TY - JOUR

T1 - Microcontainers for protection of oral vaccines, in vitro and in vivo evaluation

AU - von Halling Laier, Christoffer

AU - Gibson, Blake

AU - Moreno, Jorge Alberto S.

AU - Rades, Thomas

AU - Hook, Sarah

AU - Nielsen, Line Hagner

AU - Boisen, Anja

PY - 2019

Y1 - 2019

N2 - Oral vaccines are highly desirable due to simple logistics, mass vaccination potential and for mucosal immunity. Subunit vaccines are preferred due to high safety, but are inherently difficult to deliver orally, thus providing motivation for the use of advanced oral delivery systems. Polymeric devices in micrometer size (microcontainers) were tested here for this purpose. Microcontainers were loaded with a vaccine consisting of spray dried cubosomes with OVA and Quil-A, and coated with a pH-sensitive lid for oral delivery to C57Bl/6 mice. The microcontainers were explored in vitro and in vivo for their potential as oral vaccine delivery system in an oral prime-boost setting and as an oral booster after a subcutaneously injected prime. The residence time of microcontainers in the small intestine was less than one hour. Eudragit® L100–55 was therefore chosen as lid material on the microcontainers as it remained stable in vitro at pH 4.7, which simulated the maximal pH of the stomach, and allowed release of the cubosomes within 30–60 min at pH 6.6, which simulated the mean pH of the distal half of the small intestine. In vitro small angle X-ray scattering showed that cubosomes dissolved in small intestinal fluid when not confined in microcontainers but when loaded into microcontainers they were released as hexosomes. However, while microcontainers could protect and release particles with OVA and Quil-A within relevant time frames in vitro, an immune response was not elicited in vivo after oral administration. Nonetheless, some effect was observed when the microcontainers were used to deliver oral boosters following a subcutaneous prime. This work indicates that oral vaccination with subunit vaccines has potential when combined with a parenteral prime and that oral delivery systems like microcontainers may be used to increase the potency of vaccines with low oral immunogenicity.

AB - Oral vaccines are highly desirable due to simple logistics, mass vaccination potential and for mucosal immunity. Subunit vaccines are preferred due to high safety, but are inherently difficult to deliver orally, thus providing motivation for the use of advanced oral delivery systems. Polymeric devices in micrometer size (microcontainers) were tested here for this purpose. Microcontainers were loaded with a vaccine consisting of spray dried cubosomes with OVA and Quil-A, and coated with a pH-sensitive lid for oral delivery to C57Bl/6 mice. The microcontainers were explored in vitro and in vivo for their potential as oral vaccine delivery system in an oral prime-boost setting and as an oral booster after a subcutaneously injected prime. The residence time of microcontainers in the small intestine was less than one hour. Eudragit® L100–55 was therefore chosen as lid material on the microcontainers as it remained stable in vitro at pH 4.7, which simulated the maximal pH of the stomach, and allowed release of the cubosomes within 30–60 min at pH 6.6, which simulated the mean pH of the distal half of the small intestine. In vitro small angle X-ray scattering showed that cubosomes dissolved in small intestinal fluid when not confined in microcontainers but when loaded into microcontainers they were released as hexosomes. However, while microcontainers could protect and release particles with OVA and Quil-A within relevant time frames in vitro, an immune response was not elicited in vivo after oral administration. Nonetheless, some effect was observed when the microcontainers were used to deliver oral boosters following a subcutaneous prime. This work indicates that oral vaccination with subunit vaccines has potential when combined with a parenteral prime and that oral delivery systems like microcontainers may be used to increase the potency of vaccines with low oral immunogenicity.

KW - C57Bl/6

KW - Cubosomes

KW - Eudragit L100–55

KW - Microdevices

KW - Ovalbumin

KW - Quil-A

U2 - 10.1016/j.jconrel.2018.11.030

DO - 10.1016/j.jconrel.2018.11.030

M3 - Journal article

C2 - 30550938

AN - SCOPUS:85058238565

VL - 294

SP - 91

EP - 101

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -