Acute Phase Responses to Novel, Investigational Vaccines in Toxicology Studies: The Relationship Between C-Reactive Protein and Other Acute Phase Proteins.
The objective of this study was to determine the effects of investigational vaccine candidates on acute-phase proteins (APPs) as determined in GLP toxicology studies. Sixty-four GLP toxicity studies, which were submitted to the Food and Drug Administration from 2008 to 2012 in support of proposed clinical investigations, were reviewed and entered into a database. These studies employed the intramuscular route of injection and were conducted using New Zealand White rabbits. A retrospective review of these GLP toxicity studies was conducted to evaluate the changes in plasma levels of C-reactive protein (CRP), fibrinogen, and albumin as APPs following the administration of various investigational vaccines. The incidence and intensity of responses associated with acute-phase responses both positive and negative were observed to increase in animals when treated with vaccines containing more potent immunological components such as novel adjuvants that activate Toll-like receptors in the investigational vaccine products. Changes in plasma levels of CRP were prominent among these responses and provided a basis to propose a classification scheme of H, M, L, and N responding groups. These changes in plasma proteins reflect an activation of the acute-phase response and indicate increasing levels of systemic inflammation, which potentially may be correlated with important clinical adverse events.
Division of Vaccines and Related Product Applications, Office of Vaccines, Center for Biologics Evaluation and Review, Food and Drug Administration, Rockville, MD, USA martin.green@fda.hhs.gov.
Martin D
MD
Green
D000818:Animals; D002097:C-Reactive Protein / Q000032:analysis*; D005340:Fibrinogen / Q000032:analysis*; D011817:Rabbits; D012709:Serum Albumin / Q000032:analysis*; D018675:Toxicity Tests; D014612:Vaccines / Q000494:pharmacology*
D012709:Serum Albumin; D014612:Vaccines; D005340:Fibrinogen; D002097:C-Reactive Protein
C-reactive protein; acute-phase response; rabbit; toxicology studies