aAPCs in combination with an anti‐PD‐1 checkpoint blockade against murine melanoma . Later that year, Schwendeman and Moon developed self‐healing PLGA microspheres with calcium phosphate (CaHPO 4 ) adjuvant gel to enhance antigen protection for improved T cell induction . Taken together, these studies provide a roadmap for the design of biodegradable aAPCs.…”

Improving Vaccine and Immunotherapy Design Using Biomaterials

“…Encapsulation of vaccine cargo into polymeric or lipid particles is a continuing theme in the vaccine field to improve co-delivery of antigen and adjuvant, or achieve desirable delivery kinetics through controlled cargo release (Figure 2B). The particulate nature of material platforms also generally enhances uptake by APCs [29– 31]. One recent example used crosslinked lipid NPs encapsulating model antigen (ovalbumin; Ova) combined with a TLR agonist (TLRa) to increase antigen-specific T cells 13-fold by increasing retention in draining LNs [31].…”

Self-encapsulating Poly(lactic-co-glycolic acid) (PLGA) Microspheres for Intranasal Vaccine Delivery

“… a The data for MPs (10 µ g OVA)-SC is from Bailey et al 14 Data represent mean ± SEM ( n = 10 for PBS-IN, CTB-IN, and MPs-IN; and n = 5 for MPs-SC). **** p < 0.0001 against all other groups. ## p ≤ 0.01; ### p ≤ 0.001; #### p ≤ 0.0001 against PBS control-IN. † p ≤ 0.05; †† p ≤ 0.01; †††† p ≤ 0.0001 against CTB-IN. ‡‡‡ p ≤ 0.001 against MPs-IN. N.B.…”