Abstract
In this work, two different in vitro gastric digestion models were used to evaluate the stability of a live attenuated rotavirus vaccine candidate (RV3-BB) under conditions designed to mimic oral delivery in infants. First, a forced-degradation model was established at low pH to assess the buffering capacity of formulation excipients and to screen for RV3-BB stabilizers. Second, a sequential-addition model was implemented to examine RV3-BB stability under conditions more representative of oral administration to infants. RV3-BB rapidly inactivated at < pH 5.0 (37 °C, 1 h) as measured by an infectivity RT-qPCR assay. Pre-neutralization with varying volumes of infant formula (Enfamil®) or antacid (Mylanta®) conferred partial to full protection of RV3-BB. Excipients with sufficient buffering capacity to minimize acidic pH inactivation of RV3-BB were identified (e.g., succinate, acetate, adipate), however, they concomitantly destabilized RV3-BB in accelerated storage stability studies. Both effects were concentration dependent, thus excipient optimization was required to design candidate RV3-BB formulations which minimize acid-induced viral inactivation during oral delivery while not destabilizing the vaccine during long-term 2–8 °C storage. Finally, a statistical Design -of-Experiments (DOE) study examining RV3-BB stability in the in vitro sequential-addition model identified key formulation parameters likely affecting RV3-BB stability during in vivo oral delivery.
Highlights
Rotaviral infection remains a leading cause worldwide of severe diarrhea in children
Biological materials used during this study were secured by Batavia Biosciences, the Netherlands, as part of collaboration agreements with Murdoch Children'sResearch Institute (MCRI) and PT-BioFarma: the RV3-BB seed was from MCRI, the Bulk Drug Substance was from PT-BioFarma, the MA104 cells and the RV3-BB reference standard were obtained from Batavia Biosciences
We present two in vitro gastric digestion models to evaluate RV3-BB viral titer losses under conditions that mimic in vivo oral delivery
Summary
Rotaviral infection remains a leading cause worldwide of severe diarrhea in children
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