Multi-Dose Formulation Development for a Quadrivalent Human Papillomavirus Virus-Like Particle-Based Vaccine: Part I - Screening of Preservative Combinations

Kaushal Jerajani, Ying Wan, Ozan S. Kumru, Swathi R. Pullagurla, Prashant Kumar, Nitya Sharma, Oluwadara Ogun, Shweta Mapari, Sarah Brendle, Neil D. Christensen, Saurabh Batwal, Mustafa Mahedvi, Harish Rao, Vikas Dogar, Rahul Chandrasekharan, Umesh Shaligram, Sangeeta B. Joshi, David B. Volkin

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)446-457
Number of pages12
JournalJournal of Pharmaceutical Sciences
Volume112
Issue number2
DOIs
StatePublished - Feb 2023

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

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