Multi-Dose Formulation Development for a Quadrivalent Human Papillomavirus Virus-Like Particle-Based Vaccine: Part I...

Area of Science:

• Vaccinology
• Pharmaceutical Formulation
• Protein Chemistry

Background:

• Antimicrobial preservatives (APs) are crucial for multi-dose vaccine safety but can destabilize protein antigens.
• Human Papillomavirus (HPV) Virus-Like Particles (VLPs) are key vaccine components requiring stable formulations.

Purpose of the Study:

• To evaluate combined antimicrobial preservatives (APs) for multi-dose Human Papillomavirus (HPV) vaccine formulations.
• To determine if lower concentrations of multiple APs maintain both antimicrobial effectiveness and antigen stability.
• To identify optimal AP combinations for stable HPV VLP vaccine formulations.

Main Methods:

• Screening of seven different antimicrobial preservatives (APs) using empirical one-factor-at-a-time (OFAT) and statistical design-of-experiments (DOE) approaches.
• High-throughput assays for antimicrobial effectiveness (microbial growth inhibition, modified European Pharmacopeia method).
• Antigen stability assessment via serotype-specific monoclonal antibody (mAb) binding to HPV VLPs using ELISA.

Main Results:

• OFAT and DOE screening strategies were complementary, with OFAT informing DOE optimization.
• Validation experiments confirmed DOE model predictions for top AP combinations.
• Twenty candidate multi-dose formulations with two- or three-AP combinations were successfully down-selected.
• Selected AP combinations demonstrated potential for maintaining HPV VLP antigen stability.

Conclusions:

• Combined antimicrobial preservatives (APs) at reduced concentrations offer a promising strategy for stabilizing multi-dose Human Papillomavirus (HPV) vaccine formulations.
• The study successfully identified and down-selected candidate AP combinations for further long-term stability testing.
• This approach balances antimicrobial protection with antigen integrity, crucial for vaccine development.