人乳头瘤病毒
抗原
抗菌剂
类病毒颗粒
防腐剂
化学
病毒学
生物
微生物学
重组DNA
医学
食品科学
生物化学
免疫学
基因
内科学
作者
Kaushal Jerajani,Ying Wan,Ozan S. Kumru,Swathi R. Pullagurla,Prashant Kumar,Nitya Sharma,Oluwadara Ogun,Shweta Mapari,Sarah A. Brendle,Neil D. Christensen,Saurabh Batwal,Mustafa Mahedvi,Harish Rao,Vikas Dogar,Rahul Chandrasekharan,Umesh Shaligram,Sangeeta B. Joshi,David B. Volkin
标识
DOI:10.1016/j.xphs.2022.09.001
摘要
The development of multi-dose, subunit vaccine formulations can be challenging since antimicrobial preservatives (APs) often destabilize protein antigens. In this work, we evaluated Human Papillomavirus (HPV) Virus-Like Particles (VLPs) to determine if combining different APs used in approved parenteral products, each at lower concentrations than used alone, would maintain both antimicrobial effectiveness and antigen stability. To identify promising AP combinations, two different screening strategies were utilized: (1) empirical one-factor-at-a-time (OFAT) and (2) statistical design-of-experiments (DOE). Seven different APs were employed to screen for two- and three-AP combinations using high-throughput methods for antimicrobial effectiveness (i.e., microbial growth inhibition assay and a modified European Pharmacopeia method) and antigen stability (i.e., serotype-specific mAb binding to conformational epitopes of HPV6, 11, 16 VLPs by ELISA). The OFAT and DOE approaches were complementary, such that initial OFAT results (and associated lessons learned) were subsequently employed to optimize the combinations using DOE. Additional validation experiments confirmed the final selection of top AP-combinations predicted by DOE modeling. Overall, 20 candidate multi-dose formulations containing two- or three-AP combinations were down-selected. As described in Part 2 (companion paper), long-term storage stability profiles of aluminum-adjuvanted, quadrivalent HPV VLP formulations containing these lead candidate AP combinations are compared to single APs.
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