| Institution: | 1. Vaccine Drug Product Development, West Point, PA 19486, USA;2. Process Research and Development, West Point, PA 19486, USA;3. Vaccine Analytical Research and Development, West Point, PA 19486, USA;4. Vaccine Biometrics Research, West Point, PA 19486, USA;5. Infectious Diseases/Vaccines, West Point, PA 19486, USA;1. Independent Consultant, Chapel Hill, NC, USA;2. World Health Organization, Geneva, Switzerland;3. Directorate for Research, Studies and Documentation, National Public Health Organization, Athens, Greece;1. Departmentof Health Sciences, University of Genoa, Genoa, Italy;2. ScientificAdvisor of UNESCO CHAIR “Anthropology of Health – Biosphere and Healing System”, Italy;3. University Museum System of Siena (Simus), History of Medicine, University of Siena, Siena, Italy;1. Department of Medicine, South Georgia Medical Center, 2501 N Patterson St., Valdosta, GA, United States;2. Pulmonary Critical Care, Albert Einstein College of Medicine, Bronx, NY, United States;3. Economics, Valdosta State University, Valdosta, GA, United States;4. Edward Via College of Osteopathic Medicine, Auburn, AL, United States;5. Philadelphia College of Osteopathic Medicine- Moultrie, GA, United States;1. Department of Economics, University of Cantabria, Research Group on Health Economics and Health Services Management – Marqués de Valdecilla Research Institute (IDIVAL), Santander, Spain;2. Primary Care Unit, Algeciras-Norte Healthcare Unit, Algeciras, Spain;3. Preventive Medicine Unit, Costa del Sol Hospital, Marbella, Spain;4. Preventive Medicine Service, Immunosuppressed Patient Vaccination Unit, Son Espases University Hospital, Mallorca, Balearic Islands, Spain;5. Vaccines Medical Unit, Pfizer S.L.U, Alcobendas, Spain;6. Axentiva Solutions, Barcelona, Spain;7. Statistics Department, University of Barcelona, Barcelona, Spain;8. Health Economics and Outcomes Research, Pfizer S.L.U, Alcobendas, Spain;1. Translational Pediatrics and Infectious Diseases, Pediatrics Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain;2. Genetics, Vaccines and Infections Research Group (GENVIP), Instituto de Investigación Sanitaria de Santiago, University of Santiago de Compostela, Spain;3. Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain;4. Poznan University of Medical Sciences, Poland;5. Wroclaw Medical University, Poland;6. Instituto Hispalense de Pediatría, Sevilla, Spain;7. Clinical Research Center, Tartu, Estonia;8. The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences of the Ben-Gurion University of the Negev, Beer-Sheva, Israel;9. Telethon Kids Institute and School of Medicine, The University of Western Australia, Crawley, WA 6009, Australia;10. Merck & Co., Inc., Rahway, NJ, USA;11. Merck Canada Inc., Kirkland, QC, Canada;12. MSD B.V., OSS, the Netherlands;13. MSD (UK) Limited, London, United Kingdom;1. Department of Pediatric Immunology and Rheumatology, Wilhelmina Children''s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands;2. Department of Pediatrics, Carmel Medical Center, Technion Faculty of Medicine, Haifa, Israel;3. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands |
| Abstract: | Development of a vaccine drug product requires formulation optimization to ensure that the vaccine’s effectiveness is preserved upon storage throughout the shelf-life of the product. Although aluminum adjuvants have been widely used in vaccine formulations to safely and effectively potentiate an immune response, careful attention must be directed towards ensuring that the type of aluminum adjuvant does not impact the stability of the antigenic composition. PCV15 is a polysaccharide-protein conjugate vaccine comprising the pneumococcal polysaccharide (PnPs) serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F), each individually conjugated to the protein carrier CRM197. PCV15 was formulated with either amorphous aluminum hydroxyphosphate sulfate adjuvant (AAHS) or aluminum phosphate adjuvant (AP) and examined for both stability and immunogenicity. Using a collection of methods to evaluate vaccine stability, it was discovered that certain PCV15 serotypes (e.g., 6A, 19A, 19F) formulated with AAHS resulted in a reduction of immunogenicity in vivo and a reduction in recoverable dose as tested by an in vitro potency assay. The same polysaccharide-protein conjugates formulated with AP were stable regarding all measures tested. Moreover, the reduction in potency of certain serotypes correlated with chemical degradation of the polysaccharide antigen caused by the aluminum adjuvant as measured by reducing polyacrylamide gel electrophoresis (SDS-PAGE), High-Pressure Size Exclusion Chromatography coupled with UV detection (HPSEC-UV) and ELISA immunoassay. This study suggests a formulation, which includes AAHS, may negatively impact the stability of a pneumococcal polysaccharide-protein conjugate vaccine that contains phosphodiester groups. This decrease in stability would likely result in a decrease in the “active” concentration of antigen dose, and herein, it is shown that such instability directly compromised vaccine immunogenicity in an animal model. The results presented in this study help to explain critical degradation mechanisms of pneumococcal polysaccharide-protein conjugate vaccines. |
